Patent Publication Number: US-2021170043-A1

Title: Dc-sign antibody conjugates comprising sting agonists

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This application claims the benefit of U.S. Provisional Application No. 62/753,264 filed Oct. 31, 2018, the content of which are hereby incorporated by reference in its entirety. 
    
    
     SEQUENCE LISTING 
     The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Sep. 11, 2019, is named PAT058304-US-NP_SL.txt and is 536,933 bytes in size. 
     FIELD OF THE INVENTION 
     The present invention generally relates to anti-DC-SIGN antibody conjugates comprising STING agonists, and their uses for the treatment or prevention of cancer. 
     BACKGROUND OF THE INVENTION 
     Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin (DC-SIGN) is a C-type lectin receptor present on the surface of both macrophages and dendritic cells (Soilleux E J, et al. (2002) J Luekoc Biol. 71(3):445-57). DC-SIGN recognizes and binds to mannose containing carbohydrates, a class of pathogen-associated molecular patterns (PAMPs) commonly found on viruses, bacteria and fungi. This binding interaction activates phagocytic uptake and internalization of pathogens (McGreal E, et al. (2005) Curr Opin Immunol. 17 (1): 18-24, Engering A, et al. (2002) J Immunol. 168(5):2118-26). Additionally, on myeloid and pre-plasmacytoid dendritic cells, DC-SIGN mediates dendritic cell rolling interactions with blood endothelium and activation of CD4+ T cells (Geijtenbeek T, et al. (2000) Cell 100(5):575-85). 
     Besides functioning as an adhesion and internalization molecule, recent studies have also shown that DC-SIGN can initiate innate immunity by modulating toll-like receptors (den Dunnen J, et al. (2009) Cancer Immunol. Immunother. 58 (7): 1149-57), though the detailed mechanism is not yet known. Innate immunity is a rapid nonspecific immune response that fights against environmental insults including, but not limited to, pathogens such as bacteria or viruses. Adaptive immunity is a slower but more specific immune response, which confers long-lasting or protective immunity to the host and involves differentiation and activation of naïve T lymphocytes into CD4+T helper cells and/or CD8+ cytotoxic T cells, promoting cellular and humoral immunity. Antigen presentation cells of the innate immune system, such as dendritic cells or macrophages, thus serve as a critical link between the innate and adaptive immune systems by phagocytosing and processing the foreign antigens and presenting them on the cell surface to T cells, thereby activating T cell responses. In cancer biology, DC-SIGN, together with other C-type lectins, is involved in recognition of tumors by dendritic cells and considered to play a critical role in tumor-associated immune responses (van Gisbergen K P et al. (2005) Cancer Res 65(13):5935-44). Additionally, dendritic cells in the tumor microenvironment are often negatively influenced by the surrounding tumor cells and develop a suppressive phenotype (Janco J M et al. (2015) J Immunol. 194(7): 2985-2991). Novel therapies that are able to induce dendritic cell activation represent an important class of potential cancer treatments. Consequently, dendritic cells, and particularly DC-SIGN, are important targets for developing novel cancer immunotherapy treatments. 
     STING (stimulator of interferon genes) is an intracellular pattern recognition receptor (PRR) associated with the endoplasmic reticulum which acts as a cytosolic DNA sensor (Ishikawa and Barber, Nature 2008, 455(7213):674-678). It was reported that STING comprises four putative transmembrane regions (Ouyang et al., Immunity (2012) 36, 1073), and is able to activate NF-kB, STAT6, and IRF3 transcription pathways to induce expression of type I interferon (e.g., IFN-α and IFN-β) and exert a potent anti-viral state following expression (Ishikawa and Barber, Nature (2008) 455(7213):674-678; Chen et al., Cell (2011) 147, 436-446). In contrast, loss of STING rendered murine embryonic fibroblasts extremely susceptible to negative stranded virus infection, including vesicular stomatitis virus (Ishikawa and Barber, Nature (2008) 455(7213):674-678). Innate immune cells, such a dendritic cells, are potently activated through STING agonism (Woo S R et al. (2014) Immunity 41(5):830-42) and comprise a key responder population to endogenous and pharmacologic STING agonists. 
     Despite the development of a multitude of effective biologic, small molecule, and more recently cell-based therapeutics for treating cancer, significant clinical challenges, such as tumor heterogeneity, acquired resistance, and subpopulation patient responsiveness remain. There remains an urgent need for new immunotherapies for the treatment of diseases, in particular cancer. 
     SUMMARY OF THE INVENTION 
     The invention is based on the finding that targeting dendritic cells and macrophages, by way of the C-type lectin receptor DC-SIGN, with an antibody conjugated to a STING agonist induces potent dendritic cell and macrophage activation and anti-tumor immune responses. The unique combination of a DC-SIGN targeting agent and a STING agonist, engineered as a single therapeutic agent, may provide greater clinical benefit as compared to combinations of single agents alone. 
     The invention provides immunoconjugates comprising anti-DC-SIGN antibodies conjugated with STING agonists, pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof and combinations thereof, which are useful for the treatment of diseases, in particular, cancer. The invention further provides methods of treating, preventing, or ameliorating cancer comprising administering to a subject in need thereof an effective amount of an immunoconjugate of the invention. The terms “immunoconjugate” and “antibody conjugate” are used interchangeably herein. The invention also provides compounds comprising STING agonists and a linker which are useful to conjugate to an antibody and thereby make the immunostimmulatory conjugates (or Immune Stimulator Antibody Conjugates (ISACs)) of the invention. Various embodiments of the invention are described herein. 
     In one embodiment, this application discloses an immunoconjugate comprising an anti-DC-SIGN antibody (Ab), or a functional fragment thereof, coupled to an agonist of Stimulator of Interferon Genes (STING) receptor (D) via a linker (L), wherein the linker optionally comprises one or more cleavage elements. 
     In one embodiment, the immunoconjugate comprises Formula (I): 
       Ab-(L-(D) m ) n   (Formula (I))
 
     wherein:
 
Ab is an anti-DC-SIGN antibody or a functional fragment thereof;
 
L is a linker comprising one or more cleavage elements;
 
D is a drug moiety that has agonist activity against STING receptor;
 
m is an integer from 1 to 8; and
 
n is an integer from 1 to 20.
 
     In another embodiment, the immunoconjugate comprises Formula (I): 
       Ab-(L-(D) m ) n   (Formula (I))
 
     wherein:
 
Ab is an anti-DC-SIGN antibody or a functional fragment thereof;
 
L is a linker;
 
D is a drug moiety that binds to STING receptor;
 
m is an integer from 1 to 8; and
 
n is an integer from 1 to 20;
 
wherein D, or a cleavage product thereof, that is released from the immunoconjugate has STING agonist activity.
 
     In another embodiment, the immunconjugate comprises Formula (I): 
       Ab-(L-(D) m ) n   (Formula (I))
 
     wherein:
 
Ab is an anti-DC-SIGN antibody or a functional fragment thereof;
 
L is a linker;
 
D is a drug moiety that binds to STING receptor;
 
m is an integer from 1 to 8; and
 
n is an integer from 1 to 20;
 
wherein the immunoconjugate delivers D, or a cleavage product thereof, to a cell targeted by the Ab, and wherein D, or the cleavage product thereof, has STING agonist activity.
 
     In another embodiment, the immunoconjugate comprises Formula (I): 
       Ab-(L-(D) m ) n   (Formula (I))
 
     wherein:
 
Ab is an anti-DC-SIGN antibody or a functional fragment thereof;
 
L is a linker comprising one or more cleavage elements;
 
D is a drug moiety that binds to STING receptor;
 
m is an integer from 1 to 8; and
 
n is an integer from 1 to 20;
 
wherein the immunoconjugate releases D, or a cleavage product thereof, in a cell targeted by the Ab, and wherein D, or the cleavage product thereof, has STING agonist activity.
 
     In another embodiment, the immunoconjugate comprises Formula (I): 
       Ab-(L-(D) m ) n   (Formula (I))
 
     wherein:
 
Ab is an anti-DC-SIGN antibody or a functional fragment thereof;
 
L is a linker comprising one or more cleavage elements;
 
D is a drug moiety that has agonist activity against STING receptor;
 
m is an integer from 1 to 8; and
 
n is an integer from 1 to 20;
 
wherein the immunoconjugate releases D, or a cleavage product thereof, in a cell targeted by the Ab, and wherein D, or the cleavage product thereof, has STING agonist activity in the cell.
 
     In a further embodiment, the present application discloses an immunoconjugate for delivery of a STING receptor agonist to a cell, the immunoconjugate comprising Formula (I): 
       Ab-(L-(D) m ) n   (Formula (I))
 
     wherein:
 
Ab is an anti-DC-SIGN antibody or a functional fragment thereof;
 
L is a linker comprising one or more cleavage elements;
 
D is a drug moiety that binds to STING receptor;
 
m is an integer from 1 to 8; and
 
n is an integer from 1 to 20;
 
wherein the immunoconjugate specifically binds to DC-SIGN on the cell surface and is internalized into the cell, and wherein D, or a cleavage product thereof, is cleaved from L and has STING agonist activity as determined by one or more STING agonist assays selected from: an interferon stimulation assay, a hSTING wt assay, a THP1-Dual assay, a TANK binding kinase 1 (TBK1) assay, or an interferon-γ-inducible protein 10 (IP-10) secretion assay.
 
     In some embodiments, D, or the cleavage product thereof, has STING agonist activity if it binds to STING and is able to stimulate production of one or more STING-dependent cytokines in a STING-expressing cell at least 1.1-fold, 1.2-fold, 1.3-fold, 1.4-fold, 1.5-fold, 1.6-fold, 1.7-fold, 1.8-fold, 1.9-fold, 2-fold or greater than an untreated STING-expressing cell. In another embodiment, the STING-dependent cytokine is selected from interferon, type 1 interferon, IFN-α, IFN-β, type 3 interferon, IFNλ, IP10, TNF, IL-6, CXCL9, CCL4, CXCL11, CCL5, CCL3, or CCL8. In other embodiments, D, or the cleavage product thereof, has STING agonist activity if it binds to STING and is able to stimulate phosphorylation of TBK1 in a STING-expressing cell at least 1.1-fold, 1.2-fold, 1.3-fold, 1.4-fold, 1.5-fold, 1.6-fold, 1.7-fold, 1.8-fold, 1.9-fold, 2-fold or greater than an untreated STING-expressing cell. In further embodiments, D, or the cleavage product thereof, has STING agonist activity if it binds to STING and is able to stimulate expression of a STING-dependent transcript selected from any one of the transcripts listed in  FIG. 1A - FIG. 10  and  FIG. 2A - FIG. 2L  in a STING-expressing cell at least 5-fold or greater than the expression level in an untreated STING-expressing cell. In some embodiments, expression of the STING-dependent transcript is increased 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 11-fold, 12-fold, 13-fold, 14-fold, 15-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 70-fold, 80-fold, 90-fold, 100-fold, 200-fold, 300-fold, 400-fold, 500-fold, 700-fold or greater. In another embodiment, D, or the cleavage product thereof, has STING agonist activity if it binds to STING and is able to stimulate expression of a luciferase reporter gene controlled by interferon (IFN)-stimulated response elements in a STING-expressing cell at an EC50 of 20 micromolar (μM), 15 μM, 10 μM, 9 μM, 8 μM, 7 μM, 6 μM, 5 μM, 4 μM, 3 μM, 2 μM, 1 μM, or less. In other embodiments, D, or the cleavage product thereof, has STING agonist activity if it binds to STING and is able to stimulate expression of a luciferase reporter gene controlled by interferon (IFN)-stimulated response elements in a STING-expressing cell to a level equal to or greater than the level of stimulation of 50 μM of 2′3′-cGAMP. In some embodiments, the STING-expressing cell is THP1-Dual cell, and the luciferase reporter gene is the IRF-Lucia reporter gene in THP1-Dual cell, and optionally the STING agonist activity is determined by the THP1-Dual assay described for Table 7. In another embodiment, the luciferase reporter gene is the 5xlSRE-mlFNb-GL4 reporter gene and the STING-expressing cell is a cell expressing wild-type human STING protein, and optionally the STING agonist activity is determined by the hSTING wt assay described in Table 7. In other embodiments, the immunoconjugate stimulates IP-10 secretion from a STING-expressing cell targeted by the Ab at an EC50 of 5 nanomolar (nM) or less in an IP-10 secretion assay. 
     In some embodiments disclosed herein, the immunoconjugate is parenterally administered. In some embodiments, the Ab specifically binds to human DC-SIGN. In some embodiments, the Ab does not bind to human L-SIGN. In some embodiments, the Ab is human or humanized. In other embodiments, the Ab is a monoclonal antibody. 
     In some embodiments of the immunconjugate disclosed herein, the Ab comprises a modified Fc region. In one embodiment, the Ab comprises cysteine at one or more of the following positions, which are numbered according to EU numbering: 
     (a) positions 152, 360 and 375 of the antibody heavy chain, and 
     (b) positions 107, 159, and 165 of the antibody light chain. 
     In some embodiments, the anti-DC-SIGN antibody specifically binds to an epitope comprising the amino acid sequence of SEQ ID NOs: 320-323. In some embodiments, the anti-DC-SIGN antibody comprises:
         a. a heavy chain variable region that comprises an HCDR1 (Heavy Chain Complementarity Determining Region 1) of SEQ ID NO:1, an HCDR2 (Heavy Chain Complementarity Determining Region 2) of SEQ ID NO:2, and an HCDR3 (Heavy Chain Complementarity Determining Region 3) of SEQ ID NO:3; and a light chain variable region that comprises an LCDR1 (Light Chain Complementarity Determining Region 1) of SEQ ID NO:14, an LCDR2 (Light Chain Complementarity Determining Region 2) of SEQ ID NO:15, and an LCDR3 (Light Chain Complementarity Determining Region 3) of SEQ ID NO:16;   b. a heavy chain variable region that comprises an HCDR1 of SEQ ID NO:25, an HCDR2 of SEQ ID NO:26, and an HCDR3 of SEQ ID NO:27; and a light chain variable region that comprises an LCDR1 of SEQ ID NO:38, an LCDR2 of SEQ ID NO:39, and an LCDR3 of SEQ ID NO:40;   c. a heavy chain variable region that comprises an HCDR1 of SEQ ID NO:49, an HCDR2 of SEQ ID NO:26, and an HCDR3 of SEQ ID NO:50; and a light chain variable region that comprises an LCDR1 of SEQ ID NO:59, an LCDR2 of SEQ ID NO:39, and an LCDR3 of SEQ ID NO:60;   d. a heavy chain variable region that comprises an HCDR1 of SEQ ID NO:74, an HCDR2 of SEQ ID NO:26, and an HCDR3 of SEQ ID NO:50; and a light chain variable region that comprises an LCDR1 of SEQ ID NO:59, an LCDR2 of SEQ ID NO:39, and an LCDR3 of SEQ ID NO:82;   e. a heavy chain variable region that comprises an HCDR1 of SEQ ID NO:88, an HCDR2 of SEQ ID NO:26, and an HCDR3 of SEQ ID NO:50; and a light chain variable region that comprises an LCDR1 of SEQ ID NO:94, an LCDR2 of SEQ ID NO:95, and an LCDR3 of SEQ ID NO:82;   f. a heavy chain variable region that comprises an HCDR1 of SEQ ID NO:111, an HCDR2 of SEQ ID NO:26, and an HCDR3 of SEQ ID NO:27; and a light chain variable region that comprises an LCDR1 of SEQ ID NO:38, an LCDR2 of SEQ ID NO:39, and an LCDR3 of SEQ ID NO:118;   g. a heavy chain variable region that comprises an HCDR1 of SEQ ID NO:49, an HCDR2 of SEQ ID NO:26, and an HCDR3 of SEQ ID NO:50; and a light chain variable region that comprises an LCDR1 of SEQ ID NO:59, an LCDR2 of SEQ ID NO:39, and an LCDR3 of SEQ ID NO:124;   h. a heavy chain variable region that comprises an HCDR1 of SEQ ID NO:74, an HCDR2 of SEQ ID NO:26, and an HCDR3 of SEQ ID NO:50; and a light chain variable region that comprises an LCDR1 of SEQ ID NO:59, an LCDR2 of SEQ ID NO:39, and an LCDR3 of SEQ ID NO:124;   i. a heavy chain variable region that comprises an HCDR1 of SEQ ID NO:88, an HCDR2 of SEQ ID NO:26, and an HCDR3 of SEQ ID NO:50; and a light chain variable region that comprises an LCDR1 of SEQ ID NO:94, an LCDR2 of SEQ ID NO:95, and an LCDR3 of SEQ ID NO:124;   j. a heavy chain variable region that comprises an HCDR1 of SEQ ID NO:138, an HCDR2 of SEQ ID NO:139, and an HCDR3 of SEQ ID NO:140; and a light chain variable region that comprises an LCDR1 of SEQ ID NO:59, an LCDR2 of SEQ ID NO:39, and an LCDR3 of SEQ ID NO:118;   k. a heavy chain variable region that comprises an HCDR1 of SEQ ID NO:153, an HCDR2 of SEQ ID NO:154, and an HCDR3 of SEQ ID NO:155; and a light chain variable region that comprises an LCDR1 of SEQ ID NO:166, an LCDR2 of SEQ ID NO:167, and an LCDR3 of SEQ ID NO:168;   l. a heavy chain variable region that comprises an HCDR1 of SEQ ID NO:178, an HCDR2 of SEQ ID NO:179, and an HCDR3 of SEQ ID NO:180; and a light chain variable region that comprises an LCDR1 of SEQ ID NO:191, an LCDR2 of SEQ ID NO:192, and an LCDR3 of SEQ ID NO:193;   m. a heavy chain variable region that comprises an HCDR1 of SEQ ID NO:203, an HCDR2 of SEQ ID NO:204, and an HCDR3 of SEQ ID NO:205; and a light chain variable region that comprises an LCDR1 of SEQ ID NO:216, an LCDR2 of SEQ ID NO:217, and an LCDR3 of SEQ ID NO:218;   n. a heavy chain variable region that comprises an HCDR1 of SEQ ID NO:227, an HCDR2 of SEQ ID NO:228, and an HCDR3 of SEQ ID NO:229; and a light chain variable region that comprises an LCDR1 of SEQ ID NO:216, an LCDR2 of SEQ ID NO:217, and an LCDR3 of SEQ ID NO:238;   o. a heavy chain variable region that comprises an HCDR1 of SEQ ID NO:244, an HCDR2 of SEQ ID NO:26, and an HCDR3 of SEQ ID NO:245; and a light chain variable region that comprises an LCDR1 of SEQ ID NO:253, an LCDR2 of SEQ ID NO:254, and an LCDR3 of SEQ ID NO:255;   p. a heavy chain variable region that comprises an HCDR1 of SEQ ID NO:264, an HCDR2 of SEQ ID NO:265, and an HCDR3 of SEQ ID NO:266; and a light chain variable region that comprises an LCDR1 of SEQ ID NO:277, an LCDR2 of SEQ ID NO:278, and an LCDR3 of SEQ ID NO:279;   q. a heavy chain variable region that comprises an HCDR1 of SEQ ID NO:264, an HCDR2 of SEQ ID NO:265, and an HCDR3 of SEQ ID NO:296; and a light chain variable region that comprises an LCDR1 of SEQ ID NO:277, an LCDR2 of SEQ ID NO:278, and an LCDR3 of SEQ ID NO:279.       

     In some embodiments, the anti-DC-SIGN antibody comprises:
         a. A heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:10, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:21;   b. A heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:34, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:45;   c. A heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:55, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:64;   d. A heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:34, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:70;   e. A heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:78, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:84;   f. A heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:90, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:99;   g. A heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:103, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:107;   h. A heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:114, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:120;   i. A heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:55, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:126;   j. A heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:78, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:130;   k. A heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:90, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:134;   l. A heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:145, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:149;   m. A heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:162, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:174;   n. A heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:187, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:199;   o. A heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:212, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:223;   p. A heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:234, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:240;   q. A heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:249, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:260;   r. A heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:273, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:284;   s. A heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:288, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:292; or   t. A heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:298, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:284.       

     In some embodiments, the anti-DC-SIGN antibody comprises:
         a. A heavy chain comprising the amino acid sequence of SEQ ID NO:12, and a light chain comprising the amino acid sequence of SEQ ID NO:23;   b. A heavy chain comprising the amino acid sequence of SEQ ID NO:36, and a light chain comprising the amino acid sequence of SEQ ID NO:47;   c. A heavy chain comprising the amino acid sequence of SEQ ID NO:57, and a light chain comprising the amino acid sequence of SEQ ID NO:66;   d. A heavy chain comprising the amino acid sequence of SEQ ID NO:36, and a light chain comprising the amino acid sequence of SEQ ID NO:72;   e. A heavy chain comprising the amino acid sequence of SEQ ID NO:80, and a light chain comprising the amino acid sequence of SEQ ID NO:86;   f. A heavy chain comprising the amino acid sequence of SEQ ID NO:92, and a light chain comprising the amino acid sequence of SEQ ID NO:101;   g. A heavy chain comprising the amino acid sequence of SEQ ID NO:105, and a light chain comprising the amino acid sequence of SEQ ID NO:109;   h. A heavy chain comprising the amino acid sequence of SEQ ID NO:116, and a light chain comprising the amino acid sequence of SEQ ID NO:122;   i. A heavy chain comprising the amino acid sequence of SEQ ID NO:57, and a light chain comprising the amino acid sequence of SEQ ID NO:128;   j. A heavy chain comprising the amino acid sequence of SEQ ID NO:80, and a light chain comprising the amino acid sequence of SEQ ID NO:132;   k. A heavy chain comprising the amino acid sequence of SEQ ID NO:92, and a light chain comprising the amino acid sequence of SEQ ID NO:136;   l. A heavy chain comprising the amino acid sequence of SEQ ID NO:147, and a light chain comprising the amino acid sequence of SEQ ID NO:151;   m. A heavy chain comprising the amino acid sequence of SEQ ID NO:164, and a light chain comprising the amino acid sequence of SEQ ID NO:176;   n. A heavy chain comprising the amino acid sequence of SEQ ID NO:189, and a light chain comprising the amino acid sequence of SEQ ID NO:201;   o. A heavy chain comprising the amino acid sequence of SEQ ID NO:214, and a light chain comprising the amino acid sequence of SEQ ID NO:225;   p. A heavy chain comprising the amino acid sequence of SEQ ID NO:236, and a light chain comprising the amino acid sequence of SEQ ID NO:242;   q. A heavy chain comprising the amino acid sequence of SEQ ID NO:251, and a light chain comprising the amino acid sequence of SEQ ID NO:262;   r. A heavy chain) comprising the amino acid sequence of SEQ ID NO:275, and a light chain comprising the amino acid sequence of SEQ ID NO:286;   s. A heavy chain comprising the amino acid sequence of SEQ ID NO:290, and a light chain comprising the amino acid sequence of SEQ ID NO:294; or   t. A heavy chain comprising the amino acid sequence of SEQ ID NO:300, and a light chain comprising the amino acid sequence of SEQ ID NO:286.       

     In some embodiments, L is attached to the Ab via conjugation to one or more modified cysteine residues in the Ab. In one embodiment, L is conjugated to the Ab via modified cysteine residues at positions 152 and 375 of the heavy chain of the Ab, wherein the positions are determined according to EU numbering. In one embodiment, L is conjugated to the Ab via modified cysteine residue at position 152 of the heavy chain of the Ab, wherein the position is determined according to EU numbering. In one embodiment, L is conjugated to the Ab via modified cysteine residue at position 375 of the heavy chain of the Ab, wherein the position is determined according to EU numbering. In some embodiments, L is conjugated via a maleimide linkage to the cysteine. 
     In one embodiment of the immunoconjugates disclosed herein, D is a dinucleotide. In some cases, D is a cyclic dinucleotide (CDN). In other embodiments, D is a compound selected from any one of the compounds of Table 1, Table 2, Table 3, or Table 4. 
     In some embodiments disclosed herein, D is a compound selected from 
     
       
         
         
             
             
         
       
     
     In some embodiments disclosed herein, D is a compound selected from 
     
       
         
         
             
             
         
       
     
     In some embodiments disclosed herein, D is a compound selected from 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     In one embodiment, the present application discloses immunoconjugates wherein L is a cleavable linker comprising one or more cleavage elements. In some embodiments, L comprises two or more cleavage elements, and each cleavage element is independently selected from a self-immolative spacer and a group that is susceptible to cleavage. In some embodiments, the cleavage is selected from acid-induced cleavage, peptidase-induced cleavage, esterase-induced cleavage, glycosidase-induced cleavage, phosphodiesterase-induced cleavage, phosphatase-induced cleavage, protease-induced cleavage, lipase-induced cleavage, or disulfide bond cleavage. 
     In one embodiment of the immunconjugates disclosed herein the Linker-Drug Moiety (-(L-(D) m )), wherein m is 1, has a structure selected from: 
     
       
         
         
             
             
         
       
     
     wherein:
 
Lc is a linker component and each Lc is independently selected from a linker component as disclosed herein;
 
x is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20;
 
y is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20;
 
p is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;
 
and each cleavage element (C E ) is independently selected from a self-immolative spacer and a group that is susceptible to cleavage selected from acid-induced cleavage, peptidase-induced cleavage, esterase-induced cleavage, glycosidase induced cleavage, phosphodiesterase induced cleavage, phosphatase induced cleavage, protease induced cleavage, lipase induced cleavage or disulfide bond cleavage.
 
     In one embodiment of the immunconjugates disclosed herein the Linker (L) of the Linker-Drug Moiety (-(L-(D) m )), wherein m is 1, has a structure selected from: 
     
       
         
         
             
             
         
       
     
     wherein:
 
Lc is a linker component and each Lc is independently selected from a linker component as disclosed herein;
 
x is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20;
 
y is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20;
 
p is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;
 
and each cleavage element (C E ) is independently selected from a self-immolative spacer and a group that is susceptible to cleavage selected from acid-induced cleavage, peptidase-induced cleavage, esterase-induced cleavage, glycosidase induced cleavage, phosphodiesterase induced cleavage, phosphatase induced cleavage, protease induced cleavage, lipase induced cleavage or disulfide bond cleavage. In some embodiments, L has a structure selected from the following, or L comprises a structural component selected from the following:
 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     In some embodiments disclosed herein, the immunoconjugate is selected from the following: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     wherein:
 
each G 1  is independently selected from
 
     
       
         
         
             
             
         
       
     
     where the * of G 1  indicates the point of attachment to —CR 8 R 9 —;
 
X A  is C(═O)—, —C(═S)— or —C(═NR 11 )— and each Z 1  is NR 12 ;
 
X B  is C, and each Z 2  is N;
 
     G 2  is 
     
       
         
         
             
             
         
       
     
     where the * of G 2  indicates the point of attachment to —CR 8a R 9a —;
 
X C  is C(═O)—, —C(═S)— or —C(═NR 11 )— and each Z 3  is NR 12 ;
 
X D  is C, and each Z 4  is N;
 
Y 1  is —O—, —S—, —S(═O)—, —SO 2 —, —CH 2 —, or —CF 2 —;
 
Y 2  is —O—, —S—, —S(═O)—, —SO 2 —, —CH 2 —, or —CF 2 —;
 
Y 3  is OH, O − , OR 10 , N(R 10 ) 2 , SR 10 , SeH, Se − , BH 3 , SH or S − ;
 
Y 4  is OH, O − , OR 10 , N(R 10 ) 2 , SR 10 , SeH, Se − , BH 3 , SH or S − ;
 
Y 5  is —CH 2 —, —NH—, —O— or —S;
 
Y 6  is —CH 2 —, —NH—, —O— or —S;
 
     Y 7  is O or S; 
     Y 8  is O or S; 
     Y 9  is —CH 2 —, —NH—, —O— or —S;
 
Y 10  is —CH 2 —, —NH—, —O— or —S;
 
Y 11  is —O—, —S—, —S(═O)—, —SO 2 —, —CH 2 —, or —CF 2 —;
 
q is 1, 2 or 3;
 
each R 1  is independently partially saturated or aromatic monocyclic heterocyclyl or partially saturated or aromatic fused bicyclic heterocyclyl containing from 5-10 ring members selected from carbon atoms and 1 to 5 heteroatoms, and each heteroatoms is independently selected from O, N or S, or a tautomer thereof, wherein R 1  is substituted with 0, 1, 2, 3 or 4 substituents independently selected from —NHL 1 R 115 , F, Cl, Br, OH, SH, NH 2 , D, CD 3 , C 1 -C 6 alkyl, C 1 -C 6 alkoxyalkyl, C 1 -C 6 hydroxyalkyl, C 3 -C 8 cycloalkyl, a 3 to 6 membered heterocyclyl having 1 to 2 heteroatoms independently selected from O, N and S, —O(C 1 -C 6 alkyl), —O(C 3 -C 8 cycloalkyl), —S(C 1 -C 6 alkyl), —S(C 1 -C 6 aminoalkyl), —S(C 1 -C 6 hydroxyalkyl), —S(C 3 -C 8 cycloalkyl), —NH(C 1 -C 6 alkyl), —NH(C 3 -C 8 cycloalkyl), —N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 alkyl) (C 3 -C 8 cycloalkyl), —CN, —P(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —(CH 2 ) 1-10 C(═O)OH, —CH═CH(CH 2 ) 1-10 C(═O)OH, —NHC(O)(C 1 -C 6 alkyl), —NHC(O)(C 3 -C 8 cycloalkyl), —NHC(O)(phenyl), and —N(C 3 -C 8 cycloalkyl) 2 ;
 
each R 1a  is independently partially saturated or aromatic monocyclic heterocyclyl or partially saturated or aromatic fused bicyclic heterocyclyl containing from 5-10 ring members selected from carbon atoms and 1 to 5 heteroatoms, and each heteroatoms is independently selected from O, N or S, or a tautomer thereof, wherein R 1a  is substituted with 0, 1, 2, 3 or 4 substituents independently selected from —NHL 1 R 115 , F, Cl, Br, OH, SH, NH 2 , D, CD 3 , C 1 -C 6 alkyl, C 1 -C 6 alkoxyalkyl, C 1 -C 6 hydroxyalkyl, C 3 -C 8 cycloalkyl, a 3 to 6 membered heterocyclyl having 1 to 2 heteroatoms independently selected from O, N and S, —O(C 1 -C 6 alkyl), —O(C 3 -C 8 cycloalkyl), —S(C 1 -C 6 alkyl), —S(C 1 -C 6 aminoalkyl), —S(C 1 -C 6 hydroxyalkyl), —S(C 3 -C 8 cycloalkyl), —NH(C 1 -C 6 alkyl), —NH(C 3 -C 8 cycloalkyl), —N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 alkyl) (C 3 -C 8 cycloalkyl), —CN, —P(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —(CH 2 ) 1-10 C(═O)OH, —CH═CH(CH 2 ) 1-10 C(═O)OH, —NHC(O)(C 1 -C 6 alkyl), —NHC(O)(C 3 -C 8 cycloalkyl), —NHC(O)(phenyl), and —N(C 3 -C 8 cycloalkyl) 2 ;
 
each R 1b  is independently partially saturated or aromatic monocyclic heterocyclyl or partially saturated or aromatic fused bicyclic heterocyclyl containing from 5-10 ring members selected from carbon atoms and 1 to 5 heteroatoms, and each heteroatoms is independently selected from O, N or S, or a tautomer thereof, wherein R 1b  is substituted with 0, 1, 2, 3 or 4 substituents independently selected from —NHL 1 R 115 , F, Cl, Br, OH, SH, NH 2 , D, CD 3 , C 1 -C 6 alkyl, C 1 -C 6 alkoxyalkyl, C 1 -C 6 hydroxyalkyl, C 3 -C 8 cycloalkyl, a 3 to 6 membered heterocyclyl having 1 to 2 heteroatoms independently selected from O, N and S, —O(C 1 -C 6 alkyl), —O(C 3 -C 8 cycloalkyl), —S(C 1 -C 6 alkyl), —S(C 1 -C 6 aminoalkyl), —S(C 1 -C 6 hydroxyalkyl), —S(C 3 -C 8 cycloalkyl), —NH(C 1 -C 6 alkyl), —NH(C 3 -C 8 cycloalkyl), —N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 alkyl) (C 3 -C 8 cycloalkyl), —CN, —P(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —(CH 2 ) 1-10 C(═O)OH, —CH═CH(CH 2 ) 1-10 C(═O)OH, —NHC(O)(C 1 -C 6 alkyl), —NHC(O)(C 3 -C 8 cycloalkyl), —NHC(O)(phenyl), and —N(C 3 -C 8 cycloalkyl) 2 ;
 
each R 2  is independently selected from the group consisting of H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 2  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 2  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;
 
each R 3  is independently selected from the group consisting of —OL 1 R 115 , H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 3  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 3  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;
 
each R 4  is independently selected from the group consisting of —OL 1 R 115 , H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 4  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 4  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;
 
each R 5  is independently selected from the group consisting of —OL 1 R 115 , H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 5  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 5  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;
 
each R 6  is independently selected from the group consisting of H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 6  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 6  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;
 
each R 7  is independently selected from the group consisting of —OL 1 R 115 , H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 7  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 7  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;
 
each R 8  is independently selected from the group consisting of H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 8  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 8  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;
 
each R 9  is independently selected from the group consisting of H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 9  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 9  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;
 
each R 2a  is selected from the group consisting of H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 2a  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 2a  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3  
 
each R 3a  is selected from the group consisting of —OL 1 R 115 , H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 3a  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 3a  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;
 
each R 4a  is selected from the group consisting of —OL 1 R 115 , H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 4a  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 4a  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;
 
each R 5a  is selected from the group consisting of —OL 1 R 115 , H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 5a  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 5a  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;
 
each R 6a  is selected from the group consisting of H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 6a  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 6a  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;
 
each R 7a  is selected from the group consisting of —OL 1 R 115 , H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 7a  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 7a  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;
 
each R 8a  is selected from the group consisting of H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 8a  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 8  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;
 
each R 9a  is selected from the group consisting of H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 9a  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 9a  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;
 
each R 10  is independently selected from the group consisting of H, C 1 -C 12 alkyl, C 1 -C 6 heteroalkyl, —(CH 2 CH 2 O) n CH 2 CH 2 C(═O)OC 1 -C 6 alkyl, and
 
     
       
         
         
             
             
         
       
     
     wherein the C 1 -C 12 alkyl and C 1 -C 6 heteroalkyl of R 10  is substituted by 0, 1, 2 or 3 substituents independently selected from —OH, C 1 -C 2 alkoxy, —S—C(═O)C 1 -C 6 alkyl, halo, —CN, C 1 -C 12 alkyl, —O-aryl, _O-heteroaryl, —O-cycloalkyl, oxo, cycloalkyl, heterocyclyl, aryl, or heteroaryl, —OC(O)OC 1 -C 6 alkyland C(O)OC 1 -C 6 alkyl, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is substituted by 0, 1, 2 or 3 substituents independently selected from C 1 -C 12  alkyl, O—C 1 -C 12 alkyl, C 1 -C 12 heteroalkyl, halo, CN, OH, oxo, aryl, heteroaryl, O-aryl, O-heteroaryl, —C(═O)C 1 -C 12 alkyl, —OC(═O)C 1 -C 12 alkyl, —C(═O)OC 1 -C 12 alkyl, —OC(═O)OC 1 -C 12 alkyl, —C(═O)N(R 11 )—C 1 -C 12 alkyl, —N(R 11 )C(═O)—C 1 -C 12 alkyl; —OC(═O)N(R 11 )—C 1 -C 12 alkyl, —C(═O)-aryl, —C(═O)-heteroaryl, —OC(═O)-aryl, —C(═O)O-aryl, —OC(═O)-heteroaryl, —C(═O)O-heteroaryl, —C(═O)O-aryl, —C(═O)O-heteroaryl, —C(═O)N(R 11 )-aryl, —C(═O)N(R 11 )-heteroaryl, —N(R 11 )C(O)-aryl, —N(R 11 ) 2 C(O)-aryl, —N(R 11 )C(O)-heteroaryl, and S(O) 2 N(R 11 )-aryl;
 
each R 11  is independently selected from H and C 1 -C 6 alkyl;
 
each R 12  is independently selected from H and C 1 -C 6 alkyl;
 
optionally R 3  and R 6  are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, —O—C 2 -C 6 alkynylene, such that when R 3  and R 6  are connected, the O is bound at the R 3  position
 
optionally R 3a  and R 6a , are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, —O—C 2 -C 6 alkynylene, such that when R 3a  and R 6a  are connected, the O is bound at the R 3a  position;
 
optionally R 2  and R 3  are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, —O—C 2 -C 6 alkynylene, such that when R 2  and R 3  are connected, the O is bound at the R 3  position;
 
optionally R 2a  and R 3a , are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, —O—C 2 -C 6 alkynylene, such that when R 2a  and R 3a  are connected, the O is bound at the R 3a  position;
 
optionally R 4  and R 3  are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, —O—C 2 -C 6 alkynylene, such that when R 4  and R 3  are connected, the O is bound at the R 3  position;
 
optionally R 4a  and R 3a , are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, —O—C 2 -C 6 alkynylene, such that when R 4a  and R 3a  are connected, the O is bound at the R 3a  position;
 
optionally R 5  and R 6  are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, —O—C 2 -C 6 alkynylene, such that when R 5  and R 6  are connected, the O is bound at the R 5  position;
 
optionally R 5a  and R 6a , are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, —O—C 2 -C 6 alkynylene, such that when R 5a  and R 6a  are connected, the O is bound at the R 5a  position;
 
optionally R 5  and R 7  are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, —O—C 2 -C 6 alkynylene, such that when R 5  and R 7  are connected, the O is bound at the R 5  position;
 
optionally R 5a  and R 7a , are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, —O—C 2 -C 6 alkynylene, such that when R 5a  and R 7a  are connected, the O is bound at the R 5a  position;
 
optionally R 8  and R 9  are connected to form a C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, and
 
optionally R 8a  and R 9a  are connected to form a C 1 -C 6 alkylene, C 2 -C 6 alkenylene, O 2 —C 6 alkynylene,
 
L 1  is a linker;
 
Each R 115  is independently
 
     
       
         
         
             
             
         
       
     
     C(═O), —ON═***, —S—, —NHC(═O)CH 2 —***, —S(═O) 2 CH 2 CH 2 —***, —(CH 2 ) 2 S(═O) 2 CH 2 CH 2 —***, —NHS(═O) 2 CH 2 CH 2- ***, —NHC(═O)CH 2 CH 2 —***, —CH 2 NHCH 2 CH 2 —***, —NHCH 2 CH 2 —***, 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     where *** of R 115  indicates the point of attachment to Ab;
 
R 13  is H or methyl;
 
R 14  is H, —CH 3  or phenyl;
 
each R 110  is independently selected from H, C 1 -C 6 alkyl, F, Cl, and —OH;
 
each R 111  is independently selected from H, C 1 -C 6 alkyl, F, Cl, —NH 2 , —OCH 3 , —OCH 2 CH 3 , —N(CH 3 ) 2 , —CN, —NO 2  and —OH;
 
each R 112  is independently selected from H, C 1-6 alkyl, fluoro, benzyloxy substituted with —C(═O)OH, benzyl substituted with —C(═O)OH, C 1-4 alkoxy substituted with —C(═O)OH and C 1-4 alkyl substituted with —C(═O)OH;
 
Ab is an antibody or a functional fragment thereof; and
 
y is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.
 
     In some embodiments disclosed herein, the immunconjugates comprise a structure selected from: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     In other embodiments disclosed herein, the immunconjugates comprise a structure selected from: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     In some embodiments, the immunoconjugate has in vivo anti-tumor activity. 
     The present application also discloses a pharmaceutical composition comprising an immunconjugate as disclosed herein and a pharmaceutically acceptable excipient. 
     The present application also discloses an immunoconjugate as disclosed herein for use in combination with one or more additional therapeutic agents. In one embodiment, the additional therapeutic agent is selected from the group consisting of an inhibitor of a co-inhibitory molecule, an activator of a co-stimulatory molecule, a cytokine, an agent that reduces cytokine release syndrome (CRS), a chemotherapy, a targeted anti-cancer therapy, an oncolytic drug, a cytotoxic agent, an immune-based therapy, a vaccine, or a cell therapy. In another embodiment, the additional therapeutic agent is an inhibitor of a co-inhibitory molecule, an activator of a co-stimulatory molecule, or a cytokine, wherein: 
     (i) the co-inhibitory molecule is selected from Programmed death-1 (PD-1), Programmed death-ligand 1 (PD-L1), Lymphocyte activation gene-3 (LAG-3), or T-cell immunoglobulin domain and mucin domain 3 (TIM-3),
 
(ii) the co-stimulatory molecule is Glucocorticoid-induced TNFR-related protein (GITR), and
 
(iii) the cytokine is IL-15 complexed with a soluble form of IL-15 receptor alpha (IL-15Ra).
 
     The present application also discloses a method of treating cancer comprising administering to a patient in need thereof a therapeutically effective amount of an immunconjugate, a pharmaceutical composition thereof, or a composition comprising an immunoconjugate in combination with one or more additional therapeutic agents, as disclosed herein. 
     The present application also discloses use of an immunconjugate, a pharmaceutical composition thereof, or a composition comprising an immunoconjugate in combination with one or more additional therapeutic agents, as disclosed herein for treatment of a cancer in a subject in need thereof. 
     In another embodiment, this application discloses an immunconjugate, a pharmaceutical composition thereof, or a composition comprising an immunoconjugate in combination with one or more additional therapeutic agents, as disclosed herein for use in the treatment of cancer. 
     In yet another embodiment, disclosed herein is the use an immunconjugate, a pharmaceutical composition thereof, or a composition comprising an immunoconjugate in combination with one or more additional therapeutic agents, as disclosed herein in the manufacture of a medicament for use in the treatment of cancer. 
     In some embodiments, the cancer is selected from sarcomas, adenocarcinomas, blastomas, carcinomas, liver cancer, lung cancer, non-small cell lung cancer, small cell lung cancer, breast cancer, lymphoid cancer, colon cancer, renal cancer, urothelial cancer, prostate cancer, cancer of the pharynx, rectal cancer, renal cell carcinoma, cancer of the small intestine, esophageal cancer, melanoma, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, colorectal cancer, cancer of the anal region, cancer of the peritoneum, stomach or gastric cancer, esophageal cancer, salivary gland carcinoma, testicular cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, penile carcinoma, glioblastoma, neuroblastoma, cervical cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, chronic or acute leukemias including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, solid tumors of childhood, lymphocytic lymphoma, cancer of the bladder, cancer of the kidney or ureter, carcinoma of the renal pelvis, neoplasm of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axis tumor, brain stem glioma, pituitary adenoma, Kaposi&#39;s sarcoma, neuroendocrine tumors (including carcinoid tumors, gastrinoma, and islet cell cancer), mesothelioma, schwannoma (including acoustic neuroma), meningioma, epidermoid cancer, squamous cell cancer, T-cell lymphoma, environmentally induced cancers including those induced by asbestos, leukemia, lymphoma, acute myelogenous leukemia (AML), acute lymphoid leukemia (ALL), chronic myelogenous leukemia (CML), chronic lymphoid leukemia (CLL), myelodysplastic syndromes, B-cell acute lymphoid leukemia (“BALL”), T-cell acute lymphoid leukemia (“TALL”), B cell prolymphocytic leukemia, blastic plasmacytoid dendritic cell neoplasm, Burkitt&#39;s lymphoma, diffuse large B cell lymphoma, Follicular lymphoma, Hairy cell leukemia, small cell- or a large cell-follicular lymphoma, malignant lymphoproliferative conditions, MALT lymphoma, mantle cell lymphoma, Marginal zone lymphoma, multiple myeloma, myelodysplasia, myelodysplastic syndrome, plasmablastic lymphoma, plasmacytoid dendritic cell neoplasm, and Waldenstrom macroglobulinemia. 
     In some embodiments, the immunoconjugate is administered to the subject intravenously, intratumorally, or subcutaneously. 
     The present application also discloses an immunconjugate, a pharmaceutical composition thereof, or a composition comprising an immunoconjugate in combination with one or more additional therapeutic agents, as disclosed herein for use as a medicament. 
     This application also discloses a method of manufacturing any of the immunoconjugates as disclosed herein comprising the steps of: 
     a) Reacting D and L to form L-(D) m ; and
 
b) Reacting L-(D) m  with Ab to form the immunoconjugate Ab-(L-(D) m ) n  (Formula (I)).
 
     In another embodiment, this application discloses a compound having a structure selected from Formula (A), Formula (B), Formula (C), Formula (D), Formula (E), or Formula (F) or stereoisomers or pharmaceutically acceptable salts thereof, 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     wherein:
 
each G 1  is independently selected from
 
     
       
         
         
             
             
         
       
     
     where the * of G 1  indicates the point of attachment to —CR 8 R 9 —;
 
X A  is C(═O)—, —C(═S)— or —C(═NR 11 )— and each Z 1  is NR 12 ;
 
X B  is C, and each Z 2  is N;
 
     G 2  is 
     
       
         
         
             
             
         
       
     
     where the * of G 2  indicates the point of attachment to —CR 8a R 9a —;
 
X C  is C(═O)—, —C(═S)— or —C(═NR 11 )— and each Z 3  is NR 12 ;
 
X D  is C, and each Z 4  is N;
 
Y 1  is —O—, —S—, —S(═O)—, —SO 2 —, —CH 2 —, or —CF 2 —;
 
Y 2  is —O—, —S—, —S(═O)—, —SO 2 —, —CH 2 —, or —CF 2 —;
 
Y 3  is OH, O − , OR 10 , N(R 10 ) 2 , SR 10 , SeH, Se − , BH 3 , SH or S − ;
 
Y 4  is OH, O − , OR 10 , N(R 10 ) 2 , SR 10 , SeH, Se − , BH 3 , SH or S − ;
 
Y 5  is —CH 2 —, —NH—, —O— or —S;
 
Y 6  is —CH 2 —, —NH—, —O— or —S;
 
     Y 7  is O or S; 
     Y 8  is O or S; 
     Y 9  is —CH 2 —, —NH—, —O— or —S;
 
Y 10  is —CH 2 —, —NH—, —O— or —S;
 
Y 11  is —O—, —S—, —S(═O)—, —SO 2 —, —CH 2 —, or —CF 2 —;
 
q is 1, 2 or 3;
 
R 1  is a partially saturated or aromatic monocyclic heterocyclyl or partially saturated or aromatic fused bicyclic heterocyclyl containing from 5-10 ring members selected from carbon atoms and 1 to 5 heteroatoms, and each heteroatoms is independently selected from O, N or S, or a tautomer thereof, wherein R 1  is substituted with 0, 1, 2, 3 or 4 substituents independently selected from —NHL 1 R 15 , F, Cl, Br, OH, SH, NH 2 , D, CD 3 , C 1 -C 6 alkyl, C 1 -C 6 alkoxyalkyl, C 1 -C 6 hydroxyalkyl, C 3 -C 8 cycloalkyl, a 3 to 6 membered heterocyclyl having 1 to 2 heteroatoms independently selected from O, N and S, —O(C 1 -C 6 alkyl), —O(C 3 -C 8 cycloalkyl), —S(C 1 -C 6 alkyl), —S(C 1 -C 6 aminoalkyl), —S(C 1 -C 6 hydroxyalkyl), —S(C 3 -C 8 cycloalkyl), —NH(C 1 -C 6 alkyl), —NH(C 3 -C 8 cycloalkyl), —N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 alkyl) (C 3 -C 8 cycloalkyl), —CN, —P(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —(CH 2 ) 1-10 C(═O)OH, —CH═H(CH 2 ) 1-10 C(═O)OH, —NHC(O)(C 1 -C 6 alkyl), —NHC(O)(C 3 -C 8 cycloalkyl), —NHC(O)(phenyl), and —N(C 3 -C 8 cycloalkyl) 2 ;
 
R 1a  is a partially saturated or aromatic monocyclic heterocyclyl or partially saturated or aromatic fused bicyclic heterocyclyl containing from 5-10 ring members selected from carbon atoms and 1 to 5 heteroatoms, and each heteroatoms is independently selected from O, N or S, or a tautomer thereof, wherein R 1a  is substituted with 0, 1, 2, 3 or 4 substituents independently selected from —NHL 1 R 15 , F, Cl, Br, OH, SH, NH 2 , D, CD 3 , C 1 -C 6 alkyl, C 1 -C 6 alkoxyalkyl, C 1 -C 6 hydroxyalkyl, C 3 -C 8 cycloalkyl, a 3 to 6 membered heterocyclyl having 1 to 2 heteroatoms independently selected from O, N and S, —O(C 1 -C 6 alkyl), —O(C 3 -C 8 cycloalkyl), —S(C 1 -C 6 alkyl), —S(C 1 -C 6 aminoalkyl), —S(C 1 -C 6 hydroxyalkyl), —S(C 3 -C 8 cycloalkyl), —NH(C 1 -C 6 alkyl), —NH(C 3 -C 8 cycloalkyl), —N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 alkyl) (C 3 -C 8 cycloalkyl), —CN, —P(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —(CH 2 ) 1-10 C(═O)OH, —CH═CH(CH 2 ) 1-10 C(═O)OH, —NHC(O)(C 1 -C 6 alkyl), —NHC(O)(C 3 -C 8 cycloalkyl), —NHC(O)(phenyl), and —N(C 3 -C 8 cycloalkyl) 2 ;
 
R 1b  is a partially saturated or aromatic monocyclic heterocyclyl or partially saturated or aromatic fused bicyclic heterocyclyl containing from 5-10 ring members selected from carbon atoms and 1 to 5 heteroatoms, and each heteroatoms is independently selected from O, N or S, or a tautomer thereof, wherein R 1b  is substituted with 0, 1, 2, 3 or 4 substituents independently selected from —NHL 1 R 15 , F, Cl, Br, OH, SH, NH 2 , D, CD 3 , C 1 -C 6 alkyl, C 1 -C 6 alkoxyalkyl, C 1 -C 6 hydroxyalkyl, C 3 -C 8 cycloalkyl, a 3 to 6 membered heterocyclyl having 1 to 2 heteroatoms independently selected from O, N and S, —O(C 1 -C 6 alkyl), —O(C 3 -C 8 cycloalkyl), —S(C 1 -C 6 alkyl), —S(C 1 -C 6 aminoalkyl), —S(C 1 -C 6 hydroxyalkyl), —S(C 3 -C 8 cycloalkyl), —NH(C 1 -C 6 alkyl), —NH(C 3 -C 8 cycloalkyl), —N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 alkyl) (C 3 -C 8 cycloalkyl), —CN, —P(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —(CH 2 ) 1-10 C(═O)OH, —CH═CH(CH 2 ) 1-10 C(═O)OH, —NHC(O)(C 1 -C 6 alkyl), —NHC(O)(C 3 -C 8 cycloalkyl), —NHC(O)(phenyl), and —N(C 3 -C 8 cycloalkyl) 2 ;
 
each R 2  is independently selected from the group consisting of H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 2  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 2  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;
 
each R 3  is independently selected from the group consisting of —OL 1 R 15 , H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 3  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 3  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;
 
each R 4  is independently selected from the group consisting of —OL 1 R 15 , H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 4  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 4  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;
 
each R 5  is independently selected from the group consisting of —OL 1 R 15 , H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 5  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 5  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;
 
each R 6  is independently selected from the group consisting of H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 6  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 6  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;
 
each R 7  is independently selected from the group consisting of —OL 1 R 15 , H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 7  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 7  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;
 
each R 8  is independently selected from the group consisting of H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 8  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 8  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;
 
each R 9  is independently selected from the group consisting of H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 9  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 9  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;
 
R 2a  is selected from the group consisting of H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 2a  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 2a  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3  
 
R 3a  is selected from the group consisting of —OL 1 R 15 , H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 3a  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 3a  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;
 
R 4a  is selected from the group consisting of —OL 1 R 15 , H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 4a  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 4a  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;
 
R 5a  is selected from the group consisting of —OL 1 R 15 , H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 5a  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 5a  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;
 
R 6a  is selected from the group consisting of H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 6a  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 6a  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;
 
R 7a  is selected from the group consisting of —OL 1 R 15 , H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 7a  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 7a  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;
 
R 8a  is selected from the group consisting of H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 8a  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 8  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;
 
R 9a  is selected from the group consisting of H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 9a  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 9a  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;
 
each R 10  is independently selected from the group consisting of H, C 1 -C 12 alkyl, C 1 -C 6 heteroalkyl, —(CH 2 CH 2 O) n CH 2 CH 2 C(═O)OC 1 -C 6 alkyl, and
 
     
       
         
         
             
             
         
       
     
     wherein the C 1 -C 12 alkyl and C 1 -C 6 heteroalkyl of R 10  is substituted by 0, 1, 2 or 3 substituents independently selected from —OH, C 1 -C 12 alkoxy, —S—C(═O)C 1 -C 6 alkyl, halo, —CN, C 1 -C 12 alkyl, —O-aryl, _O-heteroaryl, —O-cycloalkyl, oxo, cycloalkyl, heterocyclyl, aryl, or heteroaryl, —OC(O)OC 1 -C 6 alkyland C(O)OC 1 -C 6 alkyl, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is substituted by 0, 1, 2 or 3 substituents independently selected from C 1 -C 12  alkyl, O—C 1 -C 12 alkyl, C 1 -C 12 heteroalkyl, halo, CN, OH, oxo, aryl, heteroaryl, O-aryl, O-heteroaryl, —C(═O)C 1 -C 12 alkyl, —OC(═O)C 1 -C 12 alkyl, —C(═O)OC 1 -C 12 alkyl, —OC(═O)OC 1 -C 12 alkyl, —C(═O)N(R 11 )—C 1 -C 12 alkyl, —N(R 11 )C(═O)—C 1 -C 12 alkyl; —OC(═O)N(R 11 )—C 1 -C 12 alkyl, —C(═O)-aryl, —C(═O)-heteroaryl, —OC(═O)-aryl, —C(═O)O-aryl, —OC(═O)-heteroaryl, —C(═O)O-heteroaryl, —C(═O)O-aryl, —C(═O)O-heteroaryl, —C(═O)N(R 11 )-aryl, —C(═O)N(R 11 )-heteroaryl, —N(R 11 )C(O)-aryl, —N(R 11 ) 2 C(O)-aryl, —N(R 11 )C(O)-heteroaryl, and S(O) 2 N(R 11 )-aryl;
 
each R 11  is independently selected from H and C 1 -C 6 alkyl;
 
each R 12  is independently selected from H and C 1 -C 6 alkyl;
 
optionally R 3  and R 6  are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, —O—C 2 -C 6 alkynylene, such that when R 3  and R 6  are connected, the O is bound at the R 3  position
 
optionally R 3a  and R 6a , are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, —O—C 2 -C 6 alkynylene, such that when R 3a  and R 6a  are connected, the O is bound at the R 3a  position;
 
optionally R 2  and R 3  are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, —O—C 2 -C 6 alkynylene, such that when R 2  and R 3  are connected, the O is bound at the R 3  position;
 
optionally R 2a  and R 3a , are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, —O—C 2 -C 6 alkynylene, such that when R 2a  and R 3a  are connected, the O is bound at the R 3a  position;
 
optionally R 4  and R 3  are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, —O—C 2 -C 6 alkynylene, such that when R 4  and R 3  are connected, the O is bound at the R 3  position;
 
optionally R 4a  and R 3a , are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, —O—C 2 -C 6 alkynylene, such that when R 4a  and R 3a  are connected, the O is bound at the R 3a  position;
 
optionally R 5  and R 6  are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, —O—C 2 -C 6 alkynylene, such that when R 5  and R 6  are connected, the O is bound at the R 5  position;
 
optionally R 5a  and R 6a , are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, —O—C 2 -C 6 alkynylene, such that when R 5a  and R 6a  are connected, the O is bound at the R 5a  position;
 
optionally R 5  and R 7  are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, —O—C 2 -C 6 alkynylene, such that when R 5  and R 7  are connected, the O is bound at the R 5  position;
 
optionally R 5a  and R 7a , are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, —O—C 2 -C 6 alkynylene, such that when R 5a  and R 7a  are connected, the O is bound at the R 5a  position;
 
optionally R 8  and R 9  are connected to form a C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, and
 
optionally R 8a  and R 9a  are connected to form a C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene,
 
L 1  is —C(═O)O(CH 2 ) m NR 11 C(═O)(CH 2 ) m —**; —C(═O)O(CH 2 ) m NR 11 C(═O)(CH 2 ) m O(CH 2 ) m —**; —C(═O)O(CH 2 ) m NR 11 C(═O)X 1 X 2 C)X 1 X 2 C(═O)(CH 2 ) m —**; —C(═O)OC(R 12 ) 2 (CH 2 ) m NR 11 C(═O)X 1 X 2 C(═O)(CH 2 ) m —**; —C(═O)O(CH 2 ) m NR 11 C(═O)X 1 X 2 C(═O)(CH 2 ) m O(CH 2 ) m —**; —C(═O)O(CH 2 ) m NR 11 C(═O)X 1 X 2 C(═O)(CH 2 ) m O(CH 2 ) m C(═O)—**; —C(═O)O(CH 2 ) m NR 11 C(═O)X 4 C(═O)NR 11  (CH 2 ) m NR 11 C(═O)(CH 2 ) m O(CH 2 ) m —**; —C(═O)O(CH 2 ) m NR 11 C(═O)X 5 C(═O)(CH 2 ) m NR 11 C(═O)(CH 2 ) m —**; —C(═O)X 4 C(═O)NR 11  (CH 2 ) m NR 11 C(═O)(CH 2 ) m O(CH 2 ) m —**; —C(═O)(CH 2 ) m NR 11 C(═O)X 1 X 2 C(═O)(CH 2 ) m —**; —C(═O)(CH 2 ) m NR 1 X 2 C(═O)(CH 2 ) m —**; —C(═O)O(CH 2 ) m X 6 C(═O)X 1 X 2 C(═O)(CH 2 ) m —**, —C(═O)(CH 2 ) m NR 11 C(═O)((CH 2 ) m O) n (CH 2 ) m —**, —C(═O)O(CH 2 ) m X 6 C(═O) (CH 2 ) m —**, —C(═O)O(CH 2 ) m X 6 C(═O)(CH 2 ) m O(CH 2 ) m —**, —C(═O)O(CH 2 ) m X 6 C(═O)X 1 X 2 C(═O)(CH 2 ) m —**, —C(═O)O(CH 2 ) m X 6 C(═O)X 1 X 2 C(═O)(CH 2 ) m O(CH 2 ) m —**, —C(═O)O(CH 2 ) m X 6 C(═O)X 1 X 2 C(═O)(CH 2 ) m O(CH 2 ) m C(═O)—**; —C(═O)O(CH 2 ) m X 6 C(═O)X 4 C(═O)NR 11 (CH 2 ) m NR 11 C(═O)(CH 2 ) m O(CH 2 ) m —**, —C(═O)X 4 C(═O)X 6 (CH 2 ) m NR 11 C(═O)(CH 2 ) m O(CH 2 ) m —**, —C(═O)(CH 2 ) m X 6 C(═O)X 1 X 2 C(═O)(CH 2 ) m **, —C(═O)O((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 C(═O)(CH 2 ) m —**; —C(═O)O((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 C(═O)(CH 2 ) m NR 11 C(═O)(CH 2 ) m —**; —C(═O)O((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 C(═O)(CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)O((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 C(═O)((CH 2 ) m O) n (CH 2 ) m —**; —C(═O)O((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)(CH 2 ) m —**; —C(═O)O((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)(CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)O((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O))X 5 C(═O) ((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)O((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 C(═O)(CH 2 ) m NR 11 C(═O)((CH 2 ) m O) n (CH 2 ) m —**; —C(═O)O((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 C(═O)(CH 2 ) m NR 11 C(═O) ((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)O((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 (CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)O((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 ((CH 2 ) m O) n (CH 2 ) m —**; —C(═O)O((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 ((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)(CH 2 ) m —**; —C(═O)O((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 ((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)(CH 2 ) m X(CH 2 ) m —**; —C(═O)O((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 ((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)O((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 (CH 2 ) m NR 11 ((CH 2 ) m O) n (CH 2 ) m —**; —C(═O)O((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 C(═O)(CH 2 ) m NR 11  ((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m **; —C(═O)O((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 (CH 2 ) m —**; —C(═O)O((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 C(═O)((CH 2 ) m O) n (CH 2 ) m —**; —C(═O)O((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 (CH 2 ) m X 3 (CH 2 ) m —**; C(═O)O(CH) m **; —C(═O)O((CH 2 ) m O) n (CH 2 ) m —**; C(═O)O(CH 2 ) m NR 11  (CH 2 ) m —**; —C(═O)O(CH 2 ) m NR 11  (CH 2 ) m C(═O)X 2 X C (═O)**; —C(═O)O(CH 2 ) m X 3 (CH 2 ) m —**; C(═O)O(CH 2 ) m X 6 C(═O)X 1 X 2 C(═O)((CH 2 ) m O) n (CH 2 ) m **; —C(═O)O((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)O((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)(CH 2 ) m —**; —C(═O)O(CH 2 ) m NR 11 C(═O(CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)O((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)(CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)O((CH 2 ) m O) n X 3 (CH 2 ) m —**; C(═O)O((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)O((CH 2 ) m O) n (CH 2 ) m C(═O)NR 11 (CH 2 ) m —**; C(═O)O(CH 2 ) m C(R 12 ) 2 —**; —C(═O)OCH 2 ) m C(R 12 ) 2 SS(CH 2 ) m NR 11 C(═O)(CH 2 ) m —**; —C(═O)O(CH 2 ) m C(═O)NR 11 (CH 2 ) m —**; C(═O)(CH 2 ) m —**; C(═O)((CH 2 ) m O) n (CH 2 ) m —**; —C(═O)(CH 2 ) m NR 11 (CH 2 ) m —**; C(═O)(CH 2 ) m NR 11  (CH 2 ) m C(═O)X 2 X 1 C(═O)—**; —C(═O)(CH 2 ) m X 3 (CH 2 ) m —**; C(═O)((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)(CH 2 ) m NR 11 C(═O)(CH 2 ) m —**; C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)(CH 2 ) m —**; —C(═O)(CH 2 ) m NR 11 C(═O(CH 2 ) m X 3 (CH 2 ) m —**; (CH 2 ) m NR 11 C(═O)X 1 X 2 C(═O)(CH 2 ) m —**; —(CH 2 ) m (CHOH)(CH 2 ) m NR 11 C(═O)X 1 X 2 C(═O)(CH 2 ) m **; —C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)(CH 2 ) m X 3 (CH 2 ) m —**; C(═O)((CH 2 ) m O) n X 3 (CH 2 ) m —**; —C(═O)((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —**; C(═O)((CH 2 ) m O) n (CH 2 ) m C(═O)NR 11 (CH 2 ) m —**; —C(═O)(CH 2 ) m C(R 12 ) 2 —**; C(═O)((CH 2 )O)(CH)NR 11 C(═O)X 5 C(═O)(CH 2 ) m **; —C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 C(═O)(CH 2 ) m NR 11 C(═O)(CH 2 ) m —**; —C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 C(═O)(CH 2 ) m X(CH 2 ) m —**; —C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 C(═O)((CH 2 ) m O) n (CH 2 ) m —**; —C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)(CH 2 ) m —**; —C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)(CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O))X 5 C(═O)((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 C(═O)(CH 2 ) m NR 11 C(═O)((CH 2 ) m O) n (CH 2 ) m —**; —C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 C(═O)(CH 2 ) m NR 11 C(═O)((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 (CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 ((CH 2 ) m O) n (CH 2 ) m —**; —C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 ((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)(CH 2 ) m —**; —C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 ((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)(CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 ((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X(CH 2 ) m NR 11 ((CH 2 ) m O) n (CH 2 ) m —**; —C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 C(═O)(CH 2 ) m NR 11  ((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 (CH 2 ) m —**; —C(═O) ((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 C(═O)((CH 2 ) m O) n (CH 2 ) m —**; —C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 (CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)(CH 2 ) m C(R 12 ) 2 SS(CH 2 ) m NR 11 C(═O)(CH 2 ) m —**; C(═O)(CH 2 ) m C(═O)NR 11 (CH 2 ) m —**; —C(═O)X 1 X 2 C(═O)(CH 2 ) m —**; C(═O)X 1 X 2 C(═O)(CH 2 ) m NR 11 C(═O)(CH 2 ) m —**; —C(═O)X 1 X 2 C(═O)(CH 2 ) m X 3 (CH 2 ) m —**; C(═O)X 1 X 2 C(═O)((CH 2 ) m O) n (CH 2 ) m —**; —C(═O)X 1 X 2 C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)(CH 2 ) m —**; —C(═O)X 1 X 2 C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)(CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)X 1 X 2 C(═O) ((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)X 1 X 2 C(═O)(CH 2 ) m NR 11 C(═O)((CH 2 ) m O) n (CH 2 ) m —**; —C(═O)X 1 X 2 C(═O)(CH 2 ) m NR 11 C(═O)((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)X 1 X 2 (CH 2 ) m X 3 (CH 2 ) m —**; C(═O)X 1 X 2 ((CH 2 ) m O) n (CH 2 ) m —**; —C(═O)X 1 X 2 ((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)(CH 2 ) m —**; —C(═O)X 1 X 2 ((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)(CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)X 1 X 2 ((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)X 1 X 2 (CH 2 ) m NR 11  ((CH 2 ) m O) n (CH 2 ) m —**; —C(═O)X 1 X 2 C(═O)(CH 2 ) m NR 11  ((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)NR 11 (CH 2 ) m —**; C(═O)NR(CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)NR 11 (CH 2 ) m NR 11 C(═O)X 1 X 2 C(═O)(CH 2 ) m —**; —C(═O)NR 11 (CH 2 ) m NR 11 C(═O)O(CH 2 ) m —**; C(═O)NR 11 (CH 2 ) m NR 11 C(═O)X 1 X 2 —**; —C(═O)NR 11  (CH 2 ) m NR 11 C(═O)X 5 ; —C(═O)NR 11 (CH 2 ) m NR 11 C(═O)(CH 2 ) m X 5 (CH 2 ) m —**; —C(═O)X 1 C(═O)NR(CH 2 ) m X 5 (CH 2 ) m —**; —C(═O)X 4 C(═O)(CH 2 ) m NR 11 C(═O)X 1 X 2 C(═O)(CH 2 ) m —**; —C(═O)NR 11 (CH 2 ) m NR 11 C(═O)(CH 2 ) m —**; C(═O)NR 11 (CH 2 ) m NR 11 C(═O)(CH 2 ) m O(CH 2 ) m —**; —C(═O)NR 11 (CH 2 ) m NR 11 C(═O)X 1 X 2 C(═O)(CH 2 ) m O(CH 2 ) m —**; —C(═O)NR 11 (CH 2 ) m NR 11 C(═O)X 1 X 2 C(═O)(CH 2 ) m O(CH 2 ) m C(═O)**; —C(═O)NR 11 (CH 2 ) m NR 11 C(═O)X 4 C(═O)NR 11 (CH 2 ) m NR 11 C(═O)(CH 2 ) m O(CH 2 ) m —**; —C(═O)NR 11 (CH 2 ) m NR 11 C(═O)X 1 X 2 C(═O)(CH 2 ) m —**; —C(═O)NR 11 (CH 2 ) m NR 11 C(═O)X 5 C(═O)(CH 2 ) m —**; —C(═O)NR 11 (CH 2 ) m NR 11 C(═O)X 5 C(═O)(CH 2 ) m NR 11 C(═O)(CH 2 ) m —**; —C(═O)NR 11 (CH 2 ) m NR 11 C(═O)X 5 C(═O)(CH 2 ) m X 3 (CH 2 ) m **; —C(═O)NR 11 (CH 2 ) m NR 11 C(═O)X C (═O)((CH 2 ) m O) n (CH 2 ) m —**; —C(═O)NR 11 (CH 2 ) m NR 11 C(═O)X 5 C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)(CH 2 ) m —**; —C(═O)NR 11 (CH 2 ) m NR 11 C(═O)X 5 C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)(CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)NR 11 (CH 2 ) m NR 1l C(═O)X 5 C(═O)((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)NR 11  (CH 2 ) m NR 11 C(═O)X 5 C(═O)(CH 2 ) m NR 11 C(═O)((CH 2 ) m O) n (CH 2 ) m —**; —C(═O)NR 11  (CH 2 ) m NR 11 C(═O)X 5 C(═O)(CH 2 ) m NR 11 C(═O)((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)NR 11 (CH 2 ) m NR 11 C(═O)X 5 (CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)NR 11 (CH 2 ) m NR 11 C(═O)X 5 ((CH 2 ) m O) n (CH 2 ) m —**; —C(═O)NR 11 (CH 2 ) m NR 11 C(═O)X 5 ((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)(CH 2 ) m —**; —C(═O)NR 11 (CH 2 ) m NR 11 C(═O)X 5 ((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)(CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)NR 11 (CH 2 ) m NR 11 C(═O)X 5 ((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)NR 11 (CH 2 ) m NR 11 C(═O)X 5 (CH 2 ) m NR 11 ((CH 2 ) m O) n (CH 2 ) m —**; —C(═O)NR 11 (CH 2 ) m NR 11 C(═O)X 5 C(═O)(CH 2 ) m NR 11 ((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m **; —C(═O)NR 11 (CH 2 ) m NR 11 C(═O)X(CH 2 ) m —**; —C(═O)NR 11 (CH 2 ) m NR 11 C(═O)X 5 C(═O)((CH 2 ) m O) n (CH 2 ) m —**; —C(═O)NR(CH 2 ) m NR 11 C(═O)X(CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)X C(═O)NR 11 (CH 2 ) m NR 11 C(═O)(CH 2 ) m —**; —C(═O)X 1 C(═O)NR 11 (CH 2 ) m X 3 (CH 2 ) m —**; C(═O)NR 11 (CH 2 ) m NR 11 C(═O)(CH 2 ) m —**; —C(═O)NR 11 (CH 2 ) m NR 11 C(═O)(CH 2 ) m X 3 (CH 2 ) m —**; C(═O)NR 11 (CH 2 ) m NR 11 C(═O)—**; —C(═O)X 1 X 2 (CH 2 ) m —**; C(═O)X 1 X 2 C(═O)((CH 2 ) m O) n (CH 2 ) m —**. —C(═O)X 1 X 2 (CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)NR 11 (CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)NR 11  ((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)X 1 X 2 C(═O) ((CH 2 ) m O) n (CH 2 ) m —**; —C(═O)X 1 X 2 C(═O)(CH 2 ) m —**; —C(═O)X 1 C(═O)(CH 2 ) m NR 11 C(═O)(CH 2 ) m —**; and C(═O)X 1 C(═O)(CH 2 ) m NR 11 C(═O)((CH 2 ) m O) n (CH 2 ) m —**;
 
where the ** of L 1  indicates the point of attachment to R 15 ;
 
     R 15  is 
     
       
         
         
             
             
         
       
     
     —ONH 2 , —NH 2 , 
     
       
         
         
             
             
         
       
     
     —N 3 , 
     
       
         
         
             
             
         
       
     
     —SH, —SR 12 , —SSR 17 , —S(═O) 2 (CH═CH 2 ), —(CH 2 ) 2 S(═O) 2 (CH═CH 2 ), —NHS(═O) 2 (CH═CH 2 ), —NHC(═O)CH 2 Br, —NHC(═O)CH 2 I, 
     
       
         
         
             
             
         
       
     
     C(O)NHNH 2 , 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     X 1  is 
     
       
         
         
             
             
         
       
     
     where the * of X 1  indicates the point of attachment to X 2 ;
 
X 2  is selected from
 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     where the * of X 2  indicates the point of attachment to X 1  or to NR 11 ; 
     X 3  is 
     
       
         
         
             
             
         
       
     
     X 4  is —O(CH 2 ) n SSC(R 12 ) 2 (CH 2 ) n — or —(CH 2 ) n C(R 12 ) 2 SS(CH 2 ) n O—; 
     X 5  is 
     
       
         
         
             
             
         
       
     
     where the ** of X 5  indicates orientation toward R 15 ; 
     X 6  is 
     
       
         
         
             
             
         
       
     
     or, where the ** of X 6  indicates orientation toward R 15 ;
 
R 17  is 2-pyridyl or 4-pyridyl;
 
each R 11  is independently selected from H and C 1 -C 6 alkyl;
 
each R 12  is independently selected from H and C 1 -C 6 alkyl;
 
each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; and
 
each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 and 18.
 
each R 110  is independently selected from H, C 1 -C 6 alkyl, F, Cl, and —OH;
 
each R 111  is independently selected from H, C 1 -C 6 alkyl, F, Cl, —NH 2 , —OCH 3 , —OCH 2 CH 3 , —N(CH 3 ) 2 , —CN, —NO 2  and —OH;
 
each R 112  is independently selected from H, C 1-6 alkyl, fluoro, benzyloxy substituted with —C(═O)OH, benzyl substituted with —C(═O)OH, C 1-4 alkoxy substituted with —C(═O)OH and C 1-4 alkyl substituted with —C(═O)OH;
 
and provided at least one of R 1 , R 1a  or R 1b  is substituted with —NHL 1 R 15 , or at least one of R 3 , R 4 , R 5 , R 7 , R 3a , R 4a , R 5a  or R 7a  is —OL 1 R 15 .
 
     In some embodiments L 1  is —C(═O)O(CH 2 ) m NR 11 C(═O)(CH 2 ) m —**; —C(═O)O(CH 2 ) m NR 11 C(═O)(CH 2 ) m O(CH 2 ) m —**; —C(═O)O(CH 2 ) m NR 11 C(═O)X 1 X 2 C(═O)(CH 2 ) m —**; —C(═O)OC(R 12 ) 2 (CH 2 ) m NR 11 C(═O)X 1 X 2 C(═O)(CH 2 ) m —**; —C(═O)O(CH 2 ) m NR 8 C(═O)X 1 X 2 C(═O)(CH 2 ) m O(CH 2 ) m —**; —C(═O)O(CH 2 ) m NR 11 C(═O)X 1 X 2 C(═O)(CH 2 ) m O(CH 2 ) m C(═O)—**; —C(═O)O(CH 2 ) m NR 11 C(═O)X 4 C(═O)NR 11  (CH 2 ) m NR 11 C(═O)(CH 2 ) m O(CH 2 ) m —**; —C(═O)O(CH 2 ) m NR 11 C(═O)X 5 C(═O)(CH 2 ) m NR 11 C(═O)(CH 2 ) m —**; —C(═O)O(CH 2 ) m X 6 C(═O)X 1 X 2 C(═O)((CH 2 ) m O) n (CH 2 ) m —**; —(CH 2 ) m NR 11 C(═O)X 1 X 2 C(═O)(CH 2 ) m —**; —(CH 2 ) m (CHOH)(CH 2 ) m NR 11 C(═O)X 1 X 2 C(═O)(CH 2 ) m **; —C(═O)X 6 C(═O)(CH 2 ) m NR 11 C(═O)X 1 X 2 C(═O)(CH 2 ) m —**; —C(═O)X 4 C(═O)NR(CH 2 ) m NR 11 C(═O)(CH 2 ) m O(CH 2 ) m —**; C(═O)(CH 2 ) m NR 11 C(═O)X 1 X 2 C(═O)(CH 2 ) m —**; —C(═O)O(CH 2 ) m X 6 C(═O)X 1 X 2 C(═O)(CH 2 ) m —**, or —C(═O)(CH 2 ) m NR 11 C(═O)((CH 2 ) m O) n (CH 2 ) m —**, where the ** of L 1  indicates the point of attachment to R 15 . 
     In some embodiments, the compound is selected from: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     In some embodiments, the compound is selected from: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     In some embodiments, the compound is selected from: 
     
       
         
         
             
             
         
       
     
     In some embodiments, the compound is selected from: 
     
       
         
         
             
             
         
       
     
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIGS. 1A-1D  show exemplary data on DC-SIGN immunoconjugates activating human DCs and macrophages in vitro. All DC-SIGN antibody C1 Immunoconjugates induced downregulation of DC-SIGN on monocyte dendritic cells and macrophages, indicating target engagement ( FIGS. 1A and 1C ) and induced monocyte dendritic cell and macrophage activation as measured by CD86 upregulation ( FIGS. 1B and 1D ). 
         FIGS. 2A-2D  show exemplary data on DC-SIGN immunoconjugates activating human DCs and macrophages in vitro. 2B2 (DAPA) immunoconjugates of C1, C18 and C31 induced downregulation of DC-SIGN on monocyte dendritic cells and macrophages ( FIGS. 2A and 2C ), indicating target engagement, and induced monocyte dendritic cell and macrophage activation as measured by CD86 upregulation ( FIGS. 2B and 2D ). 
         FIGS. 3A-3D  show exemplary data on DAR2 DC-SIGN immunoconjugates activating human DCs and macrophages in vitro. Hz 2B2 (DAPA) C1 and Hz 2B2 (DAPA) DAR2 C1 induced downregulation of DC-SIGN on monocyte dendritic cells and macrophages ( FIGS. 3A and 3C ), indicating target engagement, and induced monocyte dendritic cell and macrophage activation as measured by CD86 upregulation ( FIGS. 3B and 3D ). 
         FIGS. 4A-4D  show exemplary data on DC-SIGN immunoconjugates inducing cytokine production in Tg+ mice. All Hz 2B2 (DAPA) immunoconjugates except for C2 induced proinflammatory cytokine release at 6 hours post dose including IL-6 ( FIG. 4C ), TNFα ( FIG. 4D ) and IP-10 ( FIG. 4B ), and induced dendritic cell maturation as measured by CD86 upregulation at 24 hours post dose ( FIG. 4A ). * Indicates p value&lt;0.05, ** indicated p value of &lt;0.003, **** indicates a p value of &lt;0.0001 compared to Tg− saline treated mice calculated using a one way ANOVA with Dunnett&#39;s test. 
         FIGS. 5A-5E  show exemplary data on DC-SIGN immunoconjugates inducing cytokine production in Tg+ mice. Tg+ mice showed a robust increase in circulating plasma IP-10 ( FIG. 5A ), IFNβ ( FIG. 5B ), IL-6 ( FIG. 5C ), TNFα ( FIG. 5D ) and IL-12p70 ( FIG. 5E ). Plasma levels were analyzed by ELISA (IP-10 and IFNβ) or MesoScaleDiscovery Multiplex analysis (all other analytes). **** denotes p value of &lt;0.0001 using an ANOVA with Tukey&#39;s test compared to Tg-2B2 hlgG1 DAPA C1 group. 
         FIGS. 6A-6E  show exemplary data on DC-SIGN immunoconjugates inducing DC activation in a target dependent manner. DC-SIGN levels were significantly reduced in Tg+ mice treated with humanized 2B2 (DAPA)-C1 ( FIG. 6A ), indicating target engagement. Both CD80 and CD86 were highly upregulated in CD8+ and CD11 b+ DCs from mice treated with humanized 2B2 (DAPA)-C1 ( FIGS. 6B-6E ), demonstrating dendritic cell activation. ** denotes p value of &lt;0.004, **** denotes p value of &lt;0.0001 using an ANOVA with Tukey&#39;s test compared to Tg-2B2 hlgG1 DAPA C1 group. 
         FIGS. 7A-7D  show exemplary data on DC-SIGN immunoconjugates activating DCs in Tg+ mice. Tg+ mice treated with anti-DC-SIGN (DAPA) C1 conjugates had a significant downregulation of surface DC-SIGN ( FIGS. 7A and 7C ), indicating target engagement. Tg+ mice treated with anti-DC-SIGN (DAPA) C1 conjugates also had a robust upregulation of CD86 on the surface of dendritic cells indicative of DC activation ( FIGS. 7B and 7D ). **** denotes a p value of &lt;0.0001 compared to Tg+ mice treated with saline calculated using a one way ANOVA with Dunnett&#39;s test. 
         FIGS. 8A-8D  show exemplary data on DC-SIGN immunoconjugates inducing cytokine production in Tg+ mice. Tg+ mice treated with anti-DC-SIGN (DAPA) C1 conjugates showed robust increases in plasma IP-10 ( FIGS. 8A and 8C ) and TNFα levels ( FIGS. 8B and 8D ) indicative of activation. * Denotes a p value of &lt;0.05, ** denotes a p value of &lt;0.002 **** denotes a p value of &lt;0.0001 compared to Tg+ mice treated with saline calculated using a one way ANOVA with Dunnett&#39;s test. 
         FIGS. 9A-9B  show exemplary data on DC-SIGN immunoconjugates with different Fc formats inducing cytokine production in Tg+ mice. DAPA and WT Fc formats as well as Fab2 and Fab C1 conjugates induced IP-10 production ( FIG. 9A ). DAPA, WT and Fab2 formats induced IL-12p70 production in Tg+ mice in a target dependent manner ( FIG. 9B ). **** denotes p value&lt;0.0001, *** denotes p value of &lt;0.001, * denotes p value of &lt;0.05, using an ANOVA with Dunnett&#39;s test compared to Tg+ Isotype (DAPA) C1. 
         FIGS. 10A-10B  show exemplary data on DC-SIGN immunoconjugates with different Fc formats inducing DC activation in Tg+ mice. DAPA and WT Fc formats as well as Fab2 and Fab versions of 2B2 C1 conjugates induced DC-SIGN downregulation ( FIG. 10A ), indicative of target engagement and CD86 upregulation on DCs ( FIG. 10B ), indicative of DC activation in Tg+ mice. **** denotes p value&lt;0.0001 calculated using an ANOVA with Dunnett&#39;s test compared to Tg+ Isotype (DAPA) C1. 
         FIGS. 11A-11B  show exemplary data on DC-SIGN immunoconjugates with a WT Fc format activating human DCs and macrophages in vitro. Both WT and DAPA 2B2 C1 conjugates induced downregulation of DC-SIGN on monocyte dendritic cells, indicating target engagement ( FIG. 11A ). Both WT and DAPA 2B2 C1 conjugates induce monocyte dendritic cell activation as measured by CD86 upregulation ( FIG. 11B ). 
         FIGS. 12A-12D  show exemplary data on DC-SIGN immunoconjugates with different Fc formats inducing DC activation and cytokine production in Tg+ mice. Both DAPA and Fc silent versions of 2B2 C1 Immunoconjugates induced high levels of circulating IP-10 ( FIG. 12A ) and TNFα ( FIG. 12B ). Both DAPA and Fc silent versions of 2B2 C1 conjugates induced DC-SIGN downregulation ( FIG. 12C ) indicative of target engagement and CD86 upregulation on DCs ( FIG. 12D ) indicative of DC activation in Tg+ mice. ** denotes a p value of &lt;0.01, *** denotes a p value of &lt;0.001 compared to the appropriate Tg− control group calculated using an unpaired Student&#39;s t test. **** denotes p value of &lt;0.0001 using a one way ANOVA with Dunnett&#39;s test compared to saline treated Tg+ mice. 
         FIGS. 13A-13C  show exemplary data on DC-SIGN immunoconjugates inducing cytokine production in Tg+ mice in comparison to free CDN. Tg+ mice dosed with 1 mg/kg of 2B2 (DAPA) C1 or free T1-1 had increased circulating plasma IL-12p70 ( FIG. 13C ), TNFα ( FIG. 13B ) and IP-10 ( FIG. 13A ) levels compared to the untreated Tg+ mice and compared to mice treated with 10 μg of free T1-1 compound. ** denotes p value of 0.001, **** denotes p value of &lt;0.0001 using an ANOVA with Tukey&#39;s test compared to Tg+ untreated, *** denotes p value of &lt;0.0001 using unpaired Student&#39;s t test compared to Tg+ untreated. 
         FIGS. 14A-14C  show exemplary data on DC-SIGN immunoconjugates inducing DC activation in comparison to free CDN. DC-SIGN levels were significantly reduced in Tg+ mice treated with humanized 2B2 (DAPA)-C1 ( FIG. 14A ), indicating target engagement. CD80 and CD86 were significantly upregulated on the surface of DCs from mice treated with 2B2 (DAPA) C1 and to a greater extent than was observed in animals treated with free T1-1 ( FIGS. 14B and 14C ). ** denotes p value of 0.001, *** denotes p value of 0.0006, **** denotes p value of &lt;0.0001 using an ANOVA with Tukey&#39;s test compared to Tg+ saline. 
         FIGS. 15A-15D  show exemplary data on 1G12 DC-SIGN immunoconjugates inducing DC activation and cytokine production. Tg+ mice treated with 1G12 (DAPA) C1 had a significant downregulation of surface DC-SIGN ( FIG. 15A ), indicating target engagement, and had a significant upregulation of CD86 on the surface of dendritic cells indicating activation ( FIG. 15B ). IP-10 ( FIG. 15D ) and IL-12p70 ( FIG. 15C ) plasma levels were significantly increased in Tg+ mice treated with 1G12 (DAPA) C1 at 6 hours post dose, indicative of on target activation through DC-SIGN. **** denotes p value of &lt;0.0001 using a one way ANOVA with Dunnett&#39;s test compared to Tg− mice treated with 1G12. 
         FIGS. 16A-16C  show exemplary data on DAR2 and DAR4 versions of DC-SIGN immunoconjugates inducing DC activation and cytokine production. Both antibody and payload matched doses of 2B2 (DAPA) DAR2 C1 induced DC activation as measured by CD86 upregulation ( FIG. 16A ) as well as IL-12p70 secretion ( FIG. 16C ) and IP-10 secretion ( FIG. 16B ) in a target dependent manner. **** denotes p value of &lt;0.0001, *** denotes p value of ≤0.004, * denotes p value of 0.02 using an ANOVA with Tukey&#39;s test. 
         FIGS. 17A-17D  show exemplary data on DC-SIGN immunoconjugates enhancing antibody responses to DNP-KLH and promoing isotype switching in Tg+ mice. Mice treated with 2B2 (DAPA) C1 show a significant increase in total DNP binding IgG ( FIG. 17A ) and also in IgG2a ( FIG. 17C ) and IgG3 ( FIG. 17D ) subclasses of DNP binding antibodies but not IgG1 ( FIG. 17B ). ** denotes p value of &lt;0.01, * denotes p value of &lt;0.05 in an unpaired Student&#39;s t test compared to mock treated group. 
         FIG. 18  shows exemplary data on DC-SIGN immunoconjugates delaying tumor growth in transgenic mice expressing DC-SIGN. DC-SIGN Tg+ mice treated with 1 mpk of 2B2 (DAPA) C1 conjugate had significantly delayed tumor growth kinetics, whereas Tg− mice did not show any impairment in tumor growth after dosing of 2B2 (DAPA) C1. Both Tg+ and Tg− mice treated with unconjugated 2B2 (DAPA) antibody did not show any change in tumor volume. **** denotes p value of &lt;0.0001, * denotes p value of &lt;0.05 in an unpaired Student&#39;s t test. 
         FIGS. 19A-19B  show exemplary data on DC-SIGN immunoconjugates inducing upregulation of surface PDL1. Splenic CD11c high dendritic cells ( FIG. 19A ) and tumor resident dendritic cells and monocytic myeloid derived suppressor cells (mMDSCs) ( FIG. 19B ) showed a significant upregulation of surface PDL1 in Tg+ mice dosed with 1 mg/kg 2B2 (DAPA) C1. **** denotes p value of &lt;0.0001, * denotes p value of 0.002 using an ANOVA with Tukey&#39;s test compared to Tg+2B2 (DAPA). 
         FIGS. 20A-20F  show exemplary data on DC-SIGN immunoconjugates enhancing tumor T cell infiltration and T cell activation. Increased CD3+ T cells were observed 24 and 48 hours post dosing in Tg+ mice dosed with 2B2 (DAPA) C1 mice ( FIGS. 20A and 20B ). On day 7 post dose, a significant increase in CD8+ T cells ( FIG. 20C ) and a significant decrease in FoxP3+T regulatory cells ( FIG. 20D ) were observed in tumors from Tg+ mice dosed with 2B2 (DAPA) C1. Enhanced T cell activation as measured by CD69 upregulation was seen on CD4 and CD8 T cells in tumors from Tg+ mice dosed with 2B2 (DAPA) C1 24 hours post dose ( FIGS. 20E and 20F ). **** denotes p value of &lt;0.0001, ** denotes p value of 50.003 using an ANOVA with Tukey&#39;s test compared to Tg+ Cysmab, ** denotes p value of 0.02 using Student&#39;s t test compared to Tg− 2B2 (DAPA) C1. 
         FIGS. 21A-21B  show exemplary data on DC-SIGN immunoconjugates having enhanced anti-tumor activity in combination with anti-PDL1. Mice treated with the combination of 2B2 (DAPA) C1 and anti-PDL1 showed enhanced reduction in tumor volume ( FIG. 21A ) and enhanced infiltration of CD8 T cells in their tumors ( FIG. 21B ). **** p&lt;0.0001, *** p&lt;0.002, **p&lt;0.01, *p&lt;0.05 compared to isotype control (DAPA) C1 1 mg/kg using unpaired Student&#39;s t test. 
         FIGS. 22A-22B  show exemplary data on DAR2 DC-SIGN immunoconjugates having enhanced anti-tumor activity in combination with anti-PDL1. Mice treated with the combination of humanized 2B2 (DAPA) C1 and anti-PDL1 or humanized 2B2 (DAPA) DAR2 C1 and anti-PDL1 showed a reduction in tumor volume compared to isotype control treated animals ( FIG. 22A ) and enhanced infiltration of CD8 T cells in their tumors compared to isotype control group ( FIG. 22B ). *** indicates p value of &lt;0.001 using a one way ANOVA with Dunnet&#39;s test, ** indicates p value&lt;0.01 calculated using an unpaired Student&#39;s t test, * indicates p value&lt;0.05 calculated using an unpaired Student&#39;s t test. 
         FIGS. 23A-23B  show exemplary data on DC-SIGN immunoconjugates with different payloads having enhanced anti-tumor activity in combination with anti-PDL1. Tg+ animals treated with 2B2 (DAPA) C31 in combination with anti PDL1 had significantly smaller tumors than Tg− animals ( FIG. 23A ). Tg+ animals treated with both 2B2 (DAPA) C31 and 2B2 (DAPA) C18 at 0.3 mg/kg in combination with anti PDL1 had significantly increased tumor CD8+ T cell infiltration compared to Tg− animals treated with the same regimen ( FIG. 23B ). p&lt;0.01 using an unpaired Student&#39;s t test (compared to Tg− group with the same payload), ** p&lt;0.01 using an ANOVA with Tukey&#39;s test (compared to Tg− group with the same payload). 
         FIGS. 24A-24B  show exemplary data on 960K03 (DAPA)-C31 conjugate induces cytokine production in a target dependent manner. Transgenic mice expressing human DC-SIGN gene (Tg+) or transgene-negative littermate control (Tg−) mice were treated with 960K03 (DAPA) DAR4 C31 at 0.01, 0.03, 0.1, 0.3 or 1 milligram per kilogram body weight (mpk) intravenously (i.v.). Mice were bled 6 hours after dosing to collect plasma for analysis of circulating cytokine levels. Tg+ mice showed a robust increase in circulating plasma IP-10 ( FIG. 24A ) and TNFα ( FIG. 24B ) and Plasma levels were analyzed by ELISA (IP-10) or MesoScaleDiscovery Multiplex analysis (TNFα). **** denotes p value of &lt;0.0001 and ** denotes a p value of &lt;0.01 using a one way ANOVA with Sidak&#39;s test compared to the Tg− dose matched group. 
         FIGS. 25A-25B  show exemplary data on 960K03 (DAPA)-C31 conjugate induces dendritic cell activation in a target dependent manner. Transgenic mice expressing human DC-SIGN gene (Tg+) or transgene-negative littermate control (Tg−) mice were treated with 960K03 (DAPA) DAR4 C31 at 0.01, 0.03, 0.1, 0.3 or 1 milligram per kilogram body weight (mpk) intravenously (i.v.). Spleens were harvested 24 hours post dose and analyzed by flow cytometry to look at CD11c+ dendritic cells. DC-SIGN levels were significantly reduced in Tg+ mice treated with 960K03 (DAPA) DAR4 C31 ( FIG. 25A ), indicating target engagement. CD86 was highly upregulated on CD11c+ dendritic cells in a dose dependent manner in Tg+ mice treatment with 960K03 (DAPA) DAR4 C31 ( FIG. 25B ), demonstrating dendritic cell activation. **** denotes p value of &lt;0.0001 and ** denotes a p value of &lt;0.01 using a one way ANOVA with Sidak&#39;s test compared to the Tg− dose matched group. 
         FIGS. 26A-26C  show exemplary data on 960K03 (DAPA)-C31 conjugate is active in vitro on human monocyte DCs. Primary human monocytes were isolated from a leukapheresis using magnetic bead selection and frozen for storage in liquid nitrogen. For monocyte DC (moDC) differentiation, cells were thawed and incubated in media containing GM-CSF and IL-4 for 7 days. After the differentiation process for both moDC and moMacs, media was washed off and replaced with fresh media containing isotype control (DAPA) or 960K03 (DAPA) conjugated to C31 payload. Free T1-1 compound was used as a control. 24 hours after incubation with indicated compounds, cells were evaluated by flow cytometry for activation. 960K03 (DAPA) C31 conjugate induced downregulation of DC-SIGN on monocyte dendritic cells, indicating target engagement ( FIG. 26A ). 960K03 (DAPA) C31 induced monocyte dendritic cell activation (as measured by CD86 upregulation) with less payload than the isotype control (DAPA) C31 conjugate or unconjugated T1-1 ( FIG. 26B ). 960K03 (DAPA) C31 also induced IP-10 secretion into the culture supernatant at a higher concentration with less payload than the isotype control (DAPA) C31 conjugate or unconjugated T1-1 ( FIG. 26C ). 
         FIGS. 27A-27B  show exemplary data on 960K03 (DAPA)-C31 conjugate has anti-tumor activity in combination with anti-PDL1 therapy. Female transgenic mice expressing human DC-SIGN gene (Tg+) or DC-SIGN negative littermate controls (Tg−) were implanted with 2.5×10 5  MC38 tumor cells subcutaneously in the hind flank. Tumors were measured 3 times weekly throughout the course of the study. When tumors reached 100-200 cubic millimeters (mm 3 ), mice were given a single treatment of 0.1, 0.3 or 1 mg/kg 960K03 (DAPA) DAR4 C31. A control group received no 960K03 (DAPA) DAR4 C31. All groups were given 2 doses of anti-PDL1 clone 10F.9G2 at 10 mg/kg throughout the course of the study (every 3-4 days). Mice treated with the combination of 960K03 (DAPA) DAR4 C31 and anti-PDL1 showed enhanced reduction in tumor volume at both 0.3 mg/kg as well as the 1 mg/kg dose levels of 960K03 (DAPA) DAR4 C31 ( FIG. 27A ). **p&lt;0.01, *p&lt;0.05 compared to dose matched Tg− control group using unpaired Student&#39;s t test. 7 days after dosing with 960K03 (DAPA) DAR4 C31, tumors were analyzed by flow cytometry for T cell infiltration. Mice treated with the 960K03 (DAPA) DAR4 C31 and anti-PDL1 showed enhanced infiltration of CD8+ T cells in their tumors when compared to dose matched Tg− controls ( FIG. 27B ). **p&lt;0.01 compared to dose matched Tg− control group using a one-way ANOVA with Tukey&#39;s test. 
     
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     Various enumerated embodiments of the invention are described herein. It will be recognized that features specified in each embodiment may be combined with other specified features to provide further embodiments of the present invention. 
     Throughout the text of this application, should there be a discrepancy between the text of the specification (e.g., Table 8) and the sequence listing, the text of the specification shall prevail. 
     Definitions 
     The term “C 1 -C 6 alkyl”, as used herein, refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to six carbon atoms, and which is attached to the rest of the molecule by a single bond. Non-limiting examples of “C 1 -C 6 alkyl” groups include methyl, ethyl, 1-methylethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl and hexyl. 
     The term “C 2 -C 6 alkenyl”, as used herein, refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one double bond, having from two to six carbon atoms, which is attached to the rest of the molecule by a single bond. Non-limiting examples of “C 2 -C 6 alkenyl” groups include ethenyl, prop-1-enyl, but-1-enyl, pent-1-enyl, pent-4-enyl and penta-1,4-dienyl. 
     The term “C 2 -C 6 alkynyl”, as used herein, refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one triple bond, having from two to six carbon atoms, and which is attached to the rest of the molecule by a single bond. Non-limiting examples of “C 2 -C 6 alkynyl” groups include ethynyl, prop-1-ynyl, but-1-ynyl, pent-1-ynyl, pent-4-ynyl and penta-1,4-diynyl. 
     The term “C 1 -C 6 alkylene”, as used herein, refers to a bivalent straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to six carbon atoms. 
     The term “C 2 -C 6 alkenyl”, as used herein, refers to a bivalent straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one double bond, having from two to six carbon atoms. 
     The term “C 2 -C 6 alkynyl”, as used herein, refers to a bivalent straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one triple bond, having from two to six carbon atoms. 
     The term “C 1-6 alkoxyalkyl”, as used herein, refers to a radical of the formula —Ra—O—Ra, where each Ra is independently a C 1-6 alkyl radical as defined above. The oxygen atom may be bonded to any carbon atom in either alkyl radical. Examples of C 1-6 alkoxy include, but are not limited to, methoxy-methyl, methoxy-ethyl, ethoxy-ethyl, 1-ethoxy-propyl and 2-methoxy-butyl. 
     The term “C 1 -C 6 hydroxyalkyl”, as used herein, refers to a C 1-6 alkyl radical as defined above, wherein one of the hydrogen atoms of the C 1-6 alkyl radical is replaced by OH. Examples of hydroxyC 1-6 alkyl include, but are not limited to, hydroxy-methyl, 2-hydroxy-ethyl, 2-hydroxy-propyl, 3-hydroxy-propyl and 5-hydroxy-pentyl 
     The term “C 3 -C 8 cycloalkyl,” as used herein, refers to a saturated, monocyclic, fused bicyclic, fused tricyclic or bridged polycyclic ring system. Non-limiting examples of fused bicyclic or bridged polycyclic ring systems include bicyclo[1.1.1]pentane, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[3.2.1]octane, bicyclo[2.2.2]octane and adamantanyl. Non-limiting examples monocyclic C 3 -C 8 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups. 
     The term “C 1 -C 6 haloalkyl”, as used herein, refer to the respective “C 1 -C 6 alkyl”, as defined herein, wherein at least one of the hydrogen atoms of the “C 1 -C 6 alkyl” is replaced by a halo atom. The C 1 -C 6 haloalkyl groups can be monoC 1 -C 6 haloalkyl, wherein such C 1 -C 6 haloalkyl groups have one iodo, one bromo, one chloro or one fluoro. Additionally, the C 1 -C 6 haloalkyl groups can be diC 1 -C 6 haloalkyl wherein such C 1 -C 6 haloalkyl groups can have two halo atoms independently selected from iodo, bromo, chloro or fluoro. Furthermore, the C 1 -C 6 haloalkyl groups can be polyC 1 -C 6 haloalkyl wherein such C 1 -C 6 haloalkyl groups can have two or more of the same halo atoms or a combination of two or more different halo atoms. Such polyC 1 -C 6 haloalkyl can be perhaloC 1 -C 6 haloalkyl where all the hydrogen atoms of the respective C 1 -C 6 alkyl have been replaced with halo atoms and the halo atoms can be the same or a combination of different halo atoms. Non-limiting examples of C 1 -C 6 haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, trifluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. 
     The term “C 2 -C 6 haloalkenyl”, as used herein, refer to the respective “C 1 -C 6 alkenyl”, as defined herein, wherein at least one of the hydrogen atoms of the “C 1 -C 6 alkenyl” is replaced by a halo atom. The C 2 -C 6 haloalkenyl groups can be monoC 1 -C 6 haloalkenyl, wherein such C 1 -C 6 haloalkenyl groups have one iodo, one bromo, one chloro or one fluoro. Additionally, the C 2 -C 6 haloalkenyl groups can be diC 2 -C 6 haloalkenyl wherein such C 2 -C 6 haloalkenyl groups can have two halo atoms independently selected from iodo, bromo, chloro or fluoro. Furthermore, the C 2 -C 6 haloalkenyl groups can be polyC 2 -C 6 haloalkenyl wherein such C 2 -C 6 haloalkenyl groups can have two or more of the same halo atoms or a combination of two or more different halo atoms. 
     The term “C 2 -C 6 haloalkynyl”, as used herein, refer to the respective “C 1 -C 6 alkynyl”, as defined herein, wherein at least one of the hydrogen atoms of the “C 1 -C 6 alkynyl” is replaced by a halo atom. The C 2 -C 6 haloalkynyl groups can be monoC 1 -C 6 haloalkynyl, wherein such C 1 -C 6 haloalkynyl groups have one iodo, one bromo, one chloro or one fluoro. Additionally, the C 2 -C 6 haloalkynyl groups can be diC 2 -C 6 haloalkynyl wherein such C 2 -C 6 haloalkynyl groups can have two halo atoms independently selected from iodo, bromo, chloro or fluoro. Furthermore, the C 2 -C 6 haloalkynyl groups can be polyC 2 -C 6 haloalkynyl wherein such C 2 -C 6 haloalkenyl groups can have two or more of the same halo atoms or a combination of two or more different halo atoms. 
     The term “heteroalkyl”, as used herein, refers to an “alkyl” moiety wherein at least one of the carbon atoms has been replaced with a heteroatom such as O S, or N. 
     The term “3 to 6 membered heterocycloalkyl,” as used herein refers to a monocyclic ring structure having 3 to 6 ring members, wherein one to two of the ring members are independently selected from N, NH, NR 16 , O or —S—, wherein R 16  is C 1 -C 6 alkyl. Non-limiting examples of 3-6 membered heterocycloalkyl groups, as used herein, include aziridin-1-yl, aziridin-2-yl, aziridin-3-yl, azetadinyl, azetadin-1-yl, azetadin-2-yl, azetadin-3-yl, oxetanyl, oxetan-2-yl, oxetan-3-yl, oxetan-4-yl, thietanyl, thietan-2-yl, thietan-3-yl, thietan-4-yl, pyrrolidinyl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, pyrrolidin-4-yl, pyrrolidin-5-yl, tetrahydrofuranyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrofuran-4-yl, tetrahydrofuran-5-yl, tetrahydrothienyl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, tetrahydrothien-4-yl, tetrahydrothien-5-yl, piperidinyl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperidin-5-yl, piperidin-6-yl, tetrahydropyranyl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, tetrahydropyran-5-yl, tetrahydropyran-6-yl, tetrahydrothiopyranyl, tetrahydrothiopyran-2-yl, tetrahydrothiopyran-3-yl, tetrahydrothiopyran-4-yl, tetrahydrothiopyran-5-yl, tetrahydrothiopyran-6-yl, piperazinyl, piperazin-1-yl, piperazin-2-yl, piperazin-3-yl, piperazin-4-yl, piperazin-5-yl, piperazin-6-yl, morpholinyl, morpholin-2-yl, morpholin-3-yl, morpholin-4-yl, morpholin-5-yl, morpholin-6-yl, thiomorpholinyl, thiomorpholin-2-yl, thiomorpholin-3-yl, thiomorpholin-4-yl, thiomorpholin-5-yl, thiomorpholin-6-yl, oxathianyl, oxathian-2-yl, oxathian-3-yl, oxathian-5-yl, oxathian-6-yl, dithianyl, dithian-2-yl, dithian-3-yl, dithian-5-yl, dithian-6-yl, dioxolanyl, dioxolan-2-yl, dioxolan-4-yl, dioxolan-5-yl, thioxanyl, thioxan-2-yl, thioxan-3-yl, thioxan-4-yl, thioxan-5-yl, dithiolanyl, dithiolan-2-yl, dithiolan-4-yl, dithiolan-5-yl, pyrazolidinyl, pyrazolidin-1-yl, pyrazolidin-2-yl, pyrazolidin-3-yl, pyrazolidin-4-yl and pyrazolidin-5-yl. 
     The term “heterocyclyl”, as used herein, includes partially saturated or aromatic monocyclic or fused bicyclic heterocyclyl containing from 5-10 ring members selected from carbon atoms and 1 to 5 heteroatoms, and each heteroatoms is independently selected from O, N or S. In a preferred embodiment, the heteroatoms are nitrogen. Non-limiting examples of substituents include oxo, halo, C 1-6 alkyl, C 1-6 alkoxy, amino, C 1-6 alkylamino, di-C 1-6 alkylamino. The heterocyclic group can be attached at a heteroatom or a carbon atom. 
     For fused bicyclic heterocyclyl system, the system can be fully aromatic (i.e. both rings are aromatic). When fully aromatic, the heterocyclyl can be referred to as heteroaryl. Examples of aromatic bicyclic heteroaryl include 9-10 membered fused bicyclic heteroaryl having 2-5 heteroatoms, preferably nitrogen atoms. Non-limiting examples are: pyrrolo[2,3-b]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrrolo[3,2-b]pyridinyl, imidazo[4,5-b]pyridinyl, imidazo[4,5-c]pyridinyl, pyrazolo[4,3-d]pyridinyl, pyrazolo[4,3-c]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[3,4-d]pyridinyl, pyrazolo[3,4-b]pyridinyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrrolo[1,2-b]pyridazinyl, imidazo[1,2-c]pyrimidinyl, pyrido[3,2-d]pyrimidinyl, pyrido[4,3-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrido[2,3-d]pyrimidinyl, pyrido[2,3-b]pyrazinyl, pyrido[3,4-b]pyrazinyl, pyrimido[5,4-d]pyrimidinyl, pyrazino[2,3-b]pyrazinyl, or pyrimido[4,5-d]pyrimidinyl. Other non-limiting examples of fused bicyclic heterocyclyls include 
     
       
         
         
             
             
         
       
     
     Additionally, bicyclic heterocyclyl ring systems include heterocyclyl ring systems wherein one of the fused rings is aromatic but the other is non-aromatic. For such systems, the heterocyclyl is said to be partially saturated. Examples of partially saturated bicyclic system are for example dihydropurinones such as 2-amino-1,9-dihydro-6H-purin-9-yl-6-one and 1,9-dihydro-6H-purin-9-yl-6-one. Other examples of partially saturated bicyclic system are 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Heterocyclyl also includes a 5- or 6-membered ring aromatic heterocyclyl having 2 to 3 heteroatom (preferably nitrogen) (also referred to as 5- to 6-membered heteroaryl). Examples of monocyclic heteroaryl are: imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, 1, 2, 3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, 1,2,3-triazol-4-yl, 1,2,3-triazol-5-yl, tetrazolyl, pyrid-2-yl, pyrid-3-yl, or pyridyl-4-yl, pyridazin-3-yl, pyridazin-4-yl, pyrazin-3-yl, 2-pyrazin-2-yl, pyrazin-4-yl, pyrazin-5-yl, 2-, 4-, or 5-pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl. 
     Heterocyclyl also includes 6-membered monocyclic partially saturated ring having 1-3 heteroatoms (preferably nitrogen). Examples of partially saturated monocyclic heterocyclyl are pyrimidine-one and pyrimidine-dione, specifically pyrimidin-2(1H)-one and pyrimidin-1-yl-2,4(1H, 3H)-dione. 
     Heterocyclyl can exist in various tautomeric forms. For example, when a heterocyclyl moiety is substituted with an oxo group next to a nitrogen atom, the invention also pertains to its hydroxy tautomeric form. For example, 2-amino-1,9-dihydro-6H-purin-6-one can tautomerize into 2-amino-9H-purin-6-ol. The tautomerization is represented as follow: 
     
       
         
         
             
             
         
       
     
     As used herein, the term tautomer is used to designate 2 molecules with the same molecular formula but different connectivity, which can interconvert in a rapid equilibrium. Additional examples of tautomers are phosporothioic acid which can exist in an equilibrium as shown below. 
     
       
         
         
             
             
         
       
     
     Similarly, phosphoric acid exists as 2 tautomeric forms which interconvert in an equilibrium. 
     Additional examples of tautomers are phosporothioic acid which can exist in an equilibrium as shown below. 
     
       
         
         
             
             
         
       
     
     Similarly, phosphoric acid exists as 2 tautomeric forms which interconvert in an equilibrium. 
     In addition the phosporothioic acid and phosphoric acid moieties can exist in the respective equilibrium as shown below. 
     
       
         
         
             
             
         
       
     
     The term “Drug moiety”, as used herein, refers to a compound which binds to Stimulator of Interferon Genes (STING) receptor and which comprises one or more functional groups each of which is capable of forming a covalent bond with a linker. Examples of such functional groups include, but are not limited to, primary amines, secondary amines, hydroxyls, thiols, alkenes, alkynes and azides. In certain embodiments, such functional groups include reactive groups of Table 5 provided herein. 
     The term “sugar moiety”, as used herein, refers to the following ring structures of the compounds of the invention 
     
       
         
         
             
             
         
       
     
     wherein Y 1 , Y 2  and Y 3  are each independently selected from —O—, —S—, —S(═O)—, —SO 2 —, —CH 2 —, or —CF 2 —. 
     As used herein, when partial structures of the compounds are illustrated a wavy line ( ) indicates the point of attachment of the partial structure to the rest of the molecule. 
     As used herein, “DC-SIGN” (Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin, also known as CD209; CD209 molecule, CDSIGN; CLEC4L; DC-SIGN1) refers to a transmembrane receptor and is referred to as DC-SIGN because of its expression on the surface of dendritic cells and macrophages. The protein is involved in the innate immune system and recognizes numerous evolutionarily divergent pathogens ranging from parasites to viruses with a large impact on public health. The protein is organized into three distinct domains: an N-terminal transmembrane domain, a tandem-repeat neck domain and C-type lectin carbohydrate recognition domain. The extracellular region consisting of the C-type lectin and neck domains has a dual function as a pathogen recognition receptor and a cell adhesion receptor by binding carbohydrate ligands on the surface of microbes and endogenous cells. The neck region is important for homo-oligomerization which allows the receptor to bind multivalent ligands with high avidity. Variations in the number of 23 amino acid repeats in the neck domain of this protein are rare but have a significant impact on ligand binding ability. Human DC-SIGN is encoded by the CD209 gene (GeneID 30835) which is closely related in terms of both sequence and function to a neighboring gene (GeneID 10332; often referred to as L-SIGN). DC-SIGN and L-SIGN differ in their ligand-binding properties and distribution. Alternative splicing results in multiple variants. The human CD209 gene is mapped to chromosomal location 19p13.2, and the genomic sequence of CD209 gene can be found in GenBank at NG_012167.1. In human, there are seven DC-SIGN isoforms: 1, 3, 4, 5, 6, 7, and 8; the term “DC-SIGN” is used herein to refer collectively to all DC-SIGN isoforms. As used herein, a human DC-SIGN protein also encompasses proteins that have over its full length at least about 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with DC-SIGN isoforms: 1, 3, 4, 5, 6, 7, and 8, wherein such proteins still have at least one of the functions of DC-SIGN. The mRNA and protein sequences for human DC-SIGN isoform 1, the longest isoform, are: 
     
       
         
           
               
               
            
               
                 Homo sapiens CD209 molecule (CD209), transcript variant 1,  
                   
               
               
                 mRNA +NM_021155.3+ 
               
               
                 (SEQ ID NO: 302) 
                   
               
            
           
           
               
               
               
            
               
                 1 
                 atcacagggt gggaaataaa agctgtggcc cccaggagtt ctggacactg ggggagagtg 
                   
               
               
                   
               
               
                 61 
                 gggtgacatg agtgactcca aggaaccaag actgcagcag ctgggcctcc tggaggagga 
               
               
                   
               
               
                 121 
                 acagctgaga ggccttggat tccgacagac tcgaggatac aagagcttag cagggtgtct 
               
               
                   
               
               
                 181 
                 tggccatggt cccctggtgc tgcaactcct ctccttcacg ctcttggctg ggctccttgt 
                   
               
               
                   
               
               
                 241 
                 ccaagtgtcc aaggtcccca gctccataag tcaggaacaa tccaggcaag acgcgatcta 
                   
               
               
                   
               
               
                 301 
                 ccagaacctg acccagctta aagctgcagt gggtgagctc tcagagaaat ccaagctgca 
               
               
                   
               
               
                 361 
                 ggagatctac caggagctga cccagctgaa ggctgcagtg ggtgagcttc cagagaaatc 
               
               
                   
               
               
                 421 
                 taagctgcag gagatctacc aggagctgac ccggctgaag gctgcagtgg gtgagcttcc 
               
               
                   
               
               
                 481 
                 agagaaatct aagctgcagg agatctacca ggagctgacc tggctgaagg ctgcagtggg 
               
               
                   
               
               
                 541 
                 tgagcttcca gagaaatcta agatgcagga gatctaccag gagctgactc ggctgaaggc 
               
               
                   
               
               
                 601 
                 tgcagtgggt gagcttccag agaaatctaa gcagcaggag atctaccagg agctgacccg 
               
               
                   
               
               
                 661 
                 gctgaaggct gcagtgggtg agcttccaga gaaatctaag cagcaggaga tctaccagga 
               
               
                   
               
               
                 721 
                 gctgacccgg ctgaaggctg cagtgggtga gcttccagag aaatctaagc agcaggagat 
               
               
                   
               
               
                 781 
                 ctaccaggag ctgacccagc tgaaggctgc agtggaacgc ctgtgccacc cctgtccctg 
               
               
                   
               
               
                 841 
                 ggaatggaca ttcttccaag gaaactgtta cttcatgtct aactcccagc ggaactggca 
               
               
                   
               
               
                 901 
                 cgactccatc accgcctgca aagaagtggg ggcccagctc gtcgtaatca aaagtgctga 
               
               
                   
               
               
                 961 
                 ggagcagaac ttcctacagc tgcagtcttc cagaagtaac cgcttcacct ggatgggact 
               
               
                   
               
               
                 1021 
                 ttcagatcta aatcaggaag gcacgtggca atgggtggac ggctcacctc tgttgcccag 
               
               
                   
               
               
                 1081 
                 cttcaagcag tattggaaca gaggagagcc caacaacgtt ggggaggaag actgcgcgga 
               
               
                   
               
               
                 1141 
                 atttagtggc aatggctgga acgacgacaa atgtaatctt gccaaattct ggatctgcaa 
               
               
                   
               
               
                 1201 
                 aaagtccgca gcctcctgct ccagggatga agaacagttt ctttctccag cccctgccac 
                   
               
               
                   
               
               
                 1261 
                 cccaaacccc cctcctgcgt agcagaactt cacccccttt taagctacag ttccttctct 
                   
               
               
                   
               
               
                 1321 
                 ccatccttcg accttcacaa aatctctggg actgttcttt gtcagattct tcctccttta 
               
               
                   
               
               
                 1381 
                 gaaggctggg tcccattctg tccttcttgt catgcctcca atttcccctg gtgtagagct 
               
               
                   
               
               
                 1441 
                 tgtttttctg gcccatcctt ggagctttat gagtgagctg gtgtgggatg cctttggggg 
               
               
                   
               
               
                 1501 
                 tggacttgtg ttccaagaat ccactctctc ttccttttgg agattaggat atttgggttg 
               
               
                   
               
               
                 1561 
                 ccatgtgtag ctgctatgtc ccctggggcg ttatcttata catgcaaacc taccatctgt 
               
               
                   
               
               
                 1621 
                 tcaacttcca cctaccacct cctgcacccc tttgatcggg gacttactgg ttgcaagagc 
               
               
                   
               
               
                 1681 
                 tcattttgca ggctggaagc accagggaat taattccccc agtcaaccaa tggcacccag 
               
               
                   
               
               
                 1741 
                 agagggcatg gaggctccac gcaacccctt ccacccccac atcttccttt gtcttataca 
               
               
                   
               
               
                 1801 
                 tggcttccat ttggctgttt ctaagttgta ttctttattt tattattatt attactattt 
               
               
                   
               
               
                 1861 
                 ttcgagatgg agtttcactc ttgtcgctca ggctggagtg ccatggcgcg atcttggctc 
               
               
                   
               
               
                 1921 
                 actgcaacct ctgcctcccg ggttcaagtg attctcctgc ctcagcctca cgagtagctg 
               
               
                   
               
               
                 1981 
                 gaattacagg caggcgccac cagacccggc taattttttg tatttttagt acagatgggg 
               
               
                   
               
               
                 2041 
                 tttctccgtg ttggtcaggc tggtcttgaa ctcccgacct cagatgatct gcccgcctcg 
               
               
                   
               
               
                 2101 
                 gcctcccaaa attgctggga ttacaggtgt gagccaccgc gcctggccta ttattttttg 
               
               
                   
               
               
                 2161 
                 taagaataaa acaggtttat tgggatttgg gactctgaac agttctgtct ctactacctg 
               
               
                   
               
               
                 2221 
                 atctcctcct accacgactt tgggatctag aggagctttg gctccggctg tgacggctcc 
               
               
                   
               
               
                 2281 
                 ggccgttctc actgcggctg caccggcccc cgctgcggtc actatttctt cctctgctag 
                   
               
               
                   
               
               
                 2341 
                 gtgaattgtg cctctcctgg ctctttgaca tgtgctagtg agatttcttc cttttccttt 
               
               
                   
               
               
                 2401 
                 cggattcccc atttcttttg taggaatggt ctggactagg gttctccttc cccgcagcct 
               
               
                   
               
               
                 2461 
                 gtagtattca tcgtggtggc ccaccctctc tctccccttg gagctcttgc caaaggagga 
               
               
                   
               
               
                 2521 
                 gacaagcaga ggtctctatt ggatttctca acacctgaag aaagttgcag tgttttcctc 
               
               
                   
               
               
                 2581 
                 ttggacattg ttgtatttca aataaaccac aaatcatcat tttccaccga gccactgggc 
               
               
                   
               
               
                 2641 
                 agaattcaca ctgaagctgt cgtcctgcgt acataccatc gtccgttaaa cagagaaaga 
               
               
                   
               
               
                 2701 
                 gctgcttggc attcttcttc cgactggtac tgaacatata tacttgcccc tcaggtgagg 
               
               
                   
               
               
                 2761 
                 ttccaagttg caactgacct tgaactgaat cactctcccc acgttatttt ttaattacta 
               
               
                   
               
               
                 2821 
                 ttttttttta aagatggggt cttgctctgt cgccaggctg gagtgcagtg gcgcgatcta 
               
               
                   
               
               
                 2881 
                 ggctcactgc aacttccgcc tcccgggttc aagcgattct cctgcctcag cctcccgagt 
                   
               
               
                   
               
               
                 2941 
                 agctgggact ccactaaaag tacaaaaatt agctgggcgt gcaccactgc gcccagctaa 
               
               
                   
               
               
                 3001 
                 ttcttgtatt tttggtagag acggggtttc aacatgttga ccaggatggt ctcgatctct 
               
               
                   
               
               
                 3061 
                 tgacctcgtg attcgcccgc cgcgtcctcc caaagtgctg ggattacagg cctgagccac 
               
               
                   
               
               
                 3121 
                 cgcgcccagt ctctccccac gttcttgaac tcgggcagca catcctcaca gaaatctagg 
               
               
                   
               
               
                 3181 
                 aactgttggt aggtttcttc ctcgctgtac tccaggcttg cttcggagtc atagtcatcc 
               
               
                   
               
               
                 3241 
                 ctcctgcact gctcctttcc aaacactgta aacatgcttt taataagaag ggtaggactg 
               
               
                   
               
               
                 3301 
                 gatgttggga aatcatgtga acatctatct ccaaatctgc aagctcctgt tttactgtag 
               
               
                   
               
               
                 3361 
                 aagggacaat taactccatc cttctccatg actctgaaat ccaagggggg gttccgggtt 
               
               
                   
               
               
                 3421 
                 ttgccatgtg gcgccatttt ccaactcatt ttcagcctga tccagcatct tctggacagc 
               
               
                   
               
               
                 3481 
                 ttccggtttt tgtttcttct gtcgtttctg ttcctcctcc tctctctctt tcctctgctg 
               
               
                   
               
               
                 3541 
                 ttcttcccat tgttccttta actttcgctc ttgttcttgc cgttttctag ccacctcttc 
               
               
                   
               
               
                 3601 
                 cttttccttc tttattctga attcttcttg tgccttctgc tctctcagca accactcctc 
               
               
                   
               
               
                 3661 
                 atgtaatctt tgcctctctc ttccccatag cttttctagt tgttgttttt caataaaagt 
               
               
                   
               
               
                 3721 
                 gtcctcctct ttctgtgaga gtcctgagtc cctcagtgga gcaagttcct gctggcgttt 
               
               
                   
               
               
                 3781 
                 ctttcgtttc tccttcttca gggcggccct gtactttttg tggcttggtt tctctggaaa 
               
               
                   
               
               
                 3841 
                 tgtcaccttt tcgggcgcag ccatcttgcc ggcaccgccc cgcccctcta gttgtatcct 
               
               
                   
               
               
                 3901 
                 ttataataaa ctggtaaaca ttgtaaccgc agattcagcc caatctggtt caactttgtg 
               
               
                   
               
               
                 3961 
                 taataaaatg gcgagttgtt tttcagttgt cgtggacccc caggttgcaa gttacatacc 
               
               
                   
               
               
                 4021 
                 ctgggcatgt ccagatgaac gaagcgtgca aatccacgtg gaacctaagt gctcagaccg 
               
               
                   
               
               
                 4081 
                 aggaacaggg actgagttaa gaagtggaca ccacgtggca tgatccttga tccaatcaga 
               
               
                   
               
               
                 4141 
                 ttgagccctg gcgtgatcca gtcagatcaa gcctcctgaa tcccctcatt acaagatcca 
               
               
                   
               
               
                 4201 
                 atcatatcat gcctcactac cctctgtata taaaatctgc cccagcctcc aacttggaga 
               
               
                   
               
               
                 4261 
                 gacagatttg ggccagactc ctgtgtcctt gcttggctgc cttgcaataa atttttctct 
               
               
                   
               
               
                 4321 
                 ctacaaaa 
               
               
                   
               
            
           
           
               
               
            
               
                 CD209 antigen isoform 4 sapiens+ +NP_066978.1+ 
                   
               
            
           
           
               
               
               
            
               
                   
                 (SEQ ID NO: 303) 
                   
               
               
                 1 
                 msdskeprlq qlglleeeql rglgfrqtrg ykslagclgh gplvlqllsf tllagllvqv 
                   
               
               
                   
               
               
                 61 
                 skvpssisqe qsrqdaiyqn ltqlkaavge lseksklqei yqeltqlkaa vgelpekskl 
               
               
                   
               
               
                 121 
                 qeiyqeltrl kaavgelpek sklqeiyqel twlkaavgel pekskmqeiy qeltrlkaav 
               
               
                   
               
               
                 181 
                 gelpekskqq eiyqeltrlk aavgelpeks kqqeiyqelt rlkaavgelp ekskqqeiyq 
               
               
                   
               
               
                 241 
                 eltqlkaave rlchpcpwew tffqgncyfm snsqrnwhds itackevgaq lvviksaeeq 
               
               
                   
               
               
                 301 
                 nflqlqssrs nrftwmglsd lnqegtwqwv dgspllpsfk qywnrgepnn vgeedcaefs 
               
               
                   
               
               
                 361 
                 gngwnddkcn lakfwickks aascsrdeeq flspapatpn pppa 
               
            
           
         
       
     
     The mRNA and protein sequences of the other human DC-SIGN isoforms can be found in GeneBank with the following Accession Nos: 
     DC-SIGN isoform 3: NM_001144896.1 (mRNA)→NP_001138368.1 (protein); 
     DC-SIGN isoform 4: NM_001144897.1 (mRNA)→NP_001138369.1 (protein); 
     DC-SIGN isoform 5: NM_001144893.1 (mRNA)→NP_001138365.1 (protein); 
     DC-SIGN isoform 6: NM_001144894.1 (mRNA)→NP_001138366.1 (protein); 
     DC-SIGN isoform 7: NM_001144895.1 (mRNA)→NP_001138367.1 (protein); 
     DC-SIGN isoform 8: NM_001144899.1 (mRNA)→NP_001138371.1 (protein); 
     All the sequences above are hereby incorporated by reference. 
     As used herein, “L-SIGN” (liver/lymph node-specific intracellular adhesion molecules-3 grabbing non-integrin, also known as CLEC4M, CD299; LSIGN; CD209L; DCSIGNR; HP10347; DC-SIGN2; DC-SIGNR) refers to a transmembrane receptor and is referred to as L-SIGN because of its expression in the endothelial cells of the lymph nodes and liver. The protein is involved in the innate immune system and recognizes numerous evolutionarily divergent pathogens ranging from parasites to viruses, with a large impact on public health. The protein is organized into three distinct domains: an N-terminal transmembrane domain, a tandem-repeat neck domain and C-type lectin carbohydrate recognition domain. The extracellular region consisting of the C-type lectin and neck domains has a dual function as a pathogen recognition receptor and a cell adhesion receptor by binding carbohydrate ligands on the surface of microbes and endogenous cells. The neck region is important for homo-oligomerization which allows the receptor to bind multivalent ligands with high avidity. Variations in the number of 23 amino acid repeats in the neck domain of this protein are common and have a significant impact on ligand binding ability. This gene is closely related in terms of both sequence and function to a neighboring gene (GeneID 30835; often referred to as DC-SIGN or CD209). DC-SIGN and L-SIGN differ in their ligand-binding properties and distribution. Alternative splicing results in multiple variants. The human L-SIGN is encoded by the CLEC4M gene (GeneID 10332) which is mapped to chromosomal location 19p13.2, and the genomic sequence of CLEC4M gene can be found in GenBank at NG_029190.1. In human, there are nine L-SIGN isoforms: 1, 2, 3, 7, 8, 9, 10, 11, and 12; the term “L-SIGN” is used herein to refer collectively to all L-SIGN isoforms. As used herein, a human L-SIGN protein also encompasses proteins that have over its full length at least about 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with L-SIGN isoforms: 1, 2, 3, 7, 8, 9, 10, 11, and 12, wherein such proteins still have at least one of the functions of L-SIGN. The mRNA and protein sequences for human L-SIGN isoform 1, the longest isoform, are: 
     
       
         
           
               
               
            
               
                 Homo sapiens C-type lectin domain family 4 member M (CLEC4M),  
                   
               
               
                 transcript variant 1,mRNA +NM_014257.4+ 
               
            
           
           
               
               
               
            
               
                   
                 (SEQ ID NO: 304) 
                   
               
               
                 1 
                 acccagcttc ctgtttgtct tcctgagaga cagtagattt agaaagtgag gatcagaggg 
                   
               
               
                   
               
               
                 61 
                 tggaaaataa aagctgtggt ccccaggagt cctgaacatc tggggacagc gggaaaacat 
               
               
                   
               
               
                 121 
                 gagtgactcc aaggaaccaa gggtgcagca gctgggcctc ctggaagaag atccaacaac 
               
               
                   
               
               
                 181 
                 cagtggcatc agactttttc caagagactt tcaattccag cagatacatg gccacaagag 
               
               
                   
               
               
                 241 
                 ctctacaggg tgtcttggcc atggcgccct ggtgctgcaa ctcctctcct tcatgctctt 
               
               
                   
               
               
                 301 
                 ggctggggtc ctggtggcca tccttgtcca agtgtccaag gtccccagct ccctaagtca 
               
               
                   
               
               
                 361 
                 ggaacaatcc gagcaagacg caatctacca gaacctgacc cagcttaaag ctgcagtggg 
               
               
                   
               
               
                 421 
                 tgagctctca gagaaatcca agctgcagga gatctaccag gagctgaccc agctgaaggc 
               
               
                   
               
               
                 481 
                 tgcagtgggt gagttgccag agaaatccaa gctgcaggag atctaccagg agctgacccg 
               
               
                   
               
               
                 541 
                 gctgaaggct gcagtgggtg agttgccaga gaaatccaag ctgcaggaga tctaccagga 
               
               
                   
               
               
                 601 
                 gctgacccgg ctgaaggctg cagtgggtga gttgccagag aaatccaagc tgcaggagat 
               
               
                   
               
               
                 661 
                 ctaccaggag ctgacccggc tgaaggctgc agtgggtgag ttgccagaga aatccaagct 
               
               
                   
               
               
                 721 
                 gcaggagatc taccaggagc tgacggagct gaaggctgca gtgggtgagt tgccagagaa 
               
               
                   
               
               
                 781 
                 atccaagctg caggagatct accaggagct gacccagctg aaggctgcag tgggtgagtt 
               
               
                   
               
               
                 841 
                 gccagaccag tccaagcagc agcaaatcta tcaagaactg accgatttga agactgcatt 
               
               
                   
               
               
                 901 
                 tgaacgcctg tgccgccact gtcccaagga ctggacattc ttccaaggaa actgttactt 
               
               
                   
               
               
                 961 
                 catgtctaac tcccagcgga actggcacga ctccgtcacc gcctgccagg aagtgagggc 
               
               
                   
               
               
                 1021 
                 ccagctcgtc gtaatcaaaa ctgctgagga gcagaacttc ctacagctgc agacttccag 
               
               
                   
               
               
                 1081 
                 gagtaaccgc ttctcctgga tgggactttc agacctaaat caggaaggca cgtggcaatg 
               
               
                   
               
               
                 1141 
                 ggtggacggc tcacctctgt cacccagctt ccagcggtac tggaacagtg gagaacccaa 
               
               
                   
               
               
                 1201 
                 caatagcggg aatgaagact gtgcggaatt tagtggcagt ggctggaacg acaatcgatg 
               
               
                   
               
               
                 1261 
                 tgacgttgac aattactgga tctgcaaaaa gcccgcagcc tgcttcagag acgaatagtt 
               
               
                   
               
               
                 1321 
                 gtttccctgc tagcctcagc ctccattgtg gtatagcaga acttcaccca cttgtaagcc 
               
               
                   
               
               
                 1381 
                 agcgcttctt ctctccatcc ttggaccttc acaaatgccc tgagacggtt ctctgttcga 
               
               
                   
               
               
                 1441 
                 tttttcatcc cctatgaacc tgggtcttat tctgtccttc tgatgcctcc aagtttccct 
               
               
                   
               
               
                 1501 
                 ggtgtagagc ttgtgttctt ggcccatcct tggagcttta taagtgacct gagtgggatg 
               
               
                   
               
               
                 1561 
                 catttagggg gcgggcttgg tatgttgtat gaatccactc tctgttcctt ttggagatta 
               
               
                   
               
               
                 1621 
                 gactatttgg attcatgtgt agctgccctg tcccctgggg ctttatctca tccatgcaaa 
               
               
                   
               
               
                 1681 
                 ctaccatctg ctcaacttcc agctacaccc cgtgcaccct tttgactggg gacttgctgg 
               
               
                   
               
               
                 1741 
                 ttgaaggagc tcatcttgca ggctggaagc accagggaat taattccccc agtcaaccaa 
               
               
                   
               
               
                 1801 
                 tggcatccag agagggcatg gaggctccat acaacctctt ccacccccac atctttcttt 
               
               
                   
               
               
                 1861 
                 gtcctataca tgtcttccat ttggctgttt ctgagttgta gcctttataa taaagtggta 
               
               
                   
               
               
                 1921 
                 aatgttgtaa ctgcaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaa 
               
               
                   
               
            
           
           
               
               
            
               
                 C-type lectin domain family 4 member M isoform 1 sapiens+ +NP_055072.3+ 
                   
               
            
           
           
               
               
               
            
               
                   
                 (SEQ ID NO: 305) 
                   
               
               
                 1 
                 msdskeprvq qlglleedpt tsgirlfprd fqfqqihghk sstgclghga lvlqllsfml 
                   
               
               
                   
               
               
                 61 
                 lagvlvailv qvskvpssls qeqseqdaiy qnitqlkaav gelseksklq eiyqeltqlk 
               
               
                   
               
               
                 121 
                 aavgelpeks klqeiyqelt rlkaavgelp eksklqeiyq eltrlkaavg elpeksklqe 
               
               
                   
               
               
                 181 
                 iyqeltrlka avgelpeksk lqeiyqelte lkaavgelpe ksklqeiyqe ltqlkaavge 
               
               
                   
               
               
                 241 
                 lpdqskqqqi yqeltdlkta ferlcrhcpk dwtffqgncy fmsnsqrnwh dsvtacqevr 
               
               
                   
               
               
                 301 
                 aqlvvktae eqnflqlqts rsnrfswmgl sdlnqegtwq wydgsplsps fqrywnsgep 
               
               
                   
               
               
                 361 
                 nnsgnedcae fsgsgwndnr cdvdnywick kpaacfrde 
               
            
           
         
       
     
     The mRNA and protein sequences of the other human L-SIGN isoforms can be found in GeneBank with the following Accession Nos: 
     L-SIGN isoform 2: NM_001144904.1 (mRNA)→NP_001138376.1 (protein); 
     L-SIGN isoform 3: NP_001138382.1 (mRNA)→NP_001138383.1 (protein); 
     L-SIGN isoform 7: NM_001144906.1 (mRNA)→NP_001138378.1 (protein); 
     L-SIGN isoform 8: NM_001144910.1 (mRNA)→NP_001138382.1 (protein); 
     L-SIGN isoform 9: NM_001144909.1 (mRNA)→NP_001138381.1 (protein); 
     L-SIGN isoform 10: NM_001144908.1 (mRNA)→NP_001138380.1 (protein); 
     L-SIGN isoform 11: NM_001144907.1 (mRNA)→NP_001138379.1 (protein); 
     L-SIGN isoform 12: NM_001144905.1 (mRNA)→NP_001138377.1 (protein); 
     All the sequences above are hereby incorporated by reference. 
     The term “antibody,” as used herein, refers to a protein, or polypeptide sequence derived from an immunoglobulin molecule that specifically binds to an antigen. Antibodies can be polyclonal or monoclonal, multiple or single chain, or intact immunoglobulins, and may be derived from natural sources or from recombinant sources. A naturally occurring “antibody” is a glycoprotein comprising at least two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds. Each heavy chain is comprised of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region. The heavy chain constant region is comprised of three domains, CH1, CH2 and CH3. Each light chain is comprised of a light chain variable region (abbreviated herein as VL) and a light chain constant region. The light chain constant region is comprised of one domain, CL. The VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR). Each VH and VL is composed of three CDRs and four FRs arranged from amino-terminus to carboxyl-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy and light chains contain a binding domain that interacts with an antigen. The constant regions of the antibodies may mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (C1q) of the classical complement system. An antibody can be a monoclonal antibody, human antibody, humanized antibody, camelised antibody, or chimeric antibody. The antibodies can be of any isotype (e.g., IgG, IgE, IgM, IgD, IgA and IgY), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2) or subclass. 
     The term “antibody fragment” or “antigen-binding fragment” or “functional fragment” refers to at least one portion of an antibody, that retains the ability to specifically interact with (e.g., by binding, steric hinderance, stabilizing/destabilizing, spatial distribution) an epitope of an antigen. Examples of antibody fragments include, but are not limited to, Fab, Fab′, F(ab′) 2 , Fv fragments, scFv antibody fragments, disulfide-linked Fvs (sdFv), a Fd fragment consisting of the VH and CH1 domains, linear antibodies, single domain antibodies such as sdAb (either VL or VH), camelid VHH domains, multi-specific antibodies formed from antibody fragments such as a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region, and an isolated CDR or other epitope binding fragments of an antibody. An antigen binding fragment can also be incorporated into single domain antibodies, maxibodies, minibodies, nanobodies, intrabodies, diabodies, triabodies, tetrabodies, v-NAR and bis-scFv (see, e.g., Hollinger and Hudson, Nature Biotechnology 23:1126-1136, 2005). Antigen binding fragments can also be grafted into scaffolds based on polypeptides such as a fibronectin type III (Fn3) (see U.S. Pat. No. 6,703,199, which describes fibronectin polypeptide minibodies). The term “scFv” refers to a fusion protein comprising at least one antibody fragment comprising a variable region of a light chain and at least one antibody fragment comprising a variable region of a heavy chain, wherein the light and heavy chain variable regions are contiguously linked, e.g., via a synthetic linker, e.g., a short flexible polypeptide linker, and capable of being expressed as a single chain polypeptide, and wherein the scFv retains the specificity of the intact antibody from which it is derived. Unless specified, as used herein an scFv may have the VL and VH variable regions in either order, e.g., with respect to the N-terminal and C-terminal ends of the polypeptide, the scFv may comprise VL-linker-VH or may comprise VH-linker-VL. 
     The terms “complementarity determining region” or “CDR,” as used herein, refer to the sequences of amino acids within antibody variable regions which confer antigen specificity and binding affinity. For example, in general, there are three CDRs in each heavy chain variable region (e.g., HCDR1, HCDR2, and HCDR3) and three CDRs in each light chain variable region (LCDR1, LCDR2, and LCDR3). The precise amino acid sequence boundaries of a given CDR can be determined using any of a number of well-known schemes, including those described by Kabat et al. (1991), “Sequences of Proteins of Immunological Interest,” 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (“Kabat” numbering scheme), Al-Lazikani et al., (1997) JMB 273,927-948 (“Chothia” numbering scheme), or a combination thereof, and ImMunoGenTics (IMGT) numbering (Lefranc, M.-P., The Immunologist, 7, 132-136 (1999); Lefranc, M.-P. et al., Dev. Comp. Immunol., 27, 55-77 (2003) (“IMGT” numbering scheme). In a combined Kabat and Chothia numbering scheme for a given CDR region (for example, HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2 or LC CDR3), in some embodiments, the CDRs correspond to the amino acid residues that are defined as part of the Kabat CDR, together with the amino acid residues that are defined as part of the Chothia CDR. As used herein, the CDRs defined according to the “Chothia” number scheme are also sometimes referred to as “hypervariable loops.” 
     For example, under Kabat, the CDR amino acid residues in the heavy chain variable domain (VH) are numbered 31-35 (HCDR1) (e.g., insertion(s) after position 35), 50-65 (HCDR2), and 95-102 (HCDR3); and the CDR amino acid residues in the light chain variable domain (VL) are numbered 24-34 (LCDR1) (e.g., insertion(s) after position 27), 50-56 (LCDR2), and 89-97 (LCDR3). As another example, under Chothia, the CDR amino acids in the VH are numbered 26-32 (HCDR1) (e.g., insertion(s) after position 31), 52-56 (HCDR2), and 95-102 (HCDR3); and the amino acid residues in VL are numbered 26-32 (LCDR1) (e.g., insertion(s) after position 30), 50-52 (LCDR2), and 91-96 (LCDR3). By combining the CDR definitions of both Kabat and Chothia, the CDRs comprise or consist of, e.g., amino acid residues 26-35 (HCDR1), 50-65 (HCDR2), and 95-102 (HCDR3) in human VH and amino acid residues 24-34 (LCDR1), 50-56 (LCDR2), and 89-97 (LCDR3) in human VL. Under IMGT, the CDR amino acid residues in the VH are numbered approximately 26-35 (CDR1), 51-57 (CDR2) and 93-102 (CDR3), and the CDR amino acid residues in the VL are numbered approximately 27-32 (CDR1), 50-52 (CDR2), and 89-97 (CDR3) (numbering according to “Kabat”). Under IMGT, the CDR regions of an antibody can be determined using the program IMGT/DomainGap Align. 
     The term “epitope” includes any protein determinant capable of specific binding to an immunoglobulin or otherwise interacting with a molecule. Epitopic determinants generally consist of chemically active surface groupings of molecules such as amino acids or carbohydrate or sugar side chains and can have specific three-dimensional structural characteristics, as well as specific charge characteristics. An epitope may be “linear” or “conformational.” Conformational and linear epitopes are distinguished in that the binding to the former but not the latter is lost in the presence of denaturing solvents. 
     The phrases “monoclonal antibody” or “monoclonal antibody composition” as used herein refers to polypeptides, including antibodies, bispecific antibodies, etc., that have substantially identical amino acid sequence or are derived from the same genetic source. This term also includes preparations of antibody molecules of single molecular composition. A monoclonal antibody composition displays a single binding specificity and affinity for a particular epitope. 
     The phrase “human antibody,” as used herein, includes antibodies having variable regions in which both the framework and CDR regions are derived from sequences of human origin. Furthermore, if the antibody contains a constant region, the constant region is also derived from such human sequences, e.g., human germline sequences, or mutated versions of human germline sequences or antibody containing consensus framework sequences derived from human framework sequences analysis, for example, as described in Knappik, et al. (2000. J Mol Biol 296, 57-86). The structures and locations of immunoglobulin variable domains, e.g., CDRs, may be defined using well known numbering schemes, e.g., the Kabat numbering scheme, the Chothia numbering scheme, or a combination of Kabat and Chothia, and ImMunoGenTics (IMGT) numbering (see, e.g., Sequences of Proteins of Immunological Interest, U.S. Department of Health and Human Services (1991), eds. Kabat et al.; Al Lazikani et al., (1997) J. Mol. Bio. 273:927 948); Kabat et al., (1991) Sequences of Proteins of Immunological Interest, 5th edit., NIH Publication no. 91-3242 U.S. Department of Health and Human Services; Chothia et al., (1987) J. Mol. Biol. 196:901-917; Chothia et al., (1989) Nature 342:877-883; Al-Lazikani et al., (1997) J. Mal. Biol. 273:927-948; and Lefranc, M.-P., The Immunologist, 7, 132-136 (1999); Lefranc, M.-P. et al., Dev. Comp. Immunol., 27, 55-77 (2003)). 
     The human antibodies of the invention may include amino acid residues not encoded by human sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo, or a conservative substitution to promote stability or manufacturing). However, the term “human antibody” as used herein, is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences. 
     The phrase “recombinant human antibody” as used herein, includes all human antibodies that are prepared, expressed, created or isolated by recombinant means, such as antibodies isolated from an animal (e.g., a mouse) that is transgenic or transchromosomal for human immunoglobulin genes or a hybridoma prepared therefrom, antibodies isolated from a host cell transformed to express the human antibody, e.g., from a transfectoma, antibodies isolated from a recombinant, combinatorial human antibody library, and antibodies prepared, expressed, created or isolated by any other means that involve splicing of all or a portion of a human immunoglobulin gene, sequences to other DNA sequences. Such recombinant human antibodies have variable regions in which the framework and CDR regions are derived from human germline immunoglobulin sequences. In certain embodiments, however, such recombinant human antibodies can be subjected to in vitro mutagenesis (or, when an animal transgenic for human Ig sequences is used, in vivo somatic mutagenesis) and thus the amino acid sequences of the VH and VL regions of the recombinant antibodies are sequences that, while derived from and related to human germline VH and VL sequences, may not naturally exist within the human antibody germline repertoire in vivo. 
     The term “Fc region” as used herein refers to a polypeptide comprising the CH3, CH2 and at least a portion of the hinge region of a constant domain of an antibody. Optionally, an Fc region may include a CH4 domain, present in some antibody classes. An Fc region may comprise the entire hinge region of a constant domain of an antibody. In one embodiment, the invention comprises an Fc region and a CH1 region of an antibody. In one embodiment, the invention comprises an Fc region CH3 region of an antibody. In another embodiment, the invention comprises an Fc region, a CH1 region and a Ckappa/lambda region from the constant domain of an antibody. In one embodiment, a binding molecule of the invention comprises a constant region, e.g., a heavy chain constant region. In one embodiment, such a constant region is modified compared to a wild-type constant region. That is, the polypeptides of the invention disclosed herein may comprise alterations or modifications to one or more of the three heavy chain constant domains (CH1, CH2 or CH3) and/or to the light chain constant region domain (CL). Example modifications include additions, deletions or substitutions of one or more amino acids in one or more domains. Such changes may be included to optimize effector function, half-life, etc. 
     The term “binding specificity” as used herein refers to the ability of an individual antibody combining site to react with one antigenic determinant and not with a different antigenic determinant. The combining site of the antibody is located in the Fab portion of the molecule and is constructed from the hypervariable regions of the heavy and light chains. Binding affinity of an antibody is the strength of the reaction between a single antigenic determinant and a single combining site on the antibody. It is the sum of the attractive and repulsive forces operating between the antigenic determinant and the combining site of the antibody. 
     The term “affinity” as used herein refers to the strength of interaction between antibody and antigen at single antigenic sites. Within each antigenic site, the variable region of the antibody “arm” interacts through weak non-covalent forces with antigen at numerous sites; the more interactions, the stronger the affinity. 
     The term “conservative sequence modifications” refers to amino acid modifications that do not significantly affect or alter the binding characteristics of the antibody or antibody fragment containing the amino acid sequence. Such conservative modifications include amino acid substitutions, additions and deletions. Modifications can be introduced into an antibody or antibody fragment of the invention by standard techniques known in the art, such as site-directed mutagenesis and PCR-mediated mutagenesis. Conservative amino acid substitutions are ones in which the amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been defined in the art. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine, tryptophan), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). Thus, one or more amino acid residues within an antibody can be replaced with other amino acid residues from the same side chain family and the altered antibody can be tested using the functional assays described herein. 
     The term “homologous” or “identity” refers to the subunit sequence identity between two polymeric molecules, e.g., between two nucleic acid molecules, such as, two DNA molecules or two RNA molecules, or between two polypeptide molecules. When a subunit position in both of the two molecules is occupied by the same monomeric subunit; e.g., if a position in each of two DNA molecules is occupied by adenine, then they are homologous or identical at that position. The homology between two sequences is a direct function of the number of matching or homologous positions; e.g., if half (e.g., five positions in a polymer ten subunits in length) of the positions in two sequences are homologous, the two sequences are 50% homologous; if 90% of the positions (e.g., 9 of 10), are matched or homologous, the two sequences are 90% homologous. Percentage of “sequence identity” can be determined by comparing two optimally aligned sequences over a comparison window, where the fragment of the amino acid sequence in the comparison window may comprise additions or deletions (e.g., gaps or overhangs) as compared to the reference sequence (which does not comprise additions or deletions) for optimal alignment of the two sequences. The percentage can be calculated by determining the number of positions at which the identical amino acid residue occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the window of comparison, and multiplying the result by 100 to yield the percentage of sequence identity. The output is the percent identity of the subject sequence with respect to the query sequence. The percent identity between the two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps, and the length of each gap, which need to be introduced for optimal alignment of the two sequences. 
     The comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm. In a preferred embodiment, the percent identity between two amino acid sequences is determined using the Needleman and Wunsch ((1970) J. Mol. Biol. 48:444-453) algorithm which has been incorporated into the GAP program in the GCG software package (available at www.gcg.com), using either a Blossum 62 matrix or a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a length weight of 1, 2, 3, 4, 5, or 6. In yet another preferred embodiment, the percent identity between two nucleotide sequences is determined using the GAP program in the GCG software package (available at www.gcg.com), using a NWSgapdna.CMP matrix and a gap weight of 40, 50, 60, 70, or 80 and a length weight of 1, 2, 3, 4, 5, or 6. A particularly preferred set of parameters (and the one that should be used unless otherwise specified) are a Blossum 62 scoring matrix with a gap penalty of 12, a gap extend penalty of 4, and a frameshift gap penalty of 5. 
     The percent identity between two amino acid or nucleotide sequences can be determined using the algorithm of E. Meyers and W. Miller ((1989) CABIOS, 4:11-17) which has been incorporated into the ALIGN program (version 2.0), using a PAM120 weight residue table, a gap length penalty of 12 and a gap penalty of 4. 
     The nucleic acid and protein sequences described herein can be used as a “query sequence” to perform a search against public databases to, for example, identify other family members or related sequences. Such searches can be performed using the NBLAST and XBLAST programs (version 2.0) of Altschul, et al. (1990) J. Mol. Biol. 215:403-10. BLAST nucleotide searches can be performed with the NBLAST program, score=100, wordlength=12 to obtain nucleotide sequences homologous to a nucleic acid molecule of the invention. BLAST protein searches can be performed with the XBLAST program, score=50, wordlength=3 to obtain amino acid sequences homologous to protein molecules of the invention. To obtain gapped alignments for comparison purposes, Gapped BLAST can be utilized as described in Altschul et al., (1997) Nucleic Acids Res. 25:3389-3402. When utilizing BLAST and Gapped BLAST programs, the default parameters of the respective programs (e.g., XBLAST and NBLAST) can be used. See www.ncbi.nlm.nih.gov. 
     The terms “cancer” and “cancerous” refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth. Examples of cancer include, but are not limited to, solid tumors and hematological cancers, including carcinoma, lymphoma, blastoma (including medulloblastoma and retinoblastoma), sarcoma (including liposarcoma and synovial cell sarcoma), neuroendocrine tumors (including carcinoid tumors, gastrinoma, and islet cell cancer), mesothelioma, schwannoma (including acoustic neuroma), meningioma, adenocarcinoma, melanoma, and leukemia or lymphoid malignancies. More particular examples of such cancers include squamous cell cancer (e.g. epithelial squamous cell cancer), lung cancer including small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma, neuroblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, urinary tract cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, testicular cancer, esophageal cancer, tumors of the biliary tract, as well as head and neck cancer. Additional cancer indications are disclosed herein. 
     The terms “tumor antigen” or “cancer associated antigen” interchangeably refer to a molecule (typically a protein, carbohydrate or lipid) that is expressed on the surface of a cancer cell, either entirely or as a fragment (e.g., MHC/peptide), and which is useful for the preferential targeting of a pharmacological agent to the cancer cell. In some embodiments, a tumor antigen is a marker expressed by both normal cells and cancer cells, e.g., a lineage marker, e.g., CD19 on B cells. In some embodiments, a tumor antigen is a cell surface molecule that is overexpressed in a cancer cell in comparison to a normal cell, for instance, 1-fold over expression, 2-fold overexpression, 3-fold overexpression or more in comparison to a normal cell. In some embodiments, a tumor antigen is a cell surface molecule that is inappropriately synthesized in the cancer cell, for instance, a molecule that contains deletions, additions or mutations in comparison to the molecule expressed on a normal cell. In some embodiments, a tumor antigen will be expressed exclusively on the cell surface of a cancer cell, entirely or as a fragment (e.g., MHC/peptide), and not synthesized or expressed on the surface of a normal cell. Normally, peptides derived from endogenous proteins fill the pockets of Major histocompatibility complex (MHC) class I molecules, and are recognized by T cell receptors (TCRs) on CD8+T lymphocytes. The MHC class I complexes are constitutively expressed by all nucleated cells. In cancer, virus-specific and/or tumor-specific peptide/MHC complexes represent a unique class of cell surface targets for immunotherapy. 
     The terms “tumor-supporting antigen” or “cancer-supporting antigen” interchangeably refer to a molecule (typically a protein, carbohydrate or lipid) that is expressed on the surface of a cell that is, itself, not cancerous, but supports the cancer cells, e.g., by promoting their growth or survival e.g., resistance to immune cells. The tumor-supporting antigen itself need not play a role in supporting the tumor cells so long as the antigen is present on a cell that supports cancer cells. 
     The terms “combination” or “pharmaceutical combination,” as used herein mean a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients. The term “fixed combination” means that the active ingredients, by way of example, a compound of the invention and one or more additional therapeutic agent, are administered to a subject simultaneously in the form of a single entity or dosage. The term “non-fixed combination” means that the active ingredients, by way of example, a compound of of the invention and one or more additional therapeutic agent, are administered to a subject as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the active ingredients in the body of the subject. The latter also applies to cocktail therapy, e.g. the administration of 3 or more active ingredients. 
     The terms “composition” or “pharmaceutical composition,” as used herein, refers to a mixture of a compound of the invention with at least one and optionally more than one other pharmaceutically acceptable chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients. 
     The term “an optical isomer” or “a stereoisomer”, as used herein, refers to any of the various stereo isomeric configurations which may exist for a given compound of the present invention and includes geometric isomers. It is understood that a substituent may be attached at a chiral center of a carbon atom. The term “chiral” refers to molecules which have the property of non-superimposability on their mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner. Therefore, the invention includes enantiomers, diastereomers or racemates of the compound. “Enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a “racemic” mixture. The term is used to designate a racemic mixture where appropriate. “Diastereoisomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other. The absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer the stereochemistry at each chiral carbon may be specified by either R or S. Resolved compounds whose absolute configuration is unknown can be designated (+) or (−) depending on the direction (dextro- or levorotatory) which they rotate plane polarized light at the wavelength of the sodium D line. Certain compounds described herein contain one or more asymmetric centers or axes and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-. 
     The term “pharmaceutically acceptable carrier”, as used herein, includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drug stabilizers, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, and the like and combinations thereof, as would be known to those skilled in the art (see, for example, Remington&#39;s Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the therapeutic or pharmaceutical compositions is contemplated. 
     The term “pharmaceutically acceptable salt,” as used herein, refers to a salt which does not abrogate the biological activity and properties of the compounds of the invention, and does not cause significant irritation to a subject to which it is administered. 
     The term “subject”, as used herein, encompasses mammals and non-mammals. Examples of mammals include, but are not limited to, humans, chimpanzees, apes, monkeys, cattle, horses, sheep, goats, swine; rabbits, dogs, cats, rats, mice, guinea pigs, and the like. Examples of non-mammals include, but are not limited to, birds, fish and the like. Frequently the subject is a human. 
     The term “a subject in need of such treatment”, refers to a subject which would benefit biologically, medically or in quality of life from such treatment. 
     The term “STING” refers to STtimulator of INterferon Genes receptor, also known as TMEM173, ERIS, MITA, MPYS, SAVI, or NET23). As used herein, the terms “STING” and “STING receptor” are used interchangeably, and include different isoforms and variants of STING. The mRNA and protein sequences for human STING isoform 1, the longest isoform, are: 
     
       
         
           
               
               
            
               
                 Homo sapiens transmembrane protein 173 (TMEM173), transcript variant 1,  
                   
               
               
                 mRNA +NM_198282.3+ 
               
            
           
           
               
               
               
            
               
                   
                 [SEQ ID NO: 932] 
                   
               
               
                 1 
                 tataaaaata gctcttgtta ccggaaataa ctgttcattt ttcactcctc cctcctaggt 
                   
               
               
                   
               
               
                 61 
                 cacacttttc agaaaaagaa tctgcatcct ggaaaccaga agaaaaatat gagacgggga 
               
               
                   
               
               
                 121 
                 atcatcgtgt gatgtgtgtg ctgcctttgg ctgagtgtgt ggagtcctgc tcaggtgtta 
               
               
                   
               
               
                 181 
                 ggtacagtgt gtttgatcgt ggtggcttga ggggaacccg ctgttcagag ctgtgactgc 
               
               
                   
               
               
                 241 
                 ggctgcactc agagaagctg cccttggctg ctcgtagcgc cgggccttct ctcctcgtca 
               
               
                   
               
               
                 301 
                 tcatccagag cagccagtgt ccgggaggca gaagatgccc cactccagcc tgcatccatc 
               
               
                   
               
               
                 361 
                 catcccgtgt cccaggggtc acggggccca gaaggcagcc ttggttctgc tgagtgcctg 
               
               
                   
               
               
                 421 
                 cctggtgacc ctttgggggc taggagagcc accagagcac actctccggt acctggtgct 
               
               
                   
               
               
                 481 
                 ccacctagcc tccctgcagc tgggactgct gttaaacggg gtctgcagcc tggctgagga 
               
               
                   
               
               
                 541 
                 gctgcgccac atccactcca ggtaccgggg cagctactgg aggactgtgc gggcctgcct 
               
               
                   
               
               
                 601 
                 gggctgcccc ctccgccgtg gggccctgtt gctgctgtcc atctatttct actactccct 
               
               
                   
               
               
                 661 
                 cccaaatgcg gtcggcccgc ccttcacttg gatgcttgcc ctcctgggcc tctcgcaggc 
               
               
                   
               
               
                 721 
                 actgaacatc ctcctgggcc tcaagggcct ggccccagct gagatctctg cagtgtgtga 
               
               
                   
               
               
                 781 
                 aaaagggaat ttcaacgtgg cccatgggct ggcatggtca tattacatcg gatatctgcg 
               
               
                   
               
               
                 841 
                 gctgatcctg ccagagctcc aggcccggat tcgaacttac aatcagcatt acaacaacct 
               
               
                   
               
               
                 901 
                 gctacggggt gcagtgagcc agcggctgta tattctcctc ccattggact gtggggtgcc 
               
               
                   
               
               
                 961 
                 tgataacctg agtatggctg accccaacat tcgcttcctg gataaactgc cccagcagac 
               
               
                   
               
               
                 1021 
                 cggtgaccat gctggcatca aggatcgggt ttacagcaac agcatctatg agcttctgga 
               
               
                   
               
               
                 1081 
                 gaacgggcag cgggcgggca cctgtgtcct ggagtacgcc acccccttgc agactttgtt 
               
               
                   
               
               
                 1141 
                 tgccatgtca caatacagtc aagctggctt tagccgggag gataggcttg agcaggccaa 
               
               
                   
               
               
                 1201 
                 actcttctgc cggacacttg aggacatcct ggcagatgcc cctgagtctc agaacaactg 
               
               
                   
               
               
                 1261 
                 ccgcctcatt gcctaccagg aacctgcaga tgacagcagc ttctcgctgt cccaggaggt 
               
               
                   
               
               
                 1321 
                 tctccggcac ctgcggcagg aggaaaagga agaggttact gtgggcagct tgaagacctc 
               
               
                   
               
               
                 1381 
                 agcggtgccc agtacctcca cgatgtccca agagcctgag ctcctcatca gtggaatgga 
               
               
                   
               
               
                 1441 
                 aaagcccctc cctctccgca cggatttctc ttgagaccca gggtcaccag gccagagcct 
               
               
                   
               
               
                 1501 
                 ccagtggtct ccaagcctct ggactggggg ctctcttcag tggctgaatg tccagcagag 
               
               
                   
               
               
                 1561 
                 ctatttcctt ccacaggggg ccttgcaggg aagggtccag gacttgacat cttaagatgc 
               
               
                   
               
               
                 1621 
                 gtcttgtccc cttgggccag tcatttcccc tctctgagcc tcggtgtctt caacctgtga 
               
               
                   
               
               
                 1681 
                 aatgggatca taatcactgc cttacctccc tcacggttgt tgtgaggact gagtgtgtgg 
               
               
                   
               
               
                 1741 
                 aagtttttca taaactttgg atgctagtgt acttaggggg tgtgccaggt gtctttcatg 
               
               
                   
               
               
                 1801 
                 gggccttcca gacccactcc ccacccttct ccccttcctt tgcccgggga cgccgaactc 
               
               
                   
               
               
                 1861 
                 tctcaatggt atcaacaggc tccttcgccc tctggctcct ggtcatgttc cattattggg 
               
               
                   
               
               
                 1921 
                 gagccccagc agaagaatgg agaggaggag gaggctgagt ttggggtatt gaatcccccg 
               
               
                   
               
               
                 1981 
                 gctcccaccc tgcagcatca aggttgctat ggactctcct gccgggcaac tcttgcgtaa 
               
               
                   
               
               
                 2041 
                 tcatgactat ctctaggatt ctggcaccac ttccttccct ggccccttaa gcctagctgt 
               
               
                   
               
               
                 2101 
                 gtatcggcac ccccacccca ctagagtact ccctctcact tgcggtttcc ttatactcca 
               
               
                   
               
               
                 2161 
                 cccctttctc aacggtcctt ttttaaagca catctcagat tacccaaaaa aaaaaaaaaa 
               
               
                   
               
               
                 2221 
                 aaa 
               
               
                   
               
            
           
           
               
               
            
               
                 Homo sapiens stimulator of interferon genes protein isoform 1 +NP_938023.1+ 
                   
               
               
                 [SEQ ID NO: 933] 
                   
               
               
                 MPHSSLHPSIPCPRGHGAQKAALVLLSACLVTLWGLGEPPEHTLRYLVL 
                   
               
               
                   
               
               
                 HLASLQLGLLLNGVCSLAEELRHIHSRYRGSYWRTVRACLGCPLRRGAL 
               
               
                   
               
               
                 LLLSIYFYYSLPNAVGPPFTWMLALLGLSQALNILLGLKGLAPAEISAV 
               
               
                   
               
               
                 CEKGNFNVAHGLAWSYYIGYLRLILPELQARIRTYNQHYNNLLRGAVSQ 
               
               
                   
               
               
                 RLYILLPLDCGVPDNLSMADPNIRFLDKLPQQTGDHAGIKDRVYSNSIY 
               
               
                   
               
               
                 ELLENGQRAGTCVLEYATPLQTLFAMSQYSQAGFSREDRLEQAKLFCRT 
               
               
                   
               
               
                 LEDILADAPESQNNCRLIAYQEPADDSSFSLSQEVLRHLRQEEKEEVTV 
               
               
                   
               
               
                 GSLKTSAVPSTSTMSQEPELLISGMEKPLPLRTDFS 
               
            
           
         
       
     
     The mRNA and protein sequences for human STING isoform 2, a shorter isoform, are: 
     
       
         
           
               
               
            
               
                 Homo sapiens transmembrane protein 173 (TMEM173), transcript variant 2,  
                   
               
               
                 mRNA +NM_001301738.1+ 
               
               
                 [SEQ ID NO: 934] 
                   
               
            
           
           
               
               
               
            
               
                 1 
                 gctgcactca gagaagctgc ccttggctgc tcgtagcgcc gggccttctc tcctcgtcat 
                   
               
               
                   
               
               
                 61 
                 catccagagc agccagtgtc cgggaggcag aagatgcccc actccagcct gcatccatcc 
               
               
                   
               
               
                 121 
                 atcccgtgtc ccaggggtca cggggcccag aaggcagcct tggttctgct gagtgcctgc 
               
               
                   
               
               
                 181 
                 ctggtgaccc tttgggggct aggagagcca ccagagcaca ctctccggta cctggtgctc 
               
               
                   
               
               
                 241 
                 cacctagcct ccctgcagct gggactgctg ttaaacgggg tctgcagcct ggctgaggag 
               
               
                   
               
               
                 301 
                 ctgcgccaca tccactccag gtaccggggc agctactgga ggactgtgcg ggcctgcctg 
               
               
                   
               
               
                 361 
                 ggctgccccc tccgccgtgg ggccctgttg ctgctgtcca tctatttcta ctactccctc 
               
               
                   
               
               
                 421 
                 ccaaatgcgg tcggcccgcc cttcacttgg atgcttgccc tcctgggcct ctcgcaggca 
               
               
                   
               
               
                 481 
                 ctgaacatcc tcctgggcct caagggcctg gccccagctg agatctctgc agtgtgtgaa 
               
               
                   
               
               
                 541 
                 aaagggaatt tcaacgtggc ccatgggctg gcatggtcat attacatcgg atatctgcgg 
               
               
                   
               
               
                 601 
                 ctgatcctgc cagagctcca ggcccggatt cgaacttaca atcagcatta caacaacctg 
               
               
                   
               
               
                 661 
                 ctacggggtg cagtgagcca gcggctgtat attctcctcc cattggactg tggggtgcct 
               
               
                   
               
               
                 721 
                 gataacctga gtatggctga ccccaacatt cgcttcctgg ataaactgcc ccagcagacc 
               
               
                   
               
               
                 781 
                 ggtgaccatg ctggcatcaa ggatcgggtt tacagcaaca gcatctatga gcttctggag 
               
               
                   
               
               
                 841 
                 aacgggcagc ggaacctgca gatgacagca gcttctcgct gtcccaggag gttctccggc 
               
               
                   
               
               
                 901 
                 acctgcggca ggaggaaaag gaagaggtta ctgtgggcag cttgaagacc tcagcggtgc 
               
               
                   
               
               
                 961 
                 ccagtacctc cacgatgtcc caagagcctg agctcctcat cagtggaatg gaaaagcccc 
               
               
                   
               
               
                 1021 
                 tccctctccg cacggatttc tcttgagacc cagggtcacc aggccagagc ctccagtggt 
               
               
                   
               
               
                 1081 
                 ctccaagcct ctggactggg ggctctcttc agtggctgaa tgtccagcag agctatttcc 
               
               
                   
               
               
                 1141 
                 ttccacaggg ggccttgcag ggaagggtcc aggacttgac atcttaagat gcgtcttgtc 
               
               
                   
               
               
                 1201 
                 cccttgggcc agtcatttcc cctctctgag cctcggtgtc ttcaacctgt gaaatgggat 
               
               
                   
               
               
                 1261 
                 cataatcact gccttacctc cctcacggtt gttgtgagga ctgagtgtgt ggaagttttt 
               
               
                   
               
               
                 1321 
                 cataaacttt ggatgctagt gtacttaggg ggtgtgccag gtgtctttca tggggccttc 
               
               
                   
               
               
                 1381 
                 cagacccact ccccaccctt ctccccttcc tttgcccggg gacgccgaac tctctcaatg 
               
               
                   
               
               
                 1441 
                 gtatcaacag gctccttcgc cctctggctc ctggtcatgt tccattattg gggagcccca 
               
               
                   
               
               
                 1501 
                 gcagaagaat ggagaggagg aggaggctga gtttggggta ttgaatcccc cggctcccac 
               
               
                   
               
               
                 1561 
                 cctgcagcat caaggttgct atggactctc ctgccgggca actcttgcgt aatcatgact 
               
               
                   
               
               
                 1621 
                 atctctagga ttctggcacc acttccttcc ctggcccctt aagcctagct gtgtatcggc 
               
               
                   
               
               
                 1681 
                 acccccaccc cactagagta ctccctctca cttgcggttt ccttatactc cacccctttc 
               
               
                   
               
               
                 1741 
                 tcaacggtcc ttttttaaag cacatctcag attacccaaa aaaaaaaaaa aaaaa 
               
               
                   
               
            
           
           
               
               
            
               
                 Homo sapiens stimulator of interferon genes protein isoform 2 +NP_001288667.1+ 
                   
               
               
                 [SEQ ID NO: 935] 
                   
               
               
                 MPHSSLHPSIPCPRGHGAQKAALVLLSACLVTLWGLGEPPEHTLRYLVL 
                   
               
               
                   
               
               
                 HLASLQLGLLLNGVCSLAEELRHIHSRYRGSYWRTVRACLGCPLRRGAL 
               
               
                   
               
               
                 LLLSIYFYYSLPNAVGPPFTWMLALLGLSQALNILLGLKGLAPAEISAV 
               
               
                   
               
               
                 CEKGNFNVAHGLAWSYYIGYLRLILPELQARIRTYNQHYNNLLRGAVSQ 
               
               
                   
               
               
                 RLYILLPLDCGVPDNLSMADPNIRFLDKLPQQTGDHAGIKDRVYSNSIY 
               
               
                   
               
               
                 ELLENGQRNLQMTAASRCPRRFSGTCGRRKRKRLLWAA 
               
            
           
         
       
     
     The sequences of other human STING isoforms/SNPs (single nucleotide polymorphisms) include the following and those described in Yi, PLoS One. 2013 Oct. 21; 8(10):e77846. 
     
       
         
           
               
            
               
                 hSTING wt (wild type): Reference SNP (refSNP)  
               
               
                 Cluster Report: rs1131769 
               
               
                 [SEQ ID NO: 936] 
               
               
                 atgccccactccagcctgcatccatccatcccgtgtcccaggggtcacg 
               
               
                   
               
               
                 gggcccagaaggcagccttggttctgctgagtgcctgcctggtgaccct 
               
               
                   
               
               
                 ttgggggctaggagagccaccagagcacactctccggtacctggtgctc 
               
               
                   
               
               
                 cacctagcctccctgcagctgggactgctgttaaacggggtctgcagcc 
               
               
                   
               
               
                 tggctgaggagctgcgccacatccactccaggtaccggggcagctactg 
               
               
                   
               
               
                 gaggactgtgcgggcctgcctgggctgccccctccgccgtggggccctg 
               
               
                   
               
               
                 ttgctgctgtccatctatttctactactccctcccaaatgcggtcggcc 
               
               
                   
               
               
                 cgcccttcacttggatgcttgccctcctgggcctctcgcaggcactgaa 
               
               
                   
               
               
                 catcctcctgggcctcaagggcctggccccagctgagatctctgcagtg 
               
               
                   
               
               
                 tgtgaaaaagggaatttcaacgtggcccatgggctggcatggtcatatt 
               
               
                   
               
               
                 acatcggatatctgcggctgatcctgccagagctccaggcccggattcg 
               
               
                   
               
               
                 aacttacaatcagcattacaacaacctgctacggggtgcagtgagccag 
               
               
                   
               
               
                 cggctgtatattctcctcccattggactgtggggtgcctgataacctga 
               
               
                   
               
               
                 gtatggctgaccccaacattcgcttcctggataaactgccccagcagac 
               
               
                   
               
               
                 cggtgaccgtgctggcatcaaggatcgggtttacagcaacagcatctat 
               
               
                   
               
               
                 gagcttctggagaacgggcagcgggcgggcacctgtgtcctggagtacg 
               
               
                   
               
               
                 ccacccccttgcagactttgtttgccatgtcacaatacagtcaagctgg 
               
               
                   
               
               
                 ctttagccgggaggataggcttgagcaggccaaactcttctgccggaca 
               
               
                   
               
               
                 cttgaggacatcctggcagatgcccctgagtctcagaacaactgccgcc 
               
               
                   
               
               
                 tcattgcctaccaggaacctgcagatgacagcagcttctcgctgtccca 
               
               
                   
               
               
                 ggaggttctccggcacctgcggcaggaggaaaaggaagaggttactgtg 
               
               
                   
               
               
                 ggcagcttgaagacctcagcggtgcccagtacctccacgatgtcccaag 
               
               
                   
               
               
                 agcctgagctcctcatcagtggaatggaaaagcccctccctctccgcac 
               
               
                   
               
               
                 ggatttctcttga 
               
               
                   
               
               
                 hSTING R293Q: Reference SNP (refSNP) Cluster   
               
               
                 Report: rs1131769 rs7380824 
               
               
                 [SEQ ID NO: 937] 
               
               
                 atgccccactccagcctgcatccatccatcccgtgtcccaggggtcacg 
               
               
                   
               
               
                 gggcccagaaggcagccttggttctgctgagtgcctgcctggtgaccct 
               
               
                   
               
               
                 ttgggggctaggagagccaccagagcacactctccggtacctggtgctc 
               
               
                   
               
               
                 cacctagcctccctgcagctgggactgctgttaaacggggtctgcagcc 
               
               
                   
               
               
                 tggctgaggagctgcgccacatccactccaggtaccggggcagctactg 
               
               
                   
               
               
                 gaggactgtgcgggcctgcctgggctgccccctccgccgtggggccctg 
               
               
                   
               
               
                 ttgctgctgtccatctatttctactactccctcccaaatgcggtcggcc 
               
               
                   
               
               
                 cgcccttcacttggatgcttgccctcctgggcctctcgcaggcactgaa 
               
               
                   
               
               
                 catcctcctgggcctcaagggcctggccccagctgagatctctgcagtg 
               
               
                   
               
               
                 tgtgaaaaagggaatttcaacgtggcccatgggctggcatggtcatatt 
               
               
                   
               
               
                 acatcggatatctgcggctgatcctgccagagctccaggcccggattcg 
               
               
                   
               
               
                 aacttacaatcagcattacaacaacctgctacggggtgcagtgagccag 
               
               
                   
               
               
                 cggctgtatattctcctcccattggactgtggggtgcctgataacctga 
               
               
                   
               
               
                 gtatggctgaccccaacattcgcttcctggataaactgccccagcagac 
               
               
                   
               
               
                 cggtgaccgtgctggcatcaaggatcgggtttacagcaacagcatctat 
               
               
                   
               
               
                 gagcttctggagaacgggcagcgggcgggcacctgtgtcctggagtacg 
               
               
                   
               
               
                 ccacccccttgcagactttgtttgccatgtcacaatacagtcaagctgg 
               
               
                   
               
               
                 ctttagccgggaggataggcttgagcaggccaaactcttctgccagaca 
               
               
                   
               
               
                 cttgaggacatcctggcagatgcccctgagtctcagaacaactgccgcc 
               
               
                   
               
               
                 tcattgcctaccaggaacctgcagatgacagcagcttctcgctgtccca 
               
               
                   
               
               
                 ggaggttctccggcacctgcggcaggaggaaaaggaagaggttactgtg 
               
               
                   
               
               
                 ggcagcttgaagacctcagcggtgcccagtacctccacgatgtcccaag 
               
               
                   
               
               
                 agcctgagctcctcatcagtggaatggaaaagcccctccctctccgcac 
               
               
                   
               
               
                 ggatttctcttga 
               
               
                   
               
               
                 hSTING G230A/R293Q: Reference SNP (refSNP)    
               
               
                 ClusterReport:rs1131769 rs7380824 rs78233829 
               
               
                 [SEQ ID NO: 938] 
               
               
                 atgccccactccagcctgcatccatccatcccgtgtcccaggggtcacg 
               
               
                   
               
               
                 gggcccagaaggcagccttggttctgctgagtgcctgcctggtgaccct 
               
               
                   
               
               
                 ttgggggctaggagagccaccagagcacactctccggtacctggtgctc 
               
               
                   
               
               
                 cacctagcctccctgcagctgggactgctgttaaacggggtctgcagcc 
               
               
                   
               
               
                 tggctgaggagctgcgccacatccactccaggtaccggggcagctactg 
               
               
                   
               
               
                 gaggactgtgcgggcctgcctgggctgccccctccgccgtggggccctg 
               
               
                   
               
               
                 ttgctgctgtccatctatttctactactccctcccaaatgcggtcggcc 
               
               
                   
               
               
                 cgcccttcacttggatgcttgccctcctgggcctctcgcaggcactgaa 
               
               
                   
               
               
                 catcctcctgggcctcaagggcctggccccagctgagatctctgcagtg 
               
               
                   
               
               
                 tgtgaaaaagggaatttcaacgtggcccatgggctggcatggtcatatt 
               
               
                   
               
               
                 acatcggatatctgcggctgatcctgccagagctccaggcccggattcg 
               
               
                   
               
               
                 aacttacaatcagcattacaacaacctgctacggggtgcagtgagccag 
               
               
                   
               
               
                 cggctgtatattctcctcccattggactgtggggtgcctgataacctga 
               
               
                   
               
               
                 gtatggctgaccccaacattcgcttcctggataaactgccccagcagac 
               
               
                   
               
               
                 cgctgaccgtgctggcatcaaggatcgggtttacagcaacagcatctat 
               
               
                   
               
               
                 gagcttctggagaacgggcagcgggcgggcacctgtgtcctggagtacg 
               
               
                   
               
               
                 ccacccccttgcagactttgtttgccatgtcacaatacagtcaagctgg 
               
               
                   
               
               
                 ctttagccgggaggataggcttgagcaggccaaactcttctgccagaca 
               
               
                   
               
               
                 cttgaggacatcctggcagatgcccctgagtctcagaacaactgccgcc 
               
               
                   
               
               
                 tcattgcctaccaggaacctgcagatgacagcagcttctcgctgtccca 
               
               
                   
               
               
                 ggaggttctccggcacctgcggcaggaggaaaaggaagaggttactgtg 
               
               
                   
               
               
                 ggcagcttgaagacctcagcggtgcccagtacctccacgatgtcccaag 
               
               
                   
               
               
                 agcctgagctcctcatcagtggaatggaaaagcccctccctctccgcac 
               
               
                   
               
               
                 ggatttctcttga 
               
               
                   
               
               
                 hSTING R71H/G230A/R293Q: Reference SNP (refSNP)  
               
               
                 Cluster Report:rs1131769 rs7380824 rs78233829  
               
               
                 rs11554776 
               
               
                 [SEQ ID NO: 939] 
               
               
                 atgccccactccagcctgcatccatccatcccgtgtcccaggggtcacg 
               
               
                   
               
               
                 gggcccagaaggcagccttggttctgctgagtgcctgcctggtgaccct 
               
               
                   
               
               
                 ttgggggctaggagagccaccagagcacactctccggtacctggtgctc 
               
               
                   
               
               
                 cacctagcctccctgcagctgggactgctgttaaacggggtctgcagcc 
               
               
                   
               
               
                 tggctgaggagctgcaccacatccactccaggtaccggggcagctactg 
               
               
                   
               
               
                 gaggactgtgcgggcctgcctgggctgccccctccgccgtggggccctg 
               
               
                   
               
               
                 ttgctgctgtccatctatttctactactccctcccaaatgcggtcggcc 
               
               
                   
               
               
                 cgcccttcacttggatgcttgccctcctgggcctctcgcaggcactgaa 
               
               
                   
               
               
                 catcctcctgggcctcaagggcctggccccagctgagatctctgcagtg 
               
               
                   
               
               
                 tgtgaaaaagggaatttcaacgtggcccatgggctggcatggtcatatt 
               
               
                   
               
               
                 acatcggatatctgcggctgatcctgccagagctccaggcccggattcg 
               
               
                   
               
               
                 aacttacaatcagcattacaacaacctgctacggggtgcagtgagccag 
               
               
                   
               
               
                 cggctgtatattctcctcccattggactgtggggtgcctgataacctga 
               
               
                   
               
               
                 gtatggctgaccccaacattcgcttcctggataaactgccccagcagac 
               
               
                   
               
               
                 cgctgaccgtgctggcatcaaggatcgggtttacagcaacagcatctat 
               
               
                   
               
               
                 gagcttctggagaacgggcagcgggcgggcacctgtgtcctggagtacg 
               
               
                   
               
               
                 ccacccccttgcagactttgtttgccatgtcacaatacagtcaagctgg 
               
               
                   
               
               
                 ctttagccgggaggataggcttgagcaggccaaactcttctgccagaca 
               
               
                   
               
               
                 cttgaggacatcctggcagatgcccctgagtctcagaacaactgccgcc 
               
               
                   
               
               
                 tcattgcctaccaggaacctgcagatgacagcagcttctcgctgtccca 
               
               
                   
               
               
                 ggaggttctccggcacctgcggcaggaggaaaaggaagaggttactgtg 
               
               
                   
               
               
                 ggcagcttgaagacctcagcggtgcccagtacctccacgatgtcccaag 
               
               
                   
               
               
                 agcctgagctcctcatcagtggaatggaaaagcccctccctctccgcac 
               
               
                   
               
               
                 ggatttctcttga 
               
            
           
         
       
     
     The term “STING agonist”, as used herein, refers to a compound or antibody conjugate capable of binding to STING and activating STING. Activation of STING activity may include, for example, stimulation of inflammatory cytokines, including interferons, such as type 1 interferons, including IFN-α, IFN-β, type 3 interferons, e.g., IFNλ, IP10, TNF, IL-6, CXCL9, CCL4, CXCL11, CCL5, CCL3, or CCL8. STING agonist activity may also include stimulation of TANK binding kinase (TBK) 1 phosphorylation, interferon regulatory factor (IRF) activation (e.g., IRF3 activation), secretion of interferon-γ-inducible protein (IP-10), or other inflammatory proteins and cytokines. STING Agonist activity may be determined, for example, by the ability of a compound to stimulate activation of the STING pathway as detected using an interferon stimulation assay, a reporter gene assay (e.g., a hSTING wt assay, or a THP-1 Dual assay), a TBK1 activation assay, IP-10 assay, a STING Biochemical [3H]cGAMP Competition Assay, or other assays known to persons skilled in the art. STING Agonist activity may also be determined by the ability of a compound to increase the level of transcription of genes that encode proteins activated by STING or the STING pathway. Such activity may be detected, for example, using an RNAseq assay. In some embodiments, an assay to test for activity of a compound in a STING knock-out cell line may be used to determine if the compound is specific for STING, wherein a compound that is specific for STING would not be expected to have activity in a cell line wherein the STING pathway is partially or wholly deleted. 
     As used herein, the terms “treat,” “treating,” or “treatment” of any disease or disorder refers in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment, “treat,” “treating,” or “treatment” refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient. In yet another embodiment, “treat,” “treating,” or “treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. 
     As used herein, the term “prevent”, “preventing” or “prevention” of any disease or disorder refers to the prophylactic treatment of the disease or disorder; or delaying the onset or progression of the disease or disorder 
     The term “therapeutically effective amount” or “therapeutically effective dose” interchangeably refers to an amount sufficient to effect the desired result (i.e., reduction or inhibition of an enzyme or a protein activity, amelioration of symptoms, alleviation of symptoms or conditions, delay of disease progression, a reduction in tumor size, inhibition of tumor growth, prevention of metastasis, inhibition or prevention of viral, bacterial, fungal or parasitic infection). 
     In some embodiments, a therapeutically effective amount does not induce or cause undesirable side effects. In some embodiments, a therapeutically effective amount induces or causes side effects but only those that are acceptable by the healthcare providers in view of a patient&#39;s condition. A therapeutically effective amount can be determined by first administering a low dose, and then incrementally increasing that dose until the desired effect is achieved. A “prophylactically effective dose” or a “prophylactically effect amount”, of the molecules of the invention can prevent the onset of disease symptoms, including symptoms associated with cancer. A “therapeutically effective dose” or a “therapeutically effective amount” of the molecules of the invention can result in a decrease in severity of disease symptoms, including symptoms associated with cancer. The compound names provided herein were obtained using ChemDraw Ultra version 14.0 (CambridgeSoft®). 
     As used herein, the term “a,” “an,” “the” and similar terms used in the context of the present invention (especially in the context of the claims) are to be construed to cover both the singular and plural unless otherwise indicated herein or clearly contradicted by the context. 
     Any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulae given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Isotopes that can be incorporated into compounds of the invention include, for example, isotopes of hydrogen. 
     Unless specified otherwise, the conjugates or Drug moieties of the present invention refer to compounds of any of formulae (AA-a) through (FF-g) or formulae (A) through (F) or subformulae thereof and exemplified compounds, and salts thereof, as well as all stereoisomers (including diastereoisomers and enantiomers), rotamers, tautomers and isotopically labeled compounds (including deuterium substitutions), as well as inherently formed moieties. 
     Immunostimulatory Compounds of the Invention 
     Drug Moiety (D) 
     The Drug moiety (D) of the immunoconjugates of the invention is a compound which binds to Stimulator of Interferon Genes (STING) receptor and which comprises one or more reactive moieties each of which is capable of forming a covalent bond with a linker (L). In one aspect, Drug moiety (D) of the immunoconjugates of the invention is a dinucleotide which binds to Stimulator of Interferon Genes (STING) which comprises one or more reactive moieties capable of forming a covalent bond with a linker (L). 
     In one aspect, Drug moiety (D) of the immunoconjugates of the invention is a cyclic dinucleotide which binds to Stimulator of Interferon Genes (STING) which comprises one or more reactive moieties capable of forming a covalent bond with a linker (L). 
     In one aspect the Drug moiety (D) of the immunoconjugates of the invention is a compound having the structure of Formula (A), Formula (B), Formula (C), Formula (D), Formula (E), or Formula (F) or stereoisomers or pharmaceutically acceptable salts thereof, 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     wherein:
     each G 1  is independently selected from   

     
       
         
         
             
             
         
       
     
     where the * of G 1  indicates the point of attachment to —CR 8 R 9 —;
     X A  is C(═O)—, —C(═S)— or —C(═NR 11 )— and each Z 1  is NR 12 ;   X B  is C, and each Z 2  is N;   G 2  is   

     
       
         
         
             
             
         
       
     
     where the * of G 2  indicates the point of attachment to —CR 8a R 9a —;
     X C  is C(═O)—, —C(═S)— or —C(═NR 11 )— and each Z 3  is NR 12 ;   X D  is C, and each Z 4  is N;   Y 1  is —O—, —S—, —S(═O)—, —SO 2 —, —CH 2 —, or —CF 2 —;   Y 2  is —O—, —S—, —S(═O)—, —SO 2 —, —CH 2 —, or —CF 2 —;   Y 3  is OH, O − , OR 10 , N(R 10 ) 2 , SR 10 , SeH, Se − , BH 3 , SH or S − ;   Y 4  is OH, O − , OR 10 , N(R 10 ) 2 , SR 10 , SeH, Se − , BH 3 , SH or S − ;   Y 5  is —CH 2 —, —NH—, —O— or —S;   Y 6  is —CH 2 —, —NH—, —O— or —S;   Y 7  is O or S;   Y 8  is O or S;   Y 9  is —CH 2 —, —NH—, —O— or —S;   Y 10  is —CH 2 —, —NH—, —O— or —S;   Y 11  is —O—, —S—, —S(═O)—, —SO 2 —, —CH 2 —, or —CF 2 —;   q is 1, 2 or 3;   R 1  is a partially saturated or aromatic monocyclic heterocyclyl or partially saturated or aromatic fused bicyclic heterocyclyl containing from 5-10 ring members selected from carbon atoms and 1 to 5 heteroatoms, and each heteroatoms is independently selected from O, N or S, or a tautomer thereof, wherein R 1  is substituted with 0, 1, 2, 3 or 4 substituents independently selected from F, Cl, Br, OH, SH, NH 2 , D, CD 3 , C 1 -C 6 alkyl, C 1 -C 6 alkoxyalkyl, C 1 -C 6 hydroxyalkyl, C 3 -C 8 cycloalkyl, a 3 to 6 membered heterocyclyl having 1 to 2 heteroatoms independently selected from O, N and S, —O(C 1 -C 6 alkyl), —O(C 3 -C 8 cycloalkyl), —S(C 1 -C 6 alkyl), —S(C 1 -C 6 aminoalkyl), —S(C 1 -C 6 hydroxyalkyl), —S(C 3 -C 8 cycloalkyl), —NH(C 1 -C 6 alkyl), —NH(C 3 -C 8 cycloalkyl), —N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 alkyl) (C 3 -C 8 cycloalkyl), —CN, —P(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —(CH 2 ) 1-10 C(═O)OH, —CH═CH(CH 2 ) 1-10 C(═O)OH, —NHC(O)(C 1 -C 6 alkyl), —NHC(O)(C 3 -C 8 cycloalkyl), —NHC(O)(phenyl), and —N(C 3 -C 8 cycloalkyl) 2 ;   R 1a  is a partially saturated or aromatic monocyclic heterocyclyl or partially saturated or aromatic fused bicyclic heterocyclyl containing from 5-10 ring members selected from carbon atoms and 1 to 5 heteroatoms, and each heteroatoms is independently selected from O, N or S, or a tautomer thereof, wherein R 1a  is substituted with 0, 1, 2, 3 or 4 substituents independently selected from F, Cl, Br, OH, SH, NH 2 , D, CD 3 , C 1 -C 6 alkyl, C 1 -C 6 alkoxyalkyl, C 1 -C 6 hydroxyalkyl, C 3 -C 8 cycloalkyl, a 3 to 6 membered heterocyclyl having 1 to 2 heteroatoms independently selected from O, N and S, —O(C 1 -C 6 alkyl), —O(C 3 -C 8 cycloalkyl), —S(C 1 -C 6 alkyl), —S(C 1 -C 6 aminoalkyl), —S(C 1 -C 6 hydroxyalkyl), —S(C 3 -C 8 cycloalkyl), —NH(C 1 -C 6 alkyl), —NH(C 3 -C 8 cycloalkyl), —N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 alkyl) (C 3 -C 8 cycloalkyl), —CN, —P(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —(CH 2 ) 1-10 C(═O)OH, —CH═CH(CH 2 ) 1-10 C(═O)OH, —NHC(O)(C 1 -C 6 alkyl), —NHC(O)(C 3 -C 8 cycloalkyl), —NHC(O)(phenyl), and —N(C 3 -C 8 cycloalkyl) 2 ;   R 1b  is a partially saturated or aromatic monocyclic heterocyclyl or partially saturated or aromatic fused bicyclic heterocyclyl containing from 5-10 ring members selected from carbon atoms and 1 to 5 heteroatoms, and each heteroatoms is independently selected from O, N or S, or a tautomer thereof, wherein R 1b  is substituted with 0, 1, 2, 3 or 4 substituents independently selected from F, Cl, Br, OH, SH, NH 2 , D, CD 3 , C 1 -C 6 alkyl, C 1 -C 6 alkoxyalkyl, C 1 -C 6 hydroxyalkyl, C 3 -C 8 cycloalkyl, a 3 to 6 membered heterocyclyl having 1 to 2 heteroatoms independently selected from O, N and S, —O(C 1 -C 6 alkyl), —O(C 3 -C 8 cycloalkyl), —S(C 1 -C 6 alkyl), —S(C 1 -C 6 aminoalkyl), —S(C 1 -C 6 hydroxyalkyl), —S(C 3 -C 8 cycloalkyl), —NH(C 1 -C 6 alkyl), —NH(C 3 -C 8 cycloalkyl), —N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 alkyl) (C 3 -C 8 cycloalkyl), —CN, —P(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —(CH 2 ) 1-10 C(═O)OH, —CH═CH(CH 2 ) 1-10 C(═O)OH, —NHC(O)(C 1 -C 6 alkyl), —NHC(O)(C 3 -C 8 cycloalkyl), —NHC(O)(phenyl), and —N(C 3 -C 8 cycloalkyl) 2 ;   each R 2  is independently selected from the group consisting of H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 2  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 2  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;   each R 3  is independently selected from the group consisting of H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 3  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 3  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;   each R 4  is independently selected from the group consisting of H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 4  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 4  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;   each R 5  is independently selected from the group consisting of H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 5  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 5  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;   each R 6  is independently selected from the group consisting of H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 6  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 6  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;   each R 7  is independently selected from the group consisting of H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 7  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 7  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;   each R 8  is independently selected from the group consisting of H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 8  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 8  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;   each R 9  is independently selected from the group consisting of H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 9  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 9  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;   R 2a  is selected from the group consisting of H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 2a  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 2a  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3      R 3a  is selected from the group consisting of H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 3a  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 3a  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;   R 4a  is selected from the group consisting of H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 4a  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 4a  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;   R 5a  is selected from the group consisting of H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 5a  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 5a  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;   R 6a  is selected from the group consisting of H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 6a  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 6a  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;   R 7a  is selected from the group consisting of H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 7a  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 7a  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;   R 8a  is selected from the group consisting of H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 8a  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 8  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;   R 9a  is selected from the group consisting of H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 9a  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 9a  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;   each R 10  is independently selected from the group consisting of H, C 1 -C 12 alkyl, C 1 -C 6 heteroalkyl, —(CH 2 CH 2 O) n CH 2 CH 2 C(═O)OC 1 -C 6 alkyl, and   

     
       
         
         
             
             
         
       
     
     wherein the C 1 -C 12 alkyl and C 1 -C 6 heteroalkyl of R 10  is substituted by 0, 1, 2 or 3 substituents independently selected from —OH, C 1 -C 12 alkoxy, —S—C(═O)C 1 -C 6 alkyl, halo, —CN, C 1 -C 12 alkyl, —O-aryl, _O-heteroaryl, —O-cycloalkyl, oxo, cycloalkyl, heterocyclyl, aryl, or heteroaryl, —OC(O)OC 1 -C 6 alkyland C(O)OC 1 -C 6 alkyl, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is substituted by 0, 1, 2 or 3 substituents independently selected from C 1 -C 12  alkyl, O—C 1 -C 12 alkyl, C 1 -C 12 heteroalkyl, halo, CN, OH, oxo, aryl, heteroaryl, O-aryl, O-heteroaryl, —C(═O)C 1 -C 12 alkyl, —OC(═O)C 1 -C 12 alkyl, —C(═O)OC 1 -C 12 alkyl, —OC(═O)OC 1 -C 12 alkyl, —C(═O)N(R 11 )—C 1 -C 12 alkyl, —N(R 11 )C(═O)—C 1 -C 12 alkyl; —OC(═O)N(R 11 )—C 1 -C 12 alkyl, —C(═O)-aryl, —C(═O)-heteroaryl, —OC(═O)-aryl, —C(═O)O-aryl, —OC(═O)-heteroaryl, —C(═O)O-heteroaryl, —C(═O)O-aryl, —C(═O)O-heteroaryl, —C(═O)N(R 11 )-aryl, —C(═O)N(R 11 )-heteroaryl, —N(R 11 )C(O)-aryl, —N(R 11 ) 2 C(O)-aryl, —N(R 11 )C(O)-heteroaryl, and S(O) 2 N(R 11 )-aryl;
     each R 11  is independently selected from H and C 1 -C 6 alkyl;   each R 12  is independently selected from H and C 1 -C 6 alkyl;   optionally R 3  and R 6  are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, —O—C 2 -C 6 alkynylene, such that when R 3  and R 6  are connected, the O is bound at the R 3  position   optionally R 3a  and R 6a , are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, —O—C 2 -C 6 alkynylene, such that when R 3a  and R 6a  are connected, the O is bound at the R 3a  position;   optionally R 2  and R 3  are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, —O—C 2 -C 6 alkynylene, such that when R 2  and R 3  are connected, the O is bound at the R 3  position;   optionally R 2a  and R 3a , are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, —O—C 2 -C 6 alkynylene, such that when R 2a  and R 3a  are connected, the O is bound at the R 3a  position;   optionally R 4  and R 3  are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, —O—C 2 -C 6 alkynylene, such that when R 4  and R 3  are connected, the O is bound at the R 3  position;   optionally R 4a  and R 3a , are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, —O—C 2 -C 6 alkynylene, such that when R 4a  and R 3a  are connected, the O is bound at the R 3a  position;   optionally R 5  and R 6  are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, —O—C 2 -C 6 alkynylene, such that when R 5  and R 6  are connected, the O is bound at the R 5  position;   optionally R 5a  and R 6a , are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, —O—C 2 -C 6 alkynylene, such that when R 5a  and R 6a  are connected, the O is bound at the R 5a  position;   optionally R 5  and R 7  are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, —O—C 2 -C 6 alkynylene, such that when R 5  and R 7  are connected, the O is bound at the R 5  position;   optionally R 5a  and R 7a , are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, —O—C 2 -C 6 alkynylene, such that when R 5a  and R 7a  are connected, the O is bound at the R 5a  position;
 
optionally R 8  and R 9  are connected to form a C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, and
 
optionally R 8a  and R 9a  are connected to form a C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene.
   

     Certain aspects and examples of compounds which can be incorporated as a Drug moiety (D) in the immunoconjugates of the invention are provided in the following listing of additional, enumerated embodiments. It will be recognized that features specified in each embodiment may be combined with other specified features to provide further embodiments of the present invention. 
     Embodiment 1 
     A compound of Formula (A-1), Formula (B-1), Formula (C-1), Formula (D-1), Formula (E-1) or Formula (F-1), or stereoisomers or pharmaceutically acceptable salts thereof, 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     wherein R 1 , R 1a , R 1b , R 2 , R 2a , R 3 , R 3a , R 4 , R 4a , R 5 , R 5a , R 6 , R 6a , R 7 , R 7a , R 8 , R 8a , R 9 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , Y 8 , Y 9 , Y 10  and Y 11  are as defined above for compounds of Formula (A), Formula (B), Formula (C), Formula (D), Formula (E) and Formula (F). 
     Embodiment 2 
     A compound of Formula (A), Formula (B), Formula (C), Formula (D), Formula (A-1), Formula (B-1), Formula (C-1), Formula (D-1), Formula (E-1), or Formula (F-1), wherein R 1  is pyrimidine or purine nucleic acid base or analogue thereof, R 1a  is pyrimidine or purine nucleic acid base or analogue thereof, and R 1b  is a pyrimidine or purine nucleic acid base or analogue thereof, each of which is substituted as described in R 1 , R 1a  or R 1b  for Formula (A), Formula (BB, Formula (C), Formula (D), Formula (A-1), Formula (B-1), Formula (C-1), Formula (D-1), Formula (E-1), or Formula (F-1). 
     Embodiment 3 
     A compound of Formula (A-2), Formula (B-2), Formula (C-2), Formula (D-2), Formula (E-2) or Formula (F-2): 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     wherein R 1 , R 1a , R 1b , R 2 , R 2a , R 3 , R 3a , R 4 , R 4a , R 5 , R 5a , R 6 , R 6a , R 7 , R 7a , R 8 , R 8a , R 9 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , Y 8 , Y 9 , Y 10  and Y 11  are as defined above for compounds of Formula (A), Formula (B), Formula (C), Formula (D), Formula (E) and Formula (F). 
     Embodiment 4 
     A compound of Formula (A), Formula (A-1) or Formula (A-2) of Embodiment 1, 2 or 3 wherein:
         R 2  and R 2a  are H;   one of R 3  and R 4  is H and the other is selected from the group consisting of H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 3  or R 4  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 3  or R 4  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;   R 7  and R 7a  are H;   R 6  and R 6a  are H;   R 8 , R 9 , R 8a  and R 9a  are independently H or C 1 -C 6 alkyl, and   one of R 3a  and R 4a  is H and the other is selected from the group consisting of H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 3a  and R 4a  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 3a  or R 4a  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 .       

     Embodiment 5 
     A compound of Formula (A), Formula (A-1) or Formula (A-2) of Embodiment 1, 2, 3 or 4 wherein:
         Y 1  and Y 2  are O, CH 2  or S;   Y 3  is OH, O − , OR 10 , N(R 10 ) 2 , SH or S − ;   Y 4  is OH, O − , OR 10 , N(R 10 ) 2 , SH or S − ;   Y 5  and Y 6  are O or S;   Y 7  and Y 8  are O or S;   Y 9  and Y 10  are O or S;   R 2 , R 2a , R 6 , R 6a , R 7  and R 7a  are H;   one of R 3a  and R 4a  is H and the other is H, OH or F;   one of R 3  and R 4  is H and the other is H, OH or F; and   R 8a , R 9a , R 8  and R 9  are independently selected from H or C 1 -C 6 alkyl.       

     Embodiment 6 
     A compound of Formula (B), Formula (B-1) or Formula (B-2) of Embodiment 1, 2 or 3 wherein:
         R 2  and R 2a  are H;   one of R 3a  and R 4a  is H and the other is selected from the group consisting of H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 3a  and R 4a  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 3a  or R 4a  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;   R 7a  and R 6a  are H;   R 6  and R 4  are H;   R 8 , R 9 , R 8a  and R 9a  are independently H or C 1 -C 6 alkyl, and   one of R 5  and R 7  is H and the other is selected from the group consisting of H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 5  and R 7  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 5  or R 7  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 .       

     Embodiment 7 
     A compound of Formula (B), Formula (B-1) or Formula (B-2) of Embodiment 1, 2, 3 or 6 wherein:
         Y 1  and Y 2  are O, CH 2  or S;   Y 3  is OH, O − , OR 10 , N(R 10 ) 2 , SH or S − ;   Y 4  is OH, O − , OR 10 , N(R 10 ) 2 , SH or S − ;   Y 5  and Y 6  are O or S;   Y 7  and Y 8  are O or S;   Y 9  and Y 10  are O or S;   R 2 , R 2a , R 7a , R 6a , R 6  and R 4  are H;   one of R 3a  and R 4a  is H and the other is H, OH or F;   one of R 5  and R 7  is H and the other is H, OH or F, and   R 8a , R 9a , R 8  and R 9  are independently selected from H or C 1 -C 6 alkyl.       

     Embodiment 8 
     A compound of Formula (C), Formula (C-1) or Formula (C-2) of Embodiment 1, 2 or 3 wherein:
         R 2  and R 2a  are H;   one of R 3  and R 4  is H and the other is selected from the group consisting of H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 3  and R 4  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 3  or R 4  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;   R 4a  and R 6a  are H;   R 6  and R 7  are H;   R 8 , R 9 , R 8a  and R 9a  are independently H or C 1 -C 6 alkyl;   one of R 5a  and R 7a  is H and the other is selected from the group consisting of H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 5a  and R 7a  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 5a  or R 7a  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 .       

     Embodiment 9 
     A compound of Formula (C), Formula (C-1) or Formula (C-2) of Embodiment 1, 2, 3 or 8 wherein:
         Y 1  and Y 2  are O, CH 2  or S;   Y 3  is OH, O − , OR 10 , N(R 10 ) 2 , SH or S − ;   Y 4  is OH, O − , OR 10 , N(R 10 ) 2 , SH or S − ;   Y 5  and Y 6  are O or S;   Y 7  and Y 8  are O or S;   Y 9  and Y 10  are O or S;   R 2 , R 2a , R 4a , R 6a , R 6  and R 7  are H;   one of R 3  and R 4  is H and the other is H, OH or F;   one of R 5a  and R 7a  is H and the other is H, OH or F, and   R 8a , R 9a , R 8  and R 9  are independently selected from H or C 1 -C 6 alkyl.       

     Embodiment 10 
     A compound of Formula (D), Formula (D-1) or Formula (D-2) of Embodiment 1, 2 or 3 wherein:
         R 2  and R 2a  are H;   one of R 5a  and R 7a  is H and the other is selected from the group consisting of H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 5a  and R 7a  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 5a  or R 7a  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;   R 4a  and R 6a  are H;   R 6  and R 4  are H;   R 8 , R 9 , R 8a  and R 9a  are independently H or C 1 -C 6 alkyl, and   one of R 5  and R 7  is H and the other is selected from the group consisting of H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 5  and R 7  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 5  or R 7  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 .       

     Embodiment 11 
     A compound of Formula (D), Formula (D-1) or Formula (D-2) of Embodiment 1, 2, 3 or 10 wherein:
         Y 1  and Y 2  are O, CH 2  or S;   Y 3  is OH, O − , OR 10 , N(R 10 ) 2 , SH or S − ;   Y 4  is OH, O − , OR 10 , N(R 10 ) 2 , SH or S − ;   Y 5  and Y 6  are O or S;   Y 7  and Y 8  are O or S;   Y 9  and Y 10  are O or S;   R 2 , R 2a , R 4a , R 6a , R 6  and R 4  are H;   one of R 5a , R 7a  is H and the other is H, OH or F;   one of R 5  and R 7  is H and the other is H, OH or F, and   R 8 , R 9 , R 8a  and R 9a  are independently H or C 1 -C 6 alkyl.       

     Embodiment 12 
     A compound of Formula (E), Formula (E-1) or Formula (E-2) of Embodiment 1, 2 or 3 wherein:
         R 2  and R 2a  are H;   R 6  and R 6a  are H;   R 7a  is H;   R 8 , R 9 , R 8a  and R 9a  are independently H or C 1 -C 6 alkyl, and   one of R 3a  and R 4a  is H and the other is selected from the group consisting of H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 3a  and R 4a  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 3a  or R 4a  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;   one of R 3  and R 4  is H and the other is selected from the group consisting of H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 3  and R 4  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 3  or R 4  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 , and   one of R 5  and R 7  is H and the other is selected from the group consisting of H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 5  and R 7  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 5  or R 7  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 .       

     Embodiment 13 
     A compound of Formula (E), Formula (E-1) or Formula (E-2) of Embodiment 1, 2, 3 or 12 wherein:
         Y 1  and Y 2  are O, CH 2  or S;   Y 3  is OH, O − , OR 10 , N(R 10 ) 2 , SH or S − ;   Y 5  is O or S;   Y 7  is O or S;   Y 9  is O or S;   R 2 , R 2a , R 5a , R 6a , R 6  and R 7a  are H;   one of R 3a , R 4a  is H and the other is H, OH, OCH 3  or F;   one of R 3 , R 4  is H and the other is H, OH, OCH 3  or F;   one of R 5  and R 7  is H and the other is H, OH, OCH 3  or F, and   R 8 , R 9 , R 8a  and R 9a  are independently H or C 1 -C 6 alkyl.       

     Embodiment 14 
     A compound of Formula (F), Formula (F-1) or Formula (F-2) of Embodiment 1, 2 or 3 wherein:
         R 2  and R 2a  are H;   each R 6  and R 6a  are H;   each R 7a  and R 7  are H;   R 8 , R 9 , R 8a  and R 9a  are independently H or C 1 -C 6 alkyl, and   one of R 3a  and R 4a  is H and the other is selected from the group consisting of H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 3a  and R 4a  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 3a  or R 4a  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;   one of R 3  and R 4  is H and the other is selected from the group consisting of H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 3  and R 4  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 3  or R 4  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 , and   R 5  is selected from the group consisting of H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 5  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 5  is substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 .       

     Embodiment 15 
     A compound of Formula (F), Formula (F-1) or Formula (F-2) of Embodiment 1, 2, 3 or 12 wherein:
         Y 1  and Y 2  are O, CH 2  or S;   each Y 3  is OH, O − , OR 10 , N(R 10 ) 2 , SH or S − ;   each Y 5  is O or S;   each Y 7  is independently O or S;   each Y 9  is independently O or S;   Y 11  is O, CH 2  or S;   R 2 , R 2a , R 6 , R 6a , R 6 , R 7  and R 7a  are H;   one of R 3a , R 4a  is H and the other is H, OH, OCH 3  or F;   one of R 3 , R 4  is H and the other is H, OH, OCH 3  or F;   R 5  is H, OH, OCH 3  or F, and   R 8 , R 9 , R 8a  and R 9a  are independently H or C 1 -C 6 alkyl.       

     Embodiment 16 
     A compound of any one of Embodiments 1 to 15 wherein:
         R 1  is       

     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     wherein R 1  is substituted with 0, 1 2 or 3 substituents independently selected from F, Cl, Br, OH, SH, NH 2 , D, CD 3 , C 1 -C 6 alkyl, C 1 -C 6 alkoxyalkyl, C 1 -C 6 hydroxyalkyl, C 3 -C 8 cycloalkyl, a 3 to 6 membered heterocyclyl having 1 to 2 heteroatoms independently selected from O, N and S, —O(C 1 -C 6 alkyl), —O(C 3 -C 8 cycloalkyl), —S(C 1 -C 6 alkyl), —S(C 1 -C 6 aminoalkyl), —S(C 1 -C 6 hydroxyalkyl), —S(C 3 -C 8 cycloalkyl), —NH(C 1 -C 6 alkyl), —NH(C 3 -C 8 cycloalkyl), —N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 alkyl) (C 3 -C 8 cycloalkyl), —CN, —P(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —(CH 2 ) 1-10 C(═O)OH, —CH═CH(CH 2 ) 1-10 C(═O)OH, —NHC(O)(C 1 -C 6 alkyl), —NHC(O)(C 3 -C 8 cycloalkyl), —NHC(O)(phenyl), and —N(C 3 -C 8 cycloalkyl) 2 ;
         R 1a  is       

     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     wherein: R 1a  is substituted with 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, OH, SH, NH 2 , D, CD 3 , C 1 -C 6 alkyl, C 1 -C 6 alkoxyalkyl, C 1 -C 6 hydroxyalkyl, C 3 -C 8 cycloalkyl, a 3 to 6 membered heterocyclyl having 1 to 2 heteroatoms independently selected from O, N and S, —O(C 1 -C 6 alkyl), —O(C 3 -C 8 cycloalkyl), —S(C 1 -C 6 alkyl), —S(C 1 -C 6 aminoalkyl), —S(C 1 -C 6 hydroxyalkyl), —S(C 3 -C 8 cycloalkyl), —NH(C 1 -C 6 alkyl), —NH(C 3 -C 8 cycloalkyl), —N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 alkyl) (C 3 -C 8 cycloalkyl), —CN, —P(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —(CH 2 ) 1-10 C(═O)OH, —CH═CH(CH 2 ) 1-10 C(═O)OH, —NHC(O)(C 1 -C 6 alkyl), —NHC(O)(C 3 -C 8 cycloalkyl), —NHC(O)(phenyl), and —N(C 3 -C 8 cycloalkyl) 2 ;
         and   R 1b  is       

     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     wherein R 1b  is substituted with 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, OH, SH, NH 2 , D, CD 3 , C 1 -C 6 alkyl, C 1 -C 6 alkoxyalkyl, C 1 -C 6 hydroxyalkyl, C 3 -C 8 cycloalkyl, a 3 to 6 membered heterocyclyl having 1 to 2 heteroatoms independently selected from O, N and S, —O(C 1 -C 6 alkyl), —O(C 3 -C 8 cycloalkyl), —S(C 1 -C 6 alkyl), —S(C 1 -C 6 aminoalkyl), —S(C 1 -C 6 hydroxyalkyl), —S(C 3 -C 8 cycloalkyl), —NH(C 1 -C 6 alkyl), —NH(C 3 -C 8 cycloalkyl), —N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 alkyl) (C 3 -C 8 cycloalkyl), —CN, —P(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —(CH 2 ) 1-10 C(═O)OH, —CH═CH(CH 2 ) 1-10 C(═O)OH, —NHC(O)(C 1 -C 6 alkyl), —NHC(O)(C 3 -C 8 cycloalkyl), —NHC(O)(phenyl), and —N(C 3 -C 8 cycloalkyl) 2 . 
     Embodiment 17 
     A compound of Formula (A-3), Formula (B-3), Formula (C-3), Formula (D-3), Formula (E-3) or Formula (F-3): 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     wherein:
         Y 1  is —O—, —S—, —S(═O)—, —SO 2 —, —CH 2 —, or —CF 2 —;   Y 2  is —O—, —S—, —S(═O)—, —SO 2 —, —CH 2 —, or —CF 2 —;   Y 11  is —O—, —S—, —S(═O)—, —SO 2 —, —CH 2 —, or —CF 2 —;   Y 3  is OH, O − , OR 10 , N(R 10 ) 2 , SH or S − ;   Y 4  is OH, O − , OR 10 , N(R 10 ) 2 , SH or S − ;   Y 7  is O or S;   Y 8  is O or S;   R 1  is       

     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     wherein R 1  is substituted with 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, OH, SH, NH 2 , D, CD 3 , C 1 -C 6 alkyl, C 1 -C 6 alkoxyalkyl, C 1 -C 6 hydroxyalkyl, C 3 -C 8 cycloalkyl, a 3 to 6 membered heterocyclyl having 1 to 2 heteroatoms independently selected from O, N and S, —O(C 1 -C 6 alkyl), —O(C 3 -C 8 cycloalkyl), —S(C 1 -C 6 alkyl), —S(C 1 -C 6 aminoalkyl), —S(C 1 -C 6 hydroxyalkyl), —S(C 3 -C 8 cycloalkyl), —NH(C 1 -C 6 alkyl), —NH(C 3 -C 8 cycloalkyl), —N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 alkyl) (C 3 -C 8 cycloalkyl), —CN, —P(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —(CH 2 ) 1-10 C(═O)OH, —CH═CH(CH 2 ) 1-10 C(═O)OH, —NHC(O)(C 1 -C 6 alkyl), —NHC(O)(C 3 -C 8 cycloalkyl), —NHC(O)(phenyl), and —N(C 3 -C 8 cycloalkyl) 2 ;
         R 1a  is       

     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     wherein: R 1a  is substituted with 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, OH, SH, NH 2 , D, CD 3 , C 1 -C 6 alkyl, C 1 -C 6 alkoxyalkyl, C 1 -C 6 hydroxyalkyl, C 3 -C 8 cycloalkyl, a 3 to 6 membered heterocyclyl having 1 to 2 heteroatoms independently selected from O, N and S, —O(C 1 -C 6 alkyl), —O(C 3 -C 8 cycloalkyl), —S(C 1 -C 6 alkyl), —S(C 1 -C 6 aminoalkyl), —S(C 1 -C 6 hydroxyalkyl), —S(C 3 -C 8 cycloalkyl), —NH(C 1 -C 6 alkyl), —NH(C 3 -C 8 cycloalkyl), —N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 alkyl) (C 3 -C 8 cycloalkyl), —CN, —P(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —(CH 2 ) 1-10 C(═O)OH, —CH═CH(CH 2 ) 1-10 C(═O)OH, —NHC(O)(C 1 -C 6 alkyl), —NHC(O)(C 3 -C 8 cycloalkyl), —NHC(O)(phenyl), and —N(C 3 -C 8 cycloalkyl) 2 ;
         and   R 1b  is       

     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     wherein R 1b  is substituted with 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, OH, SH, NH 2 , D, CD 3 , C 1 -C 6 alkyl, C 1 -C 6 alkoxyalkyl, C 1 -C 6 hydroxyalkyl, C 3 -C 8 cycloalkyl, a 3 to 6 membered heterocyclyl having 1 to 2 heteroatoms independently selected from O, N and S, —O(C 1 -C 6 alkyl), —O(C 3 -C 8 cycloalkyl), —S(C 1 -C 6 alkyl), —S(C 1 -C 6 aminoalkyl), —S(C 1 -C 6 hydroxyalkyl), —S(C 3 -C 8 cycloalkyl), —NH(C 1 -C 6 alkyl), —NH(C 3 -C 8 cycloalkyl), —N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 alkyl) (C 3 -C 8 cycloalkyl), —CN, —P(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —(CH 2 ) 1-10 C(═O)OH, —CH═CH(CH 2 ) 1-10 C(═O)OH, —NHC(O)(C 1 -C 6 alkyl), —NHC(O)(C 3 -C 8 cycloalkyl), —NHC(O)(phenyl), and —N(C 3 -C 8 cycloalkyl) 2 ;
         each R 2  is independently selected from the group consisting of H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 2  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 2  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;   each R 3  is independently selected from the group consisting of H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 3  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 3  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;   each R 4  is independently selected from the group consisting of H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 4  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 4  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;   each R 5  is independently selected from the group consisting of H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 5  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 5  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;
 
each R 6  is independently selected from the group consisting of H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 6  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 6  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;
   each R 7  is independently selected from the group consisting of H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 7  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 7  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;   R 2a  is selected from the group consisting of H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 2a  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 2a  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3      R 3a  is selected from the group consisting of H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 3a  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 3a  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;   R 4a  is selected from the group consisting of H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 4a  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 4a  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;   R 5a  is selected from the group consisting of H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 5a  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 5a  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;   R 6a  is selected from the group consisting of H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 6a  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 6a  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;   R 7a  is selected from the group consisting of H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 7a  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 7a  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;   each R 10  is independently selected from the group consisting of H, C 1 -C 12 alkyl, —(CH 2 CH 2 O) n CH 2 CH 2 C(═O)OC 1 -C 6 alkyl, and       

     
       
         
         
             
             
         
       
     
     wherein the C 1 -C 12 alkyl of R 10  is substituted by 0, 1, 2 or 3 substituents independently selected from —OH, C 1 -C 12 alkoxy, —S—C(═O)C 1 -C 6 alkyl and C(O)OC 1 -C 6 alkyl;
         optionally R 3  and R 6  are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, —O—C 2 -C 6 alkynylene, such that when R 3  and R 6  are connected, the O is bound at the R 3  position   optionally R 3a  and R 6a , are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, —O—C 2 -C 6 alkynylene, such that when R 3a  and R 6a  are connected, the O is bound at the R 3a  position;   optionally R 2  and R 3  are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, —O—C 2 -C 6 alkynylene, such that when R 2  and R 3  are connected, the O is bound at the R 3  position;   optionally R 2a  and R 3a , are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, —O—C 2 -C 6 alkynylene, such that when R 2a  and R 3a  are connected, the O is bound at the R 3a  position;   optionally R 4  and R 3  are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, —O—C 2 -C 6 alkynylene, such that when R 4  and R 3  are connected, the O is bound at the R 3  position;   optionally R 4a  and R 3a , are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, —O—C 2 -C 6 alkynylene, such that when R 4a  and R 3a  are connected, the O is bound at the R 3a  position;   optionally R 5  and R 6  are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, —O—C 2 -C 6 alkynylene, such that when R 5  and R 6  are connected, the O is bound at the R 5  position;   optionally R 5a  and R 6a , are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, —O—C 2 -C 6 alkynylene, such that when R 5a  and R 6a  are connected, the O is bound at the R 5a  position;   optionally R 5  and R 7  are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, —O—C 2 -C 6 alkynylene, such that when R 5  and R 7  are connected, the O is bound at the R 5  position, and   optionally R 5a  and R 7a , are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, —O—C 2 -C 6 alkynylene, such that when R 5a  and R 7a  are connected, the O is bound at the R 5a  position.       

     Embodiment 18 
     The compound Formula (A-3), or a pharmaceutically acceptable salt thereof, having the structure of Formula (A-4), or a pharmaceutically acceptable salt thereof: 
     
       
         
         
             
             
         
       
     
     wherein: R 1 , R 1a , R 3 , R 3a , R 6 , R 6a , Y 3  and Y 4  are as defined in Embodiment 17. 
     Embodiment 19 
     The compound of Formula (A-4), or a pharmaceutically acceptable salt thereof, having the structure of Formula (A-4a), Formula A-4b), Formula A-4c) or Formula A-4d), or a pharmaceutically acceptable salt thereof: 
     
       
         
         
             
             
         
       
     
     wherein: R 1 , R 1a , R 3 , R 3a , R 6  and R 6a  are as defined in Embodiment 17;
         Y 3  is OR 10 , N(R 10 ) 2 , SH or S − , and   Y 4  is OR 10 , N(R 10 ) 2 , SH or S − .       

     Embodiment 20 
     The compound of Formula (A-4), or a pharmaceutically acceptable salt thereof, having the structure of Formula (A-4e), Formula (A-4f), Formula (A-4 g), Formula (A-4h), Formula (A-4i), Formula (A-4j), Formula (A-4k), Formula (A-41), Formula (A-4m), Formula (A-4n), Formula (A-4o) or Formula (A-4p), or a pharmaceutically acceptable salt thereof: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     wherein: R 1 , R 1a , R 3 , R 3a , R 6  and R 6a  are as defined in Embodiment 17;
         Y 3  is OR 10 , N(R 10 ) 2 , SH or S − , and   Y 4  is OR 10 , N(R 10 ) 2 , SH or S − .       

     Embodiment 21 
     The compound of Formula (B-3) having the structure of Formula (B-4), or a pharmaceutically acceptable salt thereof: 
     
       
         
         
             
             
         
       
     
     wherein: R 1 , R 1a , R 3 , R 3a , R 5 , R 6a , Y 3  and Y 4  are as defined in Embodiment 17. 
     Embodiment 22 
     The compound of Formula (B-4), or a pharmaceutically acceptable salt thereof, having the structure of Formula (B-4a), Formula (B-4b), Formula (B-4c) or Formula (B-4d), or a pharmaceutically acceptable salt thereof: 
     
       
         
         
             
             
         
       
     
     wherein: R 1 , R 1a , R 3a , R 5  and R 6a  are as defined in Embodiment 13;
         Y 3  is OR 10 , N(R 10 ) 2 , SH or S − , and   Y 4  is OR 10 , N(R 10 ) 2 , SH or S − .       

     Embodiment 23 
     The compound of Formula (B-4), or a pharmaceutically acceptable salt thereof, having the structure of Formula (B-4e), Formula (B-4f), Formula (B-4 g) or Formula (B-4h), or a pharmaceutically acceptable salt thereof: 
     
       
         
         
             
             
         
       
     
     wherein: R 1 , R 1a  and R 5  are as defined in Embodiment 17;
         Y 3  is OR 10 , N(R 10 ) 2 , SH or S − , and   Y 4  is OR 10 , N(R 10 ) 2 , SH or S − .       

     Embodiment 24 
     The compound of Formula (C-3) having the structure of Formula (C-4), or a pharmaceutically acceptable salt thereof: 
     
       
         
         
             
             
         
       
     
     wherein: R 1 , R 1a , R 3 , R 5a , R 6 , R 6a , Y 3  and Y 4  are as defined in Embodiment 17. 
     Embodiment 25 
     The compound of Formula (C-4), or a pharmaceutically acceptable salt thereof, having the structure of Formula (C-4a), Formula (C-4b), Formula (C-4c) or Formula (C-4d), or a pharmaceutically acceptable salt thereof: 
     
       
         
         
             
             
         
       
     
     wherein: R 1 , R 1a , R 3 , R 5a  and R 6  are as defined in Embodiment 17; Y 3  is OR 10 , N(R 10 ) 2 , SH or S − , and Y 4  is OR 10 , N(R 10 ) 2 , SH or S − . 
     Embodiment 26 
     The compound of Formula (C-4), or a pharmaceutically acceptable salt thereof, having the structure of Formula (C-4e), Formula (C-4f), Formula (C-4 g) or Formula (C-4h), or a pharmaceutically acceptable salt thereof: 
     
       
         
         
             
             
         
       
     
     wherein: R 1 , R 1a  and R 5a  are as defined in Embodiment 17;
         Y 3  is OR 10 , N(R 10 ) 2 , SH or S − , and   Y 4  is OR 10 , N(R 10 ) 2 , SH or S − .       

     Embodiment 27 
     The compound of Formula (D-3), or a pharmaceutically acceptable salt thereof, having the structure of Formula (D-4), or a pharmaceutically acceptable salt thereof: 
     
       
         
         
             
             
         
       
     
     wherein: R 1 , R 1a , R 5 , R 5a , Y 3  and Y 4  are as defined in Embodiment 17. 
     Embodiment 28 
     The compound of Formula (D-4), or a pharmaceutically acceptable salt thereof, having the structure of Formula (D-4a), Formula (D-4b), Formula (D-4c) or Formula (D-4d), or a pharmaceutically acceptable salt thereof: 
     
       
         
         
             
             
         
       
     
     wherein: R 1 , R 1a , R 5  and R 5a  are as defined in Embodiment 17;
         Y 3  is OR 10 , N(R 10 ) 2 , SH or S − , and   Y 4  is OR 10 , N(R 10 ) 2 , SH or S − .       

     Embodiment 29 
     The compound of Formula (E-3), or a pharmaceutically acceptable salt thereof, having the structure of Formula (E-4), or a pharmaceutically acceptable salt thereof: 
     
       
         
         
             
             
         
       
     
     wherein: R 1 , R 1a , R 3 , R 3a , R 4 , R 4a , R 5  and R 7  are as defined in Embodiment 17. 
     Embodiment 30 
     The compound of Formula (E-4), or a pharmaceutically acceptable salt thereof, having the structure of Formula (E-4a) or Formula (E-4b), or a pharmaceutically acceptable salt thereof: 
     
       
         
         
             
             
         
       
     
     wherein: R 1 , R 1a , R 3 , R 3a , R 4 , R 4a , R 5  and R 7  are as defined in Embodiment 17;
         and   Y 3  is OR 10 , N(R 10 ) 2 , SH or S − .       

     Embodiment 31 
     The compound of Formula (F-3), or a pharmaceutically acceptable salt thereof, having the structure of Formula (F-4), or a pharmaceutically acceptable salt thereof: 
     
       
         
         
             
             
         
       
     
     wherein: R 1 , R 1a , R 1b , R 3 , R 3a , R 4 , R 4a , R 5  and R 7  are as defined in Embodiment 17. 
     Embodiment 32 
     The compound of Formula (F-4), or a pharmaceutically acceptable salt thereof, having the structure of Formula (F-4a), Formula (F-4b), Formula (F-4c), or Formula (F-4d), or a pharmaceutically acceptable salt thereof: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     wherein: R 1 , R 1a , R 1b , R 3 , R 3a , R 4 , R 4a , R 5  and R 7  are as defined in Embodiment 17;
         and   each Y 3  is independently selected from OR 10 , N(R 10 ) 2 , SH and S − .       

     Embodiment 33 
     The compound of any one of Embodiments 1 to 32, wherein R 1  is 
     
       
         
         
             
             
         
       
     
     Embodiment 34 
     The compound of any one of Embodiments 1 to 32, wherein R 1a  is 
     
       
         
         
             
             
         
       
     
     Embodiment 35 
     The compound of any one of Embodiments 1 to 32, wherein R 1b  is 
     
       
         
         
             
             
         
       
     
     Embodiment 36 
     The compound of any one of Embodiments 1 to 32, wherein R 1  is 
     
       
         
         
             
             
         
       
     
     Embodiment 37 
     The compound of any one of Embodiments 1 to 32, wherein R 1a  is 
     
       
         
         
             
             
         
       
     
     Embodiment 38 
     The compound of any one of Embodiments 1 to 32, wherein R 1b  is 
     
       
         
         
             
             
         
       
     
     Embodiment 39. The compound of any one of Embodiments 1 to 32, wherein R 1  is 
     
       
         
         
             
             
         
       
     
     and R 1a  is 
     
       
         
         
             
             
         
       
     
     Embodiment 40 
     The compound of any one of Embodiments 1 to 32 wherein R 1  is 
     
       
         
         
             
             
         
       
     
     and R 1a  is 
     
       
         
         
             
             
         
       
     
     Embodiment 41 
     The compound of any one of Embodiments 1 to 32, wherein R 1  is 
     
       
         
         
             
             
         
       
     
     and R 1a  is 
     
       
         
         
             
             
         
       
     
     Embodiment 42 
     The compound of any one of Embodiments 1 to 32, wherein R 1  is 
     
       
         
         
             
             
         
       
     
     and R 1a  is 
     
       
         
         
             
             
         
       
     
     Embodiment 43 
     The compound of any one of Embodiments 1 to 32, wherein R 1  is 
     
       
         
         
             
             
         
       
     
     and R 1a  is 
     
       
         
         
             
             
         
       
     
     Embodiment 44 
     The compound of any one of Embodiments 1 to 32, wherein R 1  is 
     
       
         
         
             
             
         
       
     
     R 1b  is 
     
       
         
         
             
             
         
       
     
     and R 1a  is 
     
       
         
         
             
             
         
       
     
     Embodiment 45 
     The compound of any one of Embodiments 1 to 44, wherein:
         Y 3  is OH, O − , SH or S − , and   Y 4  is OH, O − , SH or S − .       

     Embodiment 46 
     The compound of any one of Embodiments 1 to 44, wherein:
         Y 3  is OH or O − , and   Y 4  is OH or O − .       

     Embodiment 47 
     The compound of any one of Embodiments 1 to 44, wherein:
         Y 3  is SH or S − , and   Y 4  is OH or O − .       

     Embodiment 48 
     The compound of any one of Embodiments 1 to 44, wherein:
         Y 3  is OH or O − , and   Y 4  is SH or S −         

     Embodiment 49 
     The compound of any one of Embodiments 1 to 44, wherein:
         Y 3  is SH or S − , and   Y 4  is SH or S −         

     Embodiment 50 
     The compound of any one of Embodiments 1 to 49 wherein:
         R 3  is —OH or F;   R 3a  is —OH or F;   R 5  is —OH or F;   R 5a  is —OH or F;   R 6  is H, and   R 6a  is H.       

     Embodiment 51 
     The compound of any one of Embodiments 1 to 49 wherein:
         R 3  is H, —OH or F;   R 3a  is H, —OCH 3 , —OH or F;   R 5  is —OH or F;   R 4 , R 4a , R 6 , R 6a , R 7 , R 7a  are H, and   R 6a  is H.       

     Embodiment 52 
     A Drug moiety (D) is a compound of Table 1: 
     
       
         
           
               
               
             
               
                 TABLE 1 
               
               
                   
               
               
                 Compound 
                   
               
               
                 No. 
                 Structure 
               
               
                   
               
             
            
               
                 T1-1 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T1-2 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T1-3 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T1-4 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T1-5 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T1-6 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T1-7 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T1-8 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T1-9 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T1-10 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T1-11 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T1-12 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T1-13 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T1-14 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T1-15 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T1-16 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T1-17 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T1-18 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T1-19 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T1-20 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T1-21 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T1-22 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T1-23 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T1-24 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T1-25 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T1-26 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T1-27 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T1-28 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T1-29 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T1-30 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T1-31 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T1-32 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T1-33 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T1-34 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T1-35 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T1-36 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T1-37 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T1-38 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T1-39 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T1-40 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T1-41 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T1-42 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T1-43 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T1-44 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T1-45 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T1-46 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T1-47 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T1-48 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T1-49 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T1-50 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T1-51 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T1-52 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T1-53 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T1-54 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T1-55 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T1-56 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T1-57 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T1-58 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T1-59 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T1-60 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T1-61 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
         
       
     
     Embodiment 53 
     A Drug moiety (D) is a compound of Table 2: 
     
       
         
           
               
               
             
               
                 TABLE 2 
               
               
                   
               
               
                 Compound 
                   
               
               
                 No. 
                 Structure 
               
               
                   
               
             
            
               
                 T2-1 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T2-2 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T2-3 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T2-4 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T2-5 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T2-6 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T2-7 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T2-8 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T2-9 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T2-10 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T2-11 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T2-12 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T2-13 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T2-14 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T2-15 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T2-16 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T2-17 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T2-18 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T2-19 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T2-20 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T2-21 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T2-22 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T2-23 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T2-24 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T2-25 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T2-26 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T2-27 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T2-28 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T2-29 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T2-30 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T2-31 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T2-32 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T2-33 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T2-34 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T2-35 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T2-36 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T2-37 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T2-38 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T2-39 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T2-40 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T2-41 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T2-42 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T2-43 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T2-44 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T2-45 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T2-46 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T2-47 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T2-48 T1-57 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T2-49 T1-58 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T2-50 T1-59 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T2-51 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
         
       
     
     Embodiment 54 
     A Drug moiety (D) is a compound of Table 3: 
     
       
         
           
               
               
             
               
                 TABLE 3 
               
               
                   
               
               
                 Compound 
                   
               
               
                 No. 
                 Structure 
               
               
                   
               
             
            
               
                 T3-1 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T3-2 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T3-3 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T3-4 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T3-5 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T3-6 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T3-7 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T3-8 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T3-9 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T3-10 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T3-11 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T3-12 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T3-13 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T3-14 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T3-15 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T3-16 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T3-17 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T3-18 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T3-19 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T3-20 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T3-21 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
         
       
     
     Embodiment 55 
     The Drug moiety (D) is 
     
       
         
         
             
             
         
       
     
     Embodiment 56 
     The Drug moiety (D) is 
     
       
         
         
             
             
         
       
     
     Embodiment 57 
     The Drug moiety (D) is 
     
       
         
         
             
             
         
       
     
     Embodiment 58 
     The Drug moiety (D) is 
     
       
         
         
             
             
         
       
     
     Embodiment 59 
     The Drug moiety (D) is 
     
       
         
         
             
             
         
       
     
     Embodiment 60 
     The Drug moiety (D) is 
     
       
         
         
             
             
         
       
     
     Embodiment 61 
     The Drug moiety (D) is 
     
       
         
         
             
             
         
       
     
     Embodiment 62 
     The Drug moiety (D) is 
     
       
         
         
             
             
         
       
     
     Embodiment 63 
     The Drug moiety (D) is 
     
       
         
         
             
             
         
       
     
     Embodiment 64 
     The Drug moiety (D) is 
     
       
         
         
             
             
         
       
     
     Embodiment 65 
     The Drug moiety (D) is 
     
       
         
         
             
             
         
       
     
     Embodiment 66 
     The Drug moiety (D) is 
     
       
         
         
             
             
         
       
     
     Embodiment 67 
     The Drug moiety (D) is 
     
       
         
         
             
             
         
       
     
     Embodiment 68 
     The Drug moiety (D) is 
     
       
         
         
             
             
         
       
     
     Embodiment 69 
     The Drug moiety (D) is 
     
       
         
         
             
             
         
       
     
     In another aspect the Drug moiety (D) of the immunoconjugates of the invention are the compounds disclosed in Aduro (WO2016/145102). 
     In another aspect the Drug moiety (D) of the immunoconjugates of the invention are the compounds disclosed in Aduro Biotech (WO2014/093936). 
     In another aspect the Drug moiety (D) of the immunoconjugates of the invention are the compounds disclosed in Aduro and Novartis unpublished US Provisional application U.S. Ser. No. 62/362,907 filed Jul. 15, 2016. 
     In another aspect the Drug moiety (D) of the immunoconjugates of the invention are the compounds disclosed in Aduro and Novartis unpublished PCT application PCT/US2016/059506 filed 28 Oct. 2016. 
     In another aspect the Drug moiety (D) of the immunoconjugates of the invention are the compounds disclosed in Memorial Sloan Kettering et al (WO2014/179335). Such compounds are listed in Table 4. 
     In another aspect the Drug moiety (D) of the immunoconjugates of the invention are the compounds disclosed in Merck &amp; Co (WO2017/027646). Such compounds are listed in Table 4. 
     In another aspect the Drug moiety (D) of the immunoconjugates of the invention are the compounds disclosed in Merck &amp; Co (WO2017/027645). Such compounds are listed in Table 4. 
     In another aspect the Drug moiety (D) of the immunoconjugates of the invention are the compounds disclosed in GlaxoSmithKline (WO2015/185565). Such compounds are listed in Table 4. 
     In another aspect the Drug moiety (D) of the immunoconjugates of the invention are the compounds disclosed in Brock University (WO2015/074145). Such compounds are listed in Table 4. 
     In another aspect the Drug moiety (D) of the immunoconjugates of the invention are the compounds disclosed in Rutgers (U.S. Pat. No. 9,315,523). Such compounds are listed in Table 4. 
     In another aspect the Drug moiety (D) of the immunoconjugates of the invention are the compounds disclosed in Spring Bank (WO2007070598, WO2017004499 and WO2017011622). 
     Such compounds are listed in Table 4. 
     In another aspect the Drug moiety (D) of the immunoconjugates of the invention are the compounds disclosed in Invivogen (WO2016/096174. Such compounds are listed in Table 4. 
     In another aspect the Drug moiety (D) of the immunoconjugates of the invention are the compounds disclosed in Regents of Univ. California and Aduro Biotech (WO2014/189805). Such compounds are disclosed herein in  FIG. 10 ,  FIG. 11 , and  FIG. 12 . 
     In another aspect the Drug moiety (D) of the immunoconjugates of the invention are the compounds disclosed in Sperovie (WO2018009648). 
     In another aspect the Drug moiety (D) of the immunoconjugates of the invention are the compounds disclosed in Sperovie (WO2018009652). 
     In another aspect the Drug moiety (D) of the immunoconjugates of the invention are the compounds disclosed in Sperovie (WO2018013887). 
     In another aspect the Drug moiety (D) of the immunoconjugates of the invention are the compounds disclosed in Sperovie (WO2018013908).Each of the preceding applications are incorporated by reference in their entirety. 
     
       
         
           
               
               
             
               
                 TABLE 4 
               
               
                   
               
               
                 Ex. 
                   
               
               
                 No. 
                 Structure 
               
               
                   
               
             
            
               
                 T4-1 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-2 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-3 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-4 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-5 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-6 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-7 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                   
                 as RR, RS, SR and SS diastereomers 
               
               
                   
               
               
                 T4-8 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                   
                 as RR, RS, SR and SS diastereomers 
               
               
                   
               
               
                 T4-9 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                   
                 as RR, RS, SR and SS diastereomers 
               
               
                   
               
               
                 T4-10 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                   
                 as RR, RS, SR and SS diastereomers 
               
               
                   
               
               
                 T4-11 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                   
                 as RR, RS, SR and SS diastereomers 
               
               
                   
               
               
                 T4-12 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                   
                 as RR, RS, SR and SS diastereomers 
               
               
                   
               
               
                 T4-13 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                   
                 as RR, RS, SR and SS diastereomers 
               
               
                   
               
               
                 T4-14 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                   
                 as RR, RS, SR and SS diastereomers 
               
               
                   
               
               
                 T4-15 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                   
                 as RR, RS, SR and SS diastereomers 
               
               
                   
               
               
                 T4-16 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                   
                 as RR, RS, SR and SS diastereomers 
               
               
                   
               
               
                 T4-17 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                   
                 as RR, RS, SR and SS diastereomers 
               
               
                   
               
               
                 T4-18 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                   
                 as RR, RS, SR and SS diastereomers 
               
               
                   
               
               
                 T4-19 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-20 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-21 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-22 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-23 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-24 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-25 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-26 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-27 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-28 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-29 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-30 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-31 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-32 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-33 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-34 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-35 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-36 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-37 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-38 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-39 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-40 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-41 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-42 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-43 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-44 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-45 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-46 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-47 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-48 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-49 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-50 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-51 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-52 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-53 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-54 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-55 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-56 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-57 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-58 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-59 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-60 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-61 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-62 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-63 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-64 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-65 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-66 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-67 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-68 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-69 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-70 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-71 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-72 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-73 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-74 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-75 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-76 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-77 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-78 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-79 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-80 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-81 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-82 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-83 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-84 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-85 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-86 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-87 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-88 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-89 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-90 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-91 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-92 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-93 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-94 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-95 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-96 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-97 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-98 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-99 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-100 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-101 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-102 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-103 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-104 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-105 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-106 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-107 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-108 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-109 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-110 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-111 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-112 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-113 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-114 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-115 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-116 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-117 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-118 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-119 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-120 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-121 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-122 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-123 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-124 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-125 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-126 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-127 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-128 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-129 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-130 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-131 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-132 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-133 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-134 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-135 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-136 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-137 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-138 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-139 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-140 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-141 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-142 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-143 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-144 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-145 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-146 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-147 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-148 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-149 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-150 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-151 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-152 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-153 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-154 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-155 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-156 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                   
                 di 
               
               
                   
               
               
                 T4-157 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-158 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-159 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-160 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-161 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-162 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-163 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-164 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-165 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-166 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-167 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-168 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-169 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-170 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-171 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-172 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-173 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-174 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-175 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-176 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-177 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-178 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-179 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-180 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-181 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-182 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-183 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-184 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-185 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-186 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-187 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-188 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-189 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-190 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-191 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-192 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-193 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-194 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-195 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-196 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-197 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-198 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-199 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-200 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-201 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-202 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-203 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-204 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-205 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-206 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-207 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-208 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-209 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-210 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-211 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-212 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-213 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-214 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-215 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-216 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-217 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-218 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-219 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-220 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-221 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-222 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-223 T1-40 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-224 T1-41 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-225 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-226 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-227 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-228 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-229 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-230 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-231 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-232 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-233 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-234 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-235 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-236 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-237 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-238 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-239 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-240 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-241 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-242 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-243 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-244 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-245 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-246 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-247 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-248 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-249 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-250 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-251 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-252 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-253 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-254 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-255 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-256 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-257 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-258 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-259 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-260 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-261 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-262 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-263 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-264 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-265 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-266 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-267 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-268 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-269 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-270 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-271 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-272 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-273 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-274 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-275 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-276 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-277 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-278 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-279 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-280 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-281 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-282 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-283 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-284 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-285 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-286 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-287 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-288 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-289 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-290 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-291 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-292 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-293 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-294 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-295 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-296 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-297 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-298 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-299 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-300 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-301 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-302 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-303 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-304 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-305 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-306 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-307 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-308 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-309 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-310 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-311 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-312 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-313 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-314 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-315 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-316 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-317 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-318 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-319 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-320 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-321 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-322 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-323 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-324 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-325 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-326 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-327 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-328 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-329 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-330 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-331 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-332 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-333 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-334 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-335 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-336 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-337 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-338 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-339 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-340 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-341 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-342 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-343 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-344 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-345 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-346 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-347 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-348 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-349 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-350 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-351 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-352 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-353 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-354 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-355 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-356 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-357 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-358 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-359 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-360 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-361 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-362 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-363 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-364 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-365 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-366 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-367 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-368 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-369 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-370 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-371 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-372 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-373 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-374 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-375 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-376 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 T4-377 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
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                 T4-427 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                   
                 X = S, Se and BH3 
               
               
                   
               
               
                 T4-428 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                   
                 X = S and Se 
               
               
                   
               
               
                 T4-429 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
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                 n is an integer selected from 4 to 18 
               
               
                   
               
               
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                 n is an integer selected from 4 to 18 
               
               
                   
               
            
           
         
       
     
     Example Synthesis of Compounds of Formula (A) 
     Compounds of Formula (A) were made according to the synthetic description in WO2016145102. 
     Specifically, (2R,3R,3aR,5R,7aR,9R,10R,10aR,12R,14aR)-2,9-bis(6-amino-9H-purin-9-yl)-3,10-difluorooctahydro-2H,7H-difuro[3,2-d:3′,2′-j][1,3,7,9]tetraoxa[2,8]diphosphacyclododecine-5,12-bis(thiolate) 5,12-dioxide (T1-1), and (2R,3R,3aR,5R,7aR,9R,10R,10aR,12S,14aR)-2,9-bis(6-amino-9H-purin-9-yl)-3,10-difluorooctahydro-2H,7H-difuro[3,2-d:3′,2′-j][1,3,7,9]tetraoxa[2,8]diphosphacyclododecine-5,12-bis(thiolate) 5,12-dioxide (T1-6) were synthesized according to the scheme below: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Step 1: 
     Preparation of (2R,3R,4R,5R)-5-(6-benzamido-9H-purin-9-yl)-4-fluoro-2-(hydroxymethyl)tetrahydrofuran-3-yl hydrogen phosphonate (2): To a solution of N-(9-((2R,3R,4R,5R)-5-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-3-fluoro-4-hydroxytetrahydrofuran-2-yl)-9-H-purin-6-yl)benzamide (1, 2.0 g, 3.0 mmol, ChemGenes) in 1,4-dioxane (25 mL) and pyridine (8 mL) was added a solution of 2-Chloro-1,3,2-benzodioxaphosphorin-4-one (SalPCI) (0.84 g, 4.1 mmol) in 1,4-dioxane (12 mL). After 30 min, to the stirred reaction mixture at room temperature was introduced water (4 mL), and the resulting mixture was poured into a 1N aqueous NaHCO 3  solution (100 mL). This aqueous mixture was extracted with EtOAc (3×100 mL) and the layers were partitioned. The EtOAc extracts were combined and concentrated to dryness in vacuo as a colorless foam. The colorless foam was dissolved in CH 2 Cl 2  (30 mL) to give a colorless solution. To this solution was added water (0.5 mL) and a 6% (v/v) solution of dichloroacetic acid (DCA) in CH 2 Cl 2  (30 mL). After ten min of stirring at room temperature, to the red solution was charged pyridine (3.5 mL). The resulting white mixture was concentrated in vacuo and water was removed as an azeotrope after concentration with MeCN (30 mL). This azeotrope process was repeated two more times with MeCN (30 mL). On the last evaporation, the resulting white slurry of compound 2 was left in MeCN (15 mL). 
     Step 2: 
     Preparation of (2R,3R,4R,5R)-5-(6-benzamido-9H-purin-9-yl)-2-((((((2R,3R,4R,5R)-5-(6-benzamido-9H-purin-9-yl)-2-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-4-fluorotetrahydrofuran-3-yl)oxy)(2-cyanoethoxy)phosphorothioyl)oxy)methyl)-4-fluorotetrahydrofuran-3-yl hydrogenphosphonate (4): To a solution of (2R,3R,4R,5R)-5-(6-benzamido-9H-purin-9-yl)-2-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-4-fluorotetrahydrofuran-3-yl (2-cyanoethyl) diisopropylphosphoramidite (3, 2.5 g, 2.9 mmol, ChemGenes) in MeCN (20 mL) was dried through concentration in vacuo. This process was repeated two more times to remove water as an azeotrope. On the last azeotrope, to the solution of compound 3 in MeCN (7 mL) was introduced ten 3 Å molecular sieves and the solution was stored under an atmosphere of nitrogen. To a stirred mixture of compound 2 with residual pyridin-1-ium dichloroacetate in MeCN (15 mL) was added the solution of compound 3 in MeCN (7 mL). After five min, to the stirred mixture was added 3-((dimethylamino-methylidene)amino)-3H-1,2,4-dithiazole-3-thione (DDTT) (650 mg, 3.2 mmol). After 30 min, the yellow mixture was concentrated in vacuo to give compound 4 as a yellow oil. 
     Step 3: 
     Preparation of N,N′-(((2R,3R,3aR,7aR,9R,10R,10aR,12R,14aR)-5-(2-cyanoethoxy)-3,10-difluoro-12-mercapto-12-oxido-5-sulfidooctahydro-2H,7H-difuro[3,2-d:3′,2′-j][1,3,7,9]tetraoxa[2,8]diphosphacyclododecine-2,9-diyl)bis(9H-purine-9,6-diyl))dibenzamide(5): To a solution of compound 4 in CH 2 Cl 2  (60 mL) were added water (0.35 mL) and a 6% (v/v) solution of dichloroacetic acid (DCA) in CH 2 Cl 2  (60 mL). After ten min at room temperature, to the red solution was introduced pyridine (20 mL). The resulting yellow mixture was concentrated in vacuo until approximately 20 mL of the yellow mixture remained. To the yellow mixture was introduced pyridine (20 mL) and the mixture was concentrated in vacuo until approximately 20 mL of the yellow mixture remained. To the yellow mixture was added pyridine (30 mL) and the mixture was concentrated in vacuo until approximately 30 mL of the yellow mixture remained. To the stirred yellow mixture in pyridine (30 mL) was added 2-chloro-5,5-dimethyl-1,3,2-dioxaphosphorinane-2-oxide (DMOCP) (1.6 g, 8.4 mmol). After seven min, to the dark orange solution was added water (1.4 mL), followed immediately by the introduction of 3H-1,2-benzodithiol-3-one (0.71 mg, 4.2 mmol). After five min, the dark orange solution was poured into a 1N aqueous NaHCO 3  solution (400 mL). After ten min, the biphasic mixture was extracted with EtOAc (200 mL) and diethyl ether (200 mL). After separation, the aqueous layer was back extracted with EtOAc (200 mL) and diethyl ether (200 mL). The organic extracts were combined and concentrated in vacuo. To the concentrated yellow oil was added toluene (75 mL) and the mixture was evaporated in vacuo to remove residual pyridine. This procedure was repeated twice with toluene (75 mL). The resulting oil was purified by silica gel chromatography (0% to 10% MeOH in CH 2 Cl 2 ) to provide compound 5 (67 mg, 2.5% yield) as an orange oil. 
     Step 4: 
     Preparation of Compound (T1-1): To a stirred solution of compound 5 (65 mg, 0.07 mmol) in MeOH (0.9 mL) was added aqueous ammonium hydroxide (0.9 mL) and the orange slurry was heated at 50° C. After two hours, the orange solution was allowed to cool and concentrated in vacuo. The orange residue was purified by reverse phase silica gel chromatography (0% to 30% MeCN in 10 mM aqueous Triethylammonium acetate (TEAA) to obtain Compound (T1-1) (18 mg, 38% yield) as a white mono-triethylammonium salt after lyophilization. LCMS-ESI: 693.25 [M−H]− (calculated for C 20 H 22 F 2 N 10 O 8 P 2 S 2 : 694.305); Rt: 16.698′ min by HPLC conditions (10 mM TEAA, 2% to 20%); Rt: 20.026′. min by LCMS conditions (20 mM NH 4 OAc, 2% to 20%).  1 H NMR (400 MHz, 45° C., D 2 O) δ 8.44 (s, 2H), 8.24 (s, 2H), 6.52 (d, J=16.4 Hz, 2H), 5.80 (d, J=3.6 Hz, 1H), 5.67 (d, J=4.0 Hz, 1H), 5.37-5.26 (m, 2H), 4.77-4.65 (m, 4H), 4.22 (dd, J=11.4 Hz, 6.0 Hz, 2H), 3.34 (q, J=7.0 Hz, 6H), 1.43 (t, J=7.0 Hz, 9H).  19 F NMR (400 MHz, 45° C., D 2 O) δ −200.74 to −200.98 (m).  31 P NMR (45° C., D 2 O) δ 54.46. 
     The stereochemistry of this compound, as depicted was confirmed by the co-crystal structure bound to wild type STING protein. 
     The Rp,Sp isomer was also isolated after purification in the reverse phase chromatography step, to provide Compound (T1-6) as the bistriethylammonium salt after lyophilization. LCMS-ESI: 693.30 [M−H]− (calculated for C 20 H 22 F 2 N 10 O 8 P 2 S 2 : 694.05); Rt 13.830 min by HPLC conditions (10 mM TEAA, 2% to 20%). Rt 15.032 min by LCMS conditions (20 mM NH 4 OAc, 2% to 20%).  1 H NMR. (400 MHz, 45° C., D 2 O) δ 8.65 (s, 1H), 8.50 (s, 1H), 8.34 (s, 1H), 8.26 (s, 1H), 6.58 (dd, J=16.4, 2.8 Hz, 2H), 6.00 (dd, J=51.2, 3.6 Hz, 1H), 5.69 (dd, J=51.2, 3.8 Hz, 1H), 5.32-5.15 (m, 2H), 4.77-4.67 (m, 3H), 4.61 (d, J=12.4 Hz, 1H), 4.25 (dd, J=11.8, 4.2 Hz, 2H), 3.33 (q, J=7.2 Hz, 12H), 1.43 (t, J=7.2 Hz, 18H).  19 F NMR (400 MHz, 45° C., D 2 O) δ −200.75 to −201.31 (m).  31 P NMR (45° C., D 2 O) δ 54.69, 54.64. 
     Example Synthesis of Compounds of Formula (B) 
     Compounds of Formula (B) were made according to the synthetic description in WO2014189805. 
     Specifically, Compound (T1-2), 
     
       
         
         
             
             
         
       
     
     was synthesized according to the scheme below: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     To a solution of 5 g (5.15 mmol) N-benzoyl-5′-O-(4, 4′-dimethoxytrityl)-2′-O-tert-butyldimethylsilyl-3′-O-[(2-cyanoethyl)-ich N-diisopropylaminophinyl]adenosine (1) in 25 ml acetonitrile was added 0.18 ml (10 mmole) water and 1.20 g (6.2 mmole) pyridinium trifluoroacetate. After 5 minutes stirring at room temperature 25 ml tertbutylamine was added and the reaction stirred for 15 minutes at room temperature. The solvents were removed under reduced pressure to give (2R,3R,4R,5R)-5-(6-benzamido-9H-purin-9-yl)-2-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-4-((tert-butyldimethylsilyl)oxy)tetrahydrofuran-3-yl hydrogen phosphonate as a foam which was then coevaporated with acetonitrile (2×50 ml), then dissolved in 60 ml dichloromethane. To this solution was added water (0.9 ml, 50 mmole) and 60 ml of 6% (v/v) dichloroacetic acid (44 mmol) in dichloromethane. After 10 minutes at room temperature the reaction was quenched by the addition of pyridine (7.0 ml, 87 mmol), and concentrated to an oil which was dried by three co-evaporations with 40 ml anhydrous acetonitrile giving (2) in a volume of 12 ml. 
     N-benzoyl-5′-O-(4, 4′-dimethoxytrityl)-3′-O-tert-butyldimethylsilyl-2′-O-[(2-cyanoethyl)-N, N-diisopropylaminophinyl]adenosine ((3), 6.4 g, 6.6 mmole) was dissolved in 40 ml anhydrous acetonitrile and dried by three co-evaporations with 40 ml anhydrous acetonitrile, the last time leaving 20 ml. 3 Å molecular sieves were added and the solution stored under argon until used. Azeo dried (3) (6.4 g, 6.6 mmole) in 20 ml acetonitrile was added via syringe to a solution of (2) (5.15 mmol) in 12 ml of anhydrous acetonitrile. After 5 minutes stirring at room temperature, 1.14 g (5.6 mmol) of 3-((N,N-dimethylaminomethylidene) amino)-3H-1,2,4-dithiazole-5-thione (DDTT) was added and the reaction stirred for 30 minutes at room temperature. The reaction was concentrated and the residual oil dissolved in 80 ml dichloromethane. Water (0.9 ml, 50 mmol) and 80 ml of 6% (v/v) dichloroacetic acid (58 mmol) in dichloromethane was added, and the reaction stirred for 10 minutes at room temperature. 50 ml pyridine was added to quench the dichloroacetic acid. The solvents were removed under reduced pressure to give crude (2R,3R,4R,5R)-5-(6-benzamido-9H-purin-9-yl)-2-((((((2R,3R,4R,5R)-2-(6-benzamido-9H-purin-9-yl)-4-((tert-butyldimethylsilyl)oxy)-5-(hydroxymethyl)tetrahydrofuran-3-yl)oxy) (2-cyanoethoxy)phosphorothioyl)oxy)methyl)-4-((tert-butyldimethylsilyl)oxy)tetrahydrofuran-3-yl hydrogen phosphonate as a solid, which was then dissolved in 150 ml dry pyridine and concentrated down to a volume of approximately 100 ml. 2-chloro-5, 5-dimethyl-1,3,2-dioxaphosphorinane-2-oxide (DMOCP, 3.44 g, 18 mmole) was then added and the reaction stirred for 5 minutes at room temperature. 3.2 ml water was added immediately followed by addition of 3-H-1,2-benzodithiol-3-one (1.3 g, 7.7 mmole), and the reaction stirred for 5 minutes at room temperature. The reaction mix was then poured into 700 ml water containing 20 g NaHCO 3  and stirred for 5 minutes at room temperature, then poured into a separatory funnel and extracted with 800 ml 1:1ethyl acetate:diethyl ether. The aqueous layer was extracted again with 600 ml 1:1 ethyl acetate:diethyl ether. The organic layers were combined and concentrated under reduced pressure to yield approximately 11 g of an oil containing diastereoisomers (5a) and (5b). The crude mixture above was dissolved in dichloromethane and applied to a 250 g silica column. The desired diastereoisomers were eluted from the column using a gradient of ethanol in dichloromethane (0-10%). Fractions containing the desired diastereoisomers (5a) and (5b) were combined and concentrated, giving 2.26 g of approximately 50% (5a) and 50% (5b). 
     2.26 g of crude (5a) and (5b) from the silica gel column was transferred to a thick-walled glass pressure tube. 60 ml methanol and 60 ml concentrated aqueous ammonia was added and the tube was heated with stirring in an oil bath at 500C for 16 h. The reaction mixture was cooled to near ambient temperature, sparged with a stream of nitrogen gas for 30 minutes, and then transferred to a large round bottom flask. Most of the volatiles were removed under reduced pressure with caution so as to avoid foaming and bumping. If water was still present the residue was frozen and lyophilized to dryness. The lyophilized crude mixture was taken up in approximately 50 ml of CH 3 CN/10 mM aqueous triethylammonium acetate (60/40). After 0.45 micron PTFE filtration, 4-5 ml sample portions were applied to a C-18 Dynamax column (40×250 mm). Elution was performed with a gradient of acetonitrile and 10 mM aqueous triethylammonium acetate (30% to 50% CH 3 CN over 20 minutes at 50 ml/min flow). Fractions from the preparative HPLC runs containing pure (6) were pooled, evaporated to remove CH 3 CN and lyophilized to give 360 mg of pure (6) (the RpRp diastereoisomer) as the bis-triethylammonium salt. 
     To 270 mg (0.24 mmol) of (6) was added 5.0 ml of neat trimethylamine trihydrofluoride. The mixture was stirred at room temperature for approximately 40 h. After confirming completion of reaction by analytical HPLC, the sample was neutralized by dropwise addition into 45 ml of chilled, stirred 1M triethylammonium bicarbonate. The neutralized solution was desalted on a Waters C-18 Sep-Pak and the product eluted with CH 3 CN/10 mM aqueous triethylammonium acetate (5:1).The CH 3 CN was evaporated under reduced pressure and the remaining aqueous solution was frozen and lyophilized. Multiple rounds of lyophilization from water gave 122 mg (57%) of (T1-2) as the bis-triethylammonium salt.  1 H NMR (500 MHz, 45° C., (CD 3 ) 2 SO-15 μL D 2 O) δ 8.58 (s, 1H), 8.41 (s, 1H), 8.18 (s, 1H), 8.15 (s, 1H), 6.12 (d, J=8.0, 1H), 5.92 (d, J=7.0, 1H), 5.30 (td, J=8.5, 4.0, 1H), 5.24-5.21 (m, 1H), 5.03 (dd, J=7.5, 4.5, 1H), 4.39 (d, J=4, 1H), 4.23 (dd, J=10.5, 4.0, 1H), 4.18 (s, 1H), 4.14-4.08 (m, 2H), 3.85-3.83 (m, 1H), 3.73 (d, J=12.0, 1H), 3.06 (q, J=7.5, 12H), 1.15 (t, J=7.5, 1H);  31 P NMR (200 MHz, 45° C., (CD 3 )ISO-15pL D 2 O) δ 58.81, 52.54; HRMS (FT-ICR) l/z calcd for C20H24O10N10P2S2 (M−H) 689.0521, found 689.0514. 
     Example Synthesis of Compounds of Formula (A) 
     Synthesis of (2R,3R,3aS,5R,7aR,9S,10R,10aS,12R,14aR)-2,9-bis(6-amino-9H-purin-9-yl)-5,12-dimercaptotetrahydro-2H,7H,9H,14H-3,14a: 10,7a-bis(epoxymethano)difuro[3,2-d:3′,2′-j][1,3,7,9]tetraoxa[2,8]diphosphacyclododecine 5,12-dioxide (T2-45) and (2R,3R,3aS,5R,7aR,9S,10R,10aS,12S,14aR)-2,9-bis(6-amino-9H-purin-9-yl)-5,12-dimercaptotetrahydro-2H,7H,9H,14H-3,14a: 10,7a-bis(epoxymethano)difuro[3,2-d:3′,2′-j][1,3,7,9]tetraoxa[2,8]diphosphacyclododecine 5,12-dioxide (T2-44), were prepared according to the following Scheme: 
     
       
         
         
             
             
         
       
     
     Step 1: 
     Preparation of (1S,3R,4R,7S)-3-(6-benzamido-9H-purin-9-yl)-1-(hydroxymethyl)-2,5-dioxabicyclo[2.2.1]heptan-7-yl hydrogen phosphonate (2): To a solution of (1R,3R,4R,7S)-3-(6-benzamido-9H-purin-9-yl)-1-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-2,5-dioxabicyclo[2.2.1]heptan-7-yl (2-cyanoethyl) diisopropylphosphoramidite (1, 1.0 g, 1.2 mmol, Exiqon, Woburn, Mass.) in MeCN (10 mL) and H 2 O (0.05 mL) was added pyridinium trifluoroacetate (270 g, 1.5 mmol). After 25 min, to the stirring reaction mixture at room temperature was added tert-butyl amine (5.0 mL). After 15 min, the reaction solution was concentrated in vacuo and water was removed as an azeotrope after concentration with MeCN (3×15 mL) to obtain a white foam. To a solution of the white foam in 1,4-dioxane (13 mL) was added a solution of SalPCI (226 mg, 1.0 mmol), in 1,4-dioxane (5 mL). After 7 min, to the cloudy white mixture was added pyridine (3 mL). After 1 h, to the cloudy reaction mixture was introduced water (2 mL). After 5 min, the mixture was poured into a 1N NaHCO 3  solution (100 mL). The solution was extracted with EtOAc (3×100 mL) and the organic layer was condensed to dryness in vacuo. The residue was dissolved in CH 2 Cl 2  (10 mL) to give a white mixture. To this solution was added water (150 μL) and 9% (v/v) solution of DCA in CH 2 Cl 2  (10 mL). After 10 min of stirring at room temperature, to the orange solution was charged pyridine (1.5 mL). The resulting clear solution was concentrated in vacuo and water was removed as an azeotrope after concentration with MeCN (3×20 mL). On the last evaporation, the resulting cloudy slurry of compound 2 was left in MeCN (20 mL). 
     Step 2: 
     Preparation of (1R,3R,4R,7S)-3-(6-benzamido-9H-purin-9-yl)-1-((((((1R,3R,4R,7S)-3-(6-benzamido-9H-purin-9-yl)-1-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-2,5-dioxabicyclo[2.2.1]heptan-7-yl)oxy) (2-cyanoethoxy) phosphorothioyl)oxy)methyl)-2,5-dioxabicyclo[2.2.1]heptan-7-yl hydrogen phosphonate (3): A solution of compound 1 (1.0 g, 1.2 mmol, Exiqon) in MeCN (10 mL) was dried through concentration in vacuo. This process was repeated two more times to remove water as an azeotrope. On the last azeotrope, to the solution of compound 1 in MeCN (10 mL) was introduced ten 3 Å molecular sieves and the solution was stored under an atmosphere of nitrogen. To a stirred mixture of compound 2 with residual pyridinium dichloroacetate in MeCN (20 mL) was added the solution of compound 1 in MeCN (10 mL). After 40 min, to the stirred mixture was added DDTT (263 mg, 1.3 mmol). After 70 min, the yellow solution was concentrated in vacuo to give compound 3 as a yellow paste. 
     Step 3: 
     Preparation of N,N′-(((2S,3R,3aS,7aR,9R,10R,10aS,12R,14aR)-5-(2-cyanoethoxy)-12-mercapto-12-oxido-5-sulfidotetrahydro-2H,7H,9H, 14H-3,14a:10,7a-bis(epoxymethano)difuro[3,2-d:3′,2′-j][1,3,7,9]tetraoxa[2,8]diphosphacyclododecine-2,9-diyl)bis(9H-purine-9,6-diyl))dibenzamide (4): To a solution of compound 3 in CH 2 Cl 2  (30 mL) were added water (180 μL) and 8.5% (v/v) solution of DCA in CH 2 Cl 2  (20 mL). After stirring for 15 min at room temperature, to the red-orange solution was introduced pyridine (10 mL). The resulting yellow solution was concentrated in vacuo until approximately 10 mL of the yellow mixture remained. To the yellow mixture was introduced pyridine (30 mL) and the mixture was concentrated in vacuo until approximately 10 mL of the yellow mixture remained. To the yellow mixture was added pyridine (30 mL) and the mixture was concentrated in vacuo until approximately 10 mL of the yellow mixture remained. To the stirred yellow mixture in pyridine (50 mL) was added DMOCP (631 mg, 3.4 mmol). After 15 min, to the brownish yellow solution was added water (750 μL), followed immediately by the introduction of 3H-1,2-benzodithiol-3-one (304 mg, 1.8 mmol). After 30 min, the brownish yellow solution was poured into a 1N aqueous NaHCO 3  solution (250 mL). After 15 min, the biphasic mixture was extracted with EtOAc (200 mL). After separation, the aqueous layer was back extracted with EtOAc (2×150 mL). The organic extracts were combined and concentrated in vacuo. To the concentrated yellow oil was added toluene (20 mL) and the mixture was evaporated in vacuo to remove residual pyridine. This procedure was repeated again with toluene (30 mL). The resulting oil was purified by silica gel chromatography (0% to 50% MeOH in CH 2 Cl 2 ) to provide a mixture of compound 4 (604 mg, 52% yield) as beige solid. 
     Step 4: 
     Preparation of (T2-45) and (T2-44): To a stirred solution of compound 4 (472 mg, 0.5 mmol) in EtOH (5.0 mL) was added AMA (ammonium hydroxide/40% methylamine solution in water )(6.5 mL) and the yellow solution was heated at 50° C. After 2 h, the yellow solution was allowed to cool and concentrated in vacuo. The yellow residue in 10 mM TEAA (3 mL) was purified by reverse phase silica gel chromatography (0% to 25% MeCN in 10 mM aqueous TEAA) to obtain compound (T2-45) (92 mg, 27% yield) as a white triethylammonium salt after lyophilization. LCMS-ESI: 712.95 [M−H]− (calculated for C 22 H 24 N 10 O 10 P 2 S 2 : 714.56); R t : 1.06 min by UPLC (20 mM NH 4 OAc, 2% to 80% MeCN).  1 H NMR (400 MHz, 45° C., D 2 O) δ 8.45 (d, J=4.4 Hz, 2H), 8.30 (d, J=5.6 Hz, 2H), 6.36 (d, J=4.4 Hz, 2H), 5.12 (s, 4H), 4.63 (d, J=12.4 Hz, 2H), 4.34-4.24 (m, 6H), 3.33 (q, J=7.2 Hz, 12H), 2.09 (m, 1H), 1.40 (t, J=5.2 Hz, 18H).  31 P NMR (45° C., D 2 O) δ 54.57. 
     The Rp,Sp isomer was also isolated after purification in the reverse phase chromatography step, to provide compound (T2-44) (35 mg, 10% yield) as the triethylammonium salt after lyophilization. LCMS-ESI: 712.95 [M−H]− (calculated for C 22 H 24 N 10 O 10 P 2 S 2 : 714.56); R t : 1.01 min by UPLC (20 mM NH 4 OAc, 2% to 80% MeCN).  1 H NMR (400 MHz, 45° C., D 2 O) δ 8.58 (s, 1H), 8.46 (s, 1H), 8.31 (s, 1H), 8.27 (s, 1H), 6.38 (s, 2H), 5.32 (s, 1H), 5.11 (s, 1H), 5.07 (d, J=10.4 Hz, 2H), 4.62 (d, J=11.2 Hz, 1H), 4.53 (d, J=11.2 Hz, 1H), 4.41-4.31 (m, 4H), 4.24 (t, J=16.4 Hz, 1H), 3.33 (q, J=7.2 Hz, 10H), 1.41 (t, J=7.2 Hz, 15H).  31 P NMR (45° C., D 2 O) δ 55.33, 54.48. 
     Example Synthesis of Compounds of Formula (B) 
     Certain compounds of Formula (B) were made enzymatically. Specifically compound T1-25 was prepared enzymatically according to the following synthetic scheme: 
     
       
         
         
             
             
         
       
     
     The reaction was carried out in duplicate in parallel: to 100 mM aqueous (((2S,3R,4R,5R)-5-(6-amino-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methyl) phosphonic diphosphoric anhydride (a) (250 μL, 0.025 mmol; N-1007, TriLink Biotechnologies, San Diego, Calif., USA), 100 mM aqueous (((2S,3S,4R,5R)-5-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)phosphonic diphosphoric anhydride (b) (250 μL, 0.025 mmol, Sigma Cat. No 51120), Herring Sperm DNA solution (250 μL, 10 mg/mL aq.; #9605-5-D, Trevigen Inc., Gaithersburg, Md., USA) and human cGAS (1500 μL, 2.1 mg/mL, prepared as described in the next paragraph) was added reaction buffer (50 mM TRIS, 2.5 mM magnesium acetate, 10 mM KCl, pH adjusted to 8.2 with aq. NaOH 5 M; 25 mL). The reaction was incubated for 16 hours at 37° C. and 150 rpm on an orbital shaker. Completion of the reaction was confirmed through analysis of an aliquot (100 μL) of the reaction mixture, diluted with acetonitrile (100 μL), centrifuged and the desired compound formation determined by UV analysis. The reactions were mixed with acetonitrile (20 mL), incubated at room temperature on an orbital shaker for 10 minutes and after subsequent centrifugation (7000 g for 5 min) the supernatant was filtrated through a paper filter. The filtrate was mixed with acetic acid (100 μL) and directly loaded onto a 20×250 mm Inertsil Amide 5 μm column (flow rate 30 mL/min; solvent A: aqueous 10 mM ammonium acetate, 2 mM acetic acid, solvent B: acetonitrile; using an isocratic elution using 26% phase A/74% phase B, fraction size 50 mL). The fractions containing the desired compound (T1-25) were combined and the solvents were evaporated in vacuo to a final volume of about 10 mL. The concentrated compound (T1-25) solution from the first chromatography was re-purified by direct injection onto 1×50 cm Sephadex G10 HPLC column (flow rate 1.0 mL/min; mobile phase containing 0.25 mM ammonium hydroxide and 25% acetonitrile) with UV detection at 250 nm. All fractions containing the desired compound (T1-25) were combined and dried by lyophilisation to give 4.5 mg of compound (T1-25) as the bis-ammonium salt;  1 H NMR (600.1 MHz, D 2 O) δ 8.35 (br s, 1H), 8.06 (br s, 1H), 7.77 (s, 1H), 6.31 (d, J=12.8 Hz, 1H), 5.86 (s, 1H), 5.62 (s, 1H), 5.35 (d, J=50.8 Hz, 1H), 4.97 (d, J=19.0 Hz, 1H), 4.46 (s, 1H), 4.42 (s, 1H), 4.33 (s, 1H), 4.24 (s, 1H), 4.21 (s, 2H), 3.97 (s, 1H); MS m/z 677.2 [M+H]+. 
     The cGAS used in this example and the following example were prepared by cloning and expression of human and mouse cGAS. The coding region of human or mouse cGAS comprising amino acid 155-522 (human) and amino acid 147-507 (mouse) was cloned into a pET based expression vector. The resulting expression construct contained an N-terminal 6×-His-tag (SEQ ID NO: 930) followed by a ZZ-tag and an engineered HRV3C protease cleavage side allowing generation of human cGAS 155-522 and mouse cGas 147-507 with an N-terminal extension of a Gly-Pro. Both plasmids were transformed in the  E. coli  strain * BL21 (DE3) phage resistant cells (C2527H, New England BioLabs, Ipswich, Mass.) for bacterial expression. The phage resistant  E. coli  cells BL21(DE3) harboring the cGas expression plasmids were expressed at a 1.5 L scale in Infors bioreactors. Precultures were grown in LB medium. 1.5 L auto-induction media (Studier, Protein Expr Purif. 2005 May; 41(1):207-34) containing Kanamycin (50  g/mL) were inoculated with 100 mL preculture and cultivated to an OD of approximately 10 under the following conditions: temperature 37° C.; stirrer (cascade regulation via pO2) 500; pH 7.0; pO2 (cascade regulation on) 5%; flow 2.5 L/min; and gas mix (cascade regulation via pO2) 0. The temperature was then reduced to 18° C. and expression was run over night. Cells were harvested by centrifugation and lysed by using an Avestin EmulsiFlex French press. Purification was done according the published protocol by Kato et al. (PLoS One, 2013, 8(10) e76983) using Ni-affinity chromatography, a heparin purification step to remove DNA and a final size exclusion chromatography. cGAS eluted as a homogenous fraction and was concentrated to at least 5 mg/mL. 
     
       
         
           
               
               
            
               
                 (SEQ ID NO: 940) 
                   
               
               
                 Human cGAS: GPDAAPGASK LRAVLEKLKL SRDDISTAAG MVKGVVDHLL LRLKCDSAFR 
                   
               
               
                   
               
               
                 GVGLLNTGSY YEHVKISAPN EFDVMFKLEV PRIQLEEYSN TRAYYFVKFK RNPKENPLSQ 
               
               
                   
               
               
                 FLEGEILSAS KMLSKFRKII KEEINDIKDT DVIMKRKRGG SPAVTLLISE KISVDITLAL 
               
               
                   
               
               
                 ESKSSWPAST QEGLRIQNWL SAKVRKQLRL KPFYLVPKHA KEGNGFQEET WRLSF-SHIEK 
               
               
                   
               
               
                 EILNNHGKSK TCCENKEEKC CRKDCLKLMK YLLEQLKERF KDKKHLDKFS SYHVKTAFFH 
               
               
                   
               
               
                 VCTQNPQDSQ WDRKDLGLCF DNCVTYFLQC LRTEKLENYF IPEFNLFSSN LIDKRSKEFL 
               
               
                   
               
               
                 TKQIEYERNN EFPVFDEF. 
               
            
           
         
       
     
     Example Synthesis of Compounds of Formula (B) 
     Certain compounds of Formula (B) were made enzymatically. Specifically compound T1-28 was prepared enzymatically according to the following synthetic scheme: 
     
       
         
         
             
             
         
       
     
     The reaction was performed four times in parallel, each on a 26 mL scale: to 100 mM aqueous (((2S,3R,4R,5R)-5-(6-amino-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methyl)phosphonic diphosphoric anhydride (a) (250 μL, 0.025 mmol), 100 mM aqueous (((2S,3S,4S,5R)-5-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)-3-fluoro-4-hydroxytetrahydrofuran-2-yl)methyl)phosphonic diphosphoric anhydride (c) (250 μL, 0.025 mmol; N-3002, TriLink Biotechnologies), Herring Sperm DNA solution (800 μL, 10 mg/mL aq.; #9605-5-D, Trevigen Inc.) and mouse cGAS preparation (250 μL, 6.5 mg/mL, prepared as described for human cGAS above) was added reaction buffer (50 mM TRIS, 2.5 mM magnesium acetate, pH adjusted to 8.2 with aq. NaOH 5 M; 25 mL). The reaction was incubated for 16 hours at 37° C. and 150 rpm on an orbital shaker. The reactions were mixed with acetonitrile (20 mL) and incubated at room temperature on an orbital shaker for 10 min. After subsequent centrifugation (7000 g for 5 min) the supernatant of all four reactions was combined and filtrated through a paper filter. The filtrate was evaporated in vacuo to a residual volume of approximately 20 mL and mixed with 0.5 mL acetic acid (0.5 mL) and 1.0M aqueous triethylammonium acetate (5 mL). The crude material was directly injected onto the Chromolith RP18e 2.1×10 cm column. Chromatography (flowrate 80 mL/min; isocratic mobile 10 mM triethylammonium acetate and 1 vol % acetonitrile) yielded the desired compound (T1-28) fractions which were combined, mixed with aqueous 25% ammonia solution (20 μL) and dried by lyophilisation. The compound (T1-28) was obtained as bis-triethylammonium salt; 39.8 mg;  1 H NMR (600.1 MHz, D 2 O) δ 8.16 (s, 1H), 8.13 (s, 1H), 7.73 (s, 1H), 6.33 (d, J=13.9 Hz, 1H), 5.91 (d, J=8.6 Hz, 1H), 5.61 (m, 1H), 5.40 (dd, J=51.5, 2.6 Hz, 1H), 5.30 (dd, J=53.3, 3.2 Hz, 1H), 4.98 (m, 1H), 4.56 (d, J=25.8 Hz, 1H), 4.44 (d, J=9.0 Hz, 1H), 4.39 (d, J=11.8 Hz, 1H), 4.20 (m, 1H), 4.08 (d, J=12.4 Hz, 1H), 4.04 (d, J=11.8 Hz, 1H), 3.06 (q, J=7.3 Hz, 12H), 1.13 (t, J=7.3 Hz, 18H); 31P NMR (376.4 MHz, D 2 O) δ −1.68, −2.77; 19F NMR (376.4 MHz, D 2 O) δ −199.72, −203.23; MS 677.2 [M−1]−. 
     
       
         
           
               
               
            
               
                 (SEQ ID NO: 941) 
                   
               
               
                 Mouse cGAS: GPDKLKKVLD KLRLKRKDIS EAAETVNKVV ERLLRRMQKR ESEFKGVEQL 
                   
               
               
                   
               
               
                 NTGSYYEHVK ISAPNEFDVM FKLEVPRIEL QEYYETGAFY LVKFKRIPRG NPL-SHFLEGE 
               
               
                   
               
               
                 VLSATKMLSK FRKIIKEEVK EIKDIDVSVE KEKPGSPAVT LLIRNPEEIS VDIILALESK 
               
               
                   
               
               
                 GSWPISTKEG LPIQGWLGTK VRTNLRREPF YLVPKNAKDG NSFQGETWRL SF-SHTEKYIL 
               
               
                   
               
               
                 NNHGIEKTCC ESSGAKCCRK ECLKLMKYLL EQLKKEFQEL DAFCSYHVKT AIFHMWTQDP 
               
               
                   
               
               
                 QDSQWDPRNL SSCFDKLLAF FLECLRTEKL DHYFIPKFNL FSQELIDRKS KEFLSKKIEY 
               
               
                   
               
               
                 ERNNGFPIFD KL.  
               
            
           
         
       
     
     Example Synthesis of Compounds of Formula (D) 
     Specifically, (1S,3R,6R,8R,9S,11R,14R,16R,17R,18R)-8,16-bis(6-amino-9H-purin-9-yl)-17,18-difluoro-2,4,7,10,12,15-hexaoxa-3,11-diphosphatricyclo[12.2.1.16,9]octadecane-3,11-bis(thiolate) 3,11-dioxide (8) (which corresponds to compound (T2-46)) was synthesized according to the scheme below: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Step 1: 
     Preparation of (2R,3S,4R,5R)-2-(6-benzamido-9H-purin-9-yl)-5-((bis(4-methoxyphenyl) (phenyl)methoxy)methyl)-4-fluorotetrahydrofuran-3-yl (2-cyanoethyl) diisopropylphosphoramidite (2): To a solution of Compound i6 (1, 1 g, 1.5 mmol, 1 eq) (dried via co-evaporation in vacuo with anhydrous MeCN (3×3 mL)) in anhydrous THF (6 mL) was added DMAP (18 mg, 0.15 mmol, 0.1 eq) and DIPEA (0.98 mL, 5.9 mmol, 4 eq). 2-cyanoethyl N,N-diisopropyl chlorophosphoramidite (360 μL, 1.6 mmol, 1.1 eq, ChemGenes) was added and the reaction was stirred overnight. The mixture was diluted with 100 mL of EtOAc (prewashed with 5% NaHCO 3 ) and washed with brine (5×50 mL). The EtOAc layer dried over Na 2 SO 4 , filtered and concentrated in vacuo. Flash chromatography (40 g silica gel, isocratic gradient—50:44:4 DCM:Hexanes:TEA) gave 1.08 g of the compound 2. 
     Step 2: 
     Preparation of (2R,3S,4R,5R)-2-(6-benzamido-9H-purin-9-yl)-5-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-4-fluorotetrahydrofuran-3-yl hydrogen phosphonate (4): To a solution of Compound i6 (1.5 g, 2.7 mmol, 1 eq) in anhydrous dioxane (17 mL) was added anhydrous pyridine (4.7 mL, 69 mmol, 26 eq) followed by a solution of 2-chloro-1,3,2-benzodioxaphosphorin-4-one (3, 540 mg, 3.2 mmol, 1.2 eq, Sigma Aldrich) in 1,4-dioxane (8.3 mL). The reaction mixture was stirred for 1 h then diluted with 10 mL water and NaHCO 3  (3.72 g in 100 mL of water). The suspension was extracted with EtOAc (3×100 mL), the organic layers were combined, dried with Na 2 SO 4 , filtered and concentrated. Chromatography (80 g of SiO 2 , 0-50% MeOH (with 0.5% pyridine) and DCM) gave compound 4. 
     Step 3: 
     Preparation of (2R,3S,4R,5R)-2-(6-benzamido-9H-purin-9-yl)-4-fluoro-5-(hydroxymethyl)tetrahydrofuran-3-yl hydrogen phosphonate (5): To a solution of compound 4 (0.78 g, 1.1 mmol, 1 eq) in DCM (13 mL) was added water (190 μL, 11 mmol, 10 eq) and a solution of DCA (760 μL 9.2 mmol, 8.7 eq) in DCM (13 mL). The mixture was stirred for 10 min and quenched with pyridine (1.5 mL, 18 mmol, 17 eq). The mixture was concentrated in vacuo and co-evaporated with anhydrous MeCN (3×10 mL) to provide compound 5 in 4 mL of MeCN. 
     Step 4: 
     Preparation of (2R,3S,4R,5R)-2-(6-benzamido-9H-purin-9-yl)-5-((((((2R,3S,4R,5R)-2-(6-benzamido-9H-purin-9-yl)-5-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-4-fluorotetrahydrofuran-3-yl)oxy)(2-cyanoethoxy)phosphorothioyl)oxy)methyl)-4-fluorotetrahydrofuran-3-yl hydrogen phosphonate (6): Compound 2 (1.1 g, 1.2 mmol, 1.1 eq) was dried via co-evaporation in vacuo with anhydrous MeCN (3×10 mL leaving 8 mL). This solution was added to the solution of compound 5 from Step 3 and stirred for 5 min. DDTT (240 mg, 1.2 mmol, 1.1 eq) was added and the mixture was stirred for 30 min then concentrated in vacuo to provide compound 6. 
     Step 5: 
     Preparation of N,N′-(((1 S,3R,6R,8R,9S,11R, 14R,16R,17R,18R)-3-(2-cyanoethoxy)-17,18-difluoro-11-mercapto-11-oxido-3-sulfido-2,4,7,10,12,15-hexaoxa-3,11-diphosphatricyclo[12.2.1.1 69 ]octadecane-8,16-diyl)bis(9H-purine-9,6-diyl))dibenzamide (7A): To a solution of compound 6 in DCM (25 mL) was added water (190 μL, 11 mmol, 10 eq) and a solution of DCA (1.5 mL, 18 mmol, 17 eq) in DCM (25 mL). The mixture was stirred for 10 min, then quenched with pyridine (11 mL, 130 mmol, 120 eq), then concentrated in vacuo to approximately 13 mL. An additional 30 mL of anhydrous pyridine was added. The solution was treated with DMOCP (580 mg, 3.2 mmol, 3 eq) and stirred for 3 min, after which water (570 μL, 32 mmol, 30 eq) was added followed immediately by 3H-1,2-benzodithiol-3-one (260 mg, 1.6 mmol, 1.5 eq). After 5 min the solution was poured into saturated NaHCO 3  (100 mL) and extracted with EtOAc (2×100 mL). The organic layers were combined and concentrated to give ˜2.5 g of crude mixture of isomers 7A/B. Chromatography (80 g SiO 2 , MeOH:DCM 0-15% over 54 min) gave 128 mg of compound 7A. 
     Step 6: 
     Preparation of (1S,3R,6R,8R,9S,11R,14R,16R,17R,18R)-8,16-bis(6-amino-9H-purin-9-yl)-17,18-difluoro-3,11-dimercapto-2,4,7,10,12,15-hexaoxa-3,11-diphosphatricyclo[12.2.1.1 6,9 ]octadecane 3,11-dioxide (8) (which corresponds to compound (T2-46)): To a solution of 7A (70 mg) in MeOH (1.5 mL) was added NH 4 OH (1.5 mL). The reaction mixture was heated to 50° C. for 2.5 h then cooled, sparged with N 2  and concentrated in vacuo. Purification (RP MPLC—5.5 g C18—0-20% MeCN/TEAA (10 mM) over 90 column volumes) to give after lyophilization 10 mg of Compound 8. LCMS-ESI: 693.70 [M−H]− (calculated for C 20 H 22 F 2 N 10 O 8 P 2 S 2 : 694.05); R t : 8.174 min by LCMS conditions (20 mM NH 4 OAc, 2% to 50%).  1 H NMR. (400 MHz, 45° C., D 2 O) δ 8.08 (s, 1H), 7.99 (s, 1H), 6.17 (d, J=8.4, 1H), 5.84 (dd, J=52.4, 3.6 1H), 5.19-5.11 (m, 1H), 4.77 (m, 1H), 4.46-4.2 (m, 1H), 4.10-4.09 (m, 1H), 3.09 (q, J=7.2, 6H), 1.17 (t, J=7.6 Hz, 9H). 
     Intermediate i6 (used above) was prepared according to the following scheme 
     
       
         
         
             
             
         
       
     
     Step 1: 
     Preparation of (2R,3R,4R,5R)-5-(6-benzamido-9H-purin-9-yl)-2-((bis(4-methoxyphenyl) (phenyl)methoxy)methyl)-4-((tert-butyldimethylsilyl)oxy)tetrahydrofuran-3-yl trifluoromethane-sulfonate (i2): A mixture of N-(9-((2R,3R,4R,5R)-5-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-3-((tert-butyldimethylsilyl)oxy)-4-hydroxytetrahydrofuran-2-yl)-9H-purin-6-yl)benzamide (i1, 5.6 g, 7.11 mmol, ChemGenes) and DMAP (0.174 g, 1.42 mmol) was suspended in anhydrous THF (35 mL), addition of DIPEA (6.21 mL, 35.5 mmol) created a solution to which N-phenyltriflamide (5.08 g, 14.21 mmol), was added. The mixture was stirred for 3.5 h at rt, at which point it was poured into 5% brine (100 mL) and extracted with EtOAc (2×100 mL). The combined organic phases were dried (Na 2 SO 4 ) the drying agent filtered-off and concentrated on silica gel (10 g) in vacuo. The crude material was purified by chromatography on silica gel (gradient elution 25-100% EtOAc/heptane) to give the desired compound i2 as a tan solid; 5.53 g;  1 H NMR (400 MHz, CDCl 3 ) δ 9.05 (s, 1H), 8.68 (s, 1H), 8.18 (s, 1H), 8.06 (d, J=7.5 Hz, 2H), 7.66 (t, J=7.4 Hz, 1H), 7.61-7.48 (m, 4H), 7.48-7.25 (m, 7H), 6.88 (d, J=8.8 Hz, 4H), 6.04 (d, J=7.6 Hz, 1H), 5.50 (dd, J=7.5, 4.7 Hz, 1H), 5.32 (d, J=4.5 Hz, 1H), 4.50 (t, J=4.1 Hz, 1H), 3.82 (s, 6H), 3.77 (dt, J=10.8, 5.2 Hz, 1H), 3.41 (dd, J=10.8, 3.7 Hz, 1H), 0.77 (s, 9H), −0.01 (s, 3H), −0.46 (s, 3H); LCMS (Method A) Rt=1.65 min; m/z 920.5 [M+H] + . 
     Step 2: 
     Preparation of (2R,3S,4R,5R)-5-(6-benzamido-9H-purin-9-yl)-2-((bis(4-methoxyphenyl) (phenyl)methoxy)methyl)-4-((tert-butyldimethylsilyl)oxy)tetrahydrofuran-3-yl acetate (i3): A mixture of compound i2 (5.5 g, 5.98 mmol), KOAc (2.93 g, 29.9 mmol), and 18-crown-6 (1,4,7,10,13,16-hexaoxacyclooctadecane, 0.79 g, 2.99 mmol) in toluene (40 mL) was heated at 110° C. for 4 h. The reaction mixture was then cooled to rt and silica gel (10 g) added and the solvent was removed in vacuo. The crude material was purified by chromatography on silica gel (gradient elution 25-100% EtOAc/heptane) to give the desired compound i3 as a tan solid: 3.3 g;  1 H NMR (400 MHz, CDCl 3 ) δ 8.70 (s, 1H), 8.58 (s, 1H), 7.93 (s, 1H), 7.84 (d, J=7.5 Hz, 2H), 7.44 (t, J=7.4 Hz, 1H), 7.35 (t, J=7.6 Hz, 2H), 7.28 (d, J=7.2 Hz, 2H), 7.21-7.02 (m, 7H), 6.67 (dd, J=8.9, 2.1 Hz, 4H), 5.98 (s, 1H), 4.97 (dd, J=3.6, 1.4 Hz, 1H), 4.61-4.52 (m, 1H), 4.35 (s, 1H), 3.62 (s, 6H), 3.41 (dd, J=9.8, 6.2 Hz, 1H), 3.18 (dd, J=9.8, 5.6 Hz, 1H), 1.53 (s, 3H), 0.77 (s, 9H), 0.03 (s, 3H), 0.0 (s, 3H). LCMS (Method A) R t  1.68 min; m/z 830.2 [M+H] + . 
     Step 3: 
     Preparation of N-(9-((2R,3R,4S,5R)-5-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-3-((tert-butyldimethylsilyl)oxy)-4-hydroxytetrahydrofuran-2-yl)-9H-purin-6-yl)benzamide (i4): Compound i3 (6.78 g, 8.17 mmol) was dissolved in MeOH (120 mL) and a 2.0 M dimethylamine solution in MeOH (20.4 mL, 40.8 mmol) was added. The reaction mixture was stirred for 17 h at rt. Silica gel (12 g) was added and the solvent was removed in vacuo. The crude material was purified by chromatography on silica gel (gradient elution 25-75% EtOAc/heptane) to give the desired compound i4 as a tan solid: 3.9 g;  1 H NMR (400 MHz, CDCl 3 ) δ 8.94 (s, 1H), 8.65 (s, 1H), 8.16 (s, 1H), 7.97-7.90 (m, 2H), 7.58-7.38 (m, 3H), 7.38-7.32 (m, 2H), 7.32-7.00 (m, 7H), 6.80-6.65 (m, 4H), 5.83 (d, J=1.2 Hz, 1H), 5.38 (d, J=8.0 Hz, 1H), 4.42 (s, 1H), 4.29 (t, J=4.6 Hz, 1H), 4.02-3.95 (m, 1H), 3.75-3.61 (m, 6H), 3.53 (d, J=5.0 Hz, 2H), 0.81 (s, 9H), 0.0 (s, 6H). LCMS (Method A) R t  1.57 min; m/z 788.2 [M+H] + . 
     Step 4: 
     Preparation of N-(9-((2R,3S,4S,5R)-5-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-3-((tert-butyldimethylsilyl)oxy)-4-fluorotetrahydrofuran-2-yl)-9H-purin-6-yl)benzamide (i5a) and N-(9-((2R,3S,4R,5R)-5-((bis(4-methoxyphenyl)(phenyl)methoxy) methyl)-3-((tert-butyldimethylsilyl)oxy)-4-fluorotetrahydrofuran-2-yl)-9H-purin-6-yl)benzamide (i5b): Compound i4 (750 mg, 0.952 mmol) was dissolved in anhydrous DCM (7 mL) under an inert nitrogen atmosphere and the solution was cooled to 0° C. A 1.0 M solution of DAST (1.90 mL, 1.90 mmol) was added and the reaction subsequently stirred at −5° C. for 17 h using a cryo-cool to control the reaction temperature. The vessel was warmed to 0° C. and saturated NaHCO 3  (2 mL) was added. After 30 min of stirring the mixture was diluted with 5% brine (20 mL) and extracted with EtOAc (2×20 mL). The combined organics were dried (Na 2 SO 4 ) with the drying agent filtered off, silica gel (2 g) added to the filtrate and the solvent removed in vacuo. The crude material was purified by chromatography on silica gel (gradient elution 10-75% EtOAc/heptane) to give a mixture of diastereoisomers i5a and i5b as a tan solid: 193 mg; Major (2R,3S,4S,5R) diastereoisomer LCMS (Method A) R t  1.53 min; m/z 790.4 (M+H) + ; Minor (2R,3S,4R,5R) diastereoisomer R t  1.58 min; m/z 790.4 [M+H] + . 
     Step 5: 
     Preparation of N-(9-((2R,3S,4S,5R)-5-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)-9H-purin-6-yl)benzamide (i6): The diastereomeric mixture of i5a and i5b (2.0 g, 2.53 mmol) was dissolved in anhydrous THF (100 mL) and cooled to −42° C. under an inert nitrogen atmosphere before 1.0 M TBAF (3.80 mL, 3.80 mmol) was added. The reaction was stirred for 2.5 h, then quenched with saturated NaHCO 3  (20 mL). The cold bath was removed, and the slurry was stirred for 10 min before the mixture was diluted with 5% brine (150 mL) and extracted with DCM (2×100 mL). The combined organic phases were dried (Na 2 SO 4 ), with the drying agent filtered off, silica gel (4 g) added to the filtrate and the solvent removed in vacuo. The crude material was purified by chromatography on silica gel (gradient elution 25-100% EtOAc/heptane) to give the desired compound i6 as a white solid: 355 mg;  1 H NMR (400 MHz, CDCl 3 ) δ 9.16 (s, 1H), 8.64 (s, 1H), 8.23 (s, 1H), 7.99 (d, J=7.5 Hz, 2H), 7.59 (t, J=7.4 Hz, 1H), 7.48 (t, J=7.6 Hz, 2H), 7.41-7.31 (m, 3H), 7.31-7.11 (m, 7H), 6.79 (d, J=8.9 Hz, 4H), 6.16 (d, J=7.3 Hz, 1H), 5.77 (br s, 1H), 5.27-5.10 (m, 2H), 4.53 (dt, J=28.0 Hz, 3.4 Hz, 1H), 3.77 (s, 6H), 3.51 (dd, J=10.7, 3.7 Hz, 1H), 3.34 (dd, J=10.7, 3.3 Hz, 1H);  19 F NMR (376.4 MHz, CDCl 3 ) δ −197.5;  13 C NMR (101 MHz, CDCl 3 ) δ 164.66, 158.64, 158.62, 152.60, 151.43, 149.34, 144.22, 141.66, 135.29, 135.13, 133.40, 132.93, 129.96, 128.87, 127.99, 127.93, 127.86, 127.07, 122.65, 113.26, 93.85, 92.02, 87.56 (d, J=144 Hz), 83.56 (d, J=23 Hz), 77.30, 74.63 (d, J=16 Hz), 62.82 (d, J=11 Hz), 55.26; LCMS (Method A) R t  0.89 min; m/z 676.3 [M+H] + . 
     Alternatively, Intermediate i6 was also prepared according to the following Scheme 1A′: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Step 1: 
     Preparation of (2R,3R,4R,5R)-5-(6-amino-9H-purin-9-yl)-2-(hydroxymethyl)-4-((4-methoxybenzyl) oxy)tetrahydrofuran-3-ol (i8): To a suspension of adenosine (i7, 100 g, 374 mmol) in DMF (2.64 L) at 4° C. under nitrogen was added 60% sodium hydride (19.46 g, 486 mmol) in one portion and the reaction mixture stirred under nitrogen for 60 min. 4-Methoxybenzyl chloride (60.9 ml, 449 mmol) was added dropwise over a 10 min period and the suspension stirred and warmed to rt for 16 h. The reaction was quenched with water (50 mL), a short path condenser then fitted and the pale yellow mixture was heated (115° C.) in vacuo to remove the DMF (60-90° C.). The reaction volume was reduced to −300 mL and then partitioned between water (2.5 L) and EtOAc (2×500 mL) with the pH of the aqueous phase ˜8. The aqueous phase was separated and then extracted with 4:1 DCM-IPA (8×500 mL). The combined DCM-IPA phase was dried (Na 2 SO 4 ), the drying agent filtered off and the filtrate concentrated in vacuo to yield a semi-solid residue. The crude residue was stirred in EtOH (130 mL) at 55° C. for 1 h, filtered off, the solid washed with EtOH and dried in vacuo to afford a white solid (55.7 g, 38%, regioisomer ratio 86:14). This material was re-subjected to a hot slurry in EtOH (100 mL at 55° C.), hot filtered, the solid washed with cold EtOH to give the desired compound i8 as a white crystalline solid (47.22 g):  1 H NMR (400 MHz, DMSO-d 6 ) δ 8.30 (s, 1H), 8.08 (s, 1H), 7.33 (br s, 2H), 7.06 (d, J=8.6 Hz, 2H), 6.73 (d, J=8.6 Hz, 2H), 6.03 (d, J=6.3 Hz, 1H), 5.46 (dd, J=7.3, 4.4 Hz, 1H), 5.28 (d, J=5.1 Hz, 1H), 4.57 (d, J=11.6 Hz, 1H), 4.53 (dd, J=6.4, 5.0 Hz, 1H), 4.37 (d, J=11.6 Hz, 1H), 4.33 (dd, J=5.0, 2.9 Hz, 1H), 4.02 (q, J=3.3 Hz, 1H), 3.69 (s, 3H), 3.67 (m, 1H), 3.56 (m, 1H); LCMS (Method B) Rt 1.86 mins; m/z 388.0 (M+H + ). 
     Step 2: 
     Preparation of (2R,3R,4R,5R)-4-((4-methoxybenzyl)oxy)-5-(6-(tritylamino)-9H-purin-9-yl)-2-((trityloxy)methyl)tetrahydrofuran-3-ol (i9): To compound i8 (45.5 g, 117 mmol) in DMF (310 mL) was added 2,6-lutidine (68.4 mL, 587 mmol), DMAP (3.59 g, 29.4 mmol) and trityl chloride (82 g, 294 mmol). The reaction mixture was slowly heated to 80° C. The reaction mixture was stirred for 15 h at 80° C. and then cooled to rt. The reaction was poured into aq. sat. NH 4 Cl (1500 mL) and extracted with EtOAc (3×1 L). The combined organic phases were dried (Na 2 SO 4 ), the drying agent filtered off and the filtrate concentrated in vacuo. The crude product was purified by chromatography on silica gel (gradient elution EtOAc-Heptane 0-100%) to yield the desired compound i9 as an off white solid (85.79 g):  1 H NMR (400 MHz, CDCl 3 ) δ 8.01 (s, 1H), 7.87 (s, 1H), 7.41 (m, 12H), 7.28 (m, 18H), 7.18 (d, J=8.6 Hz, 2H), 6.95 (s, 1H), 6.80 (d, J=8.6 Hz, 2H), 6.11 (d, J=4.4 Hz, 1H), 4.77-4.67 (m, 2H), 4.62 (d, J=11.6 Hz, 1H), 4.32 (q, J=5.3 Hz, 1H), 4.21 (m, 1H), 3.79 (s, 3H), 3.49 (dd, J=10.5, 3.3 Hz, 1H), 3.36 (dd, J=10.5, 4.5 Hz, 1H), 2.66 (d, J=5.7 Hz, 1H); LCMS (Method G) Rt 1.53 mins; m/z 872.0 (M+H + ). 
     Step 3: 
     Preparation of (2R,4S,5R)-4-((4-methoxybenzyl)oxy)-5-(6-(tritylamino)-9H-purin-9-yl)-2-((trityloxy) methyl)dihydrofuran-3(2H)-one (i10): To a solution of Dess-Martin Periodinane (DMP, 3.04 g, 7.17 mmol) in DCM (72 mL) at rt was added tert-butanol (0.713 mL, 7.45 mmol) and sodium carbonate (0.134 g, 1.261 mmol), followed by a dropwise addition over 1 h of a solution of compound i9 (5.00 g, 5.73 mmol) in DCM (72 mL). The resulting reaction mixture was stirred at rt for 4 h before additional DCM (110 mL) was added. After a further 3 h additional DMP (0.63 g) and DCM (50 mL) were added. The reaction stirred for 13 h and then quenched by addition of sat. Na 2 S 2 O 5  (40 mL), sat. NaHCO 3  (150 mL) and brine (50 mL). The organic phase was separated and the aqueous phase then re-extracted with DCM (2×150 mL). The combined DCM was dried (Na 2 SO 4 ), the drying agent filtered off and the filtrate concentrated in vacuo. The crude material was purified by chromatography on silica gel (gradient elution EtOAc/heptane (0-80%) to afford compound i10 as a white foam (4.36 g):  1 H NMR (400 MHz, CDCl 3 ) b 7.95 (s, 1H), 7.78 (s, 1H), 7.46-7.15 (m, 30H), 7.05 (d, J=8.6 Hz, 2H), 6.98 (s, 1H), 6.73 (d, J=8.6 Hz, 2H), 6.13 (d, J=7.8 Hz, 1H), 5.23 (dd, J=7.9, 0.8 Hz, 1H), 4.80 (d, J=11.8 Hz, 1H), 4.72 (d, J=11.8 Hz, 1H), 4.35 (ddd, J=4.0, 2.4, 0.8 Hz, 1H), 3.76 (s, 3H), 3.52 (dd, J=10.5, 4.0 Hz, 1H), 3.43 (dd, J=10.5, 2.4 Hz, 1H); LCMS (Method C) Rt 1.53 mins; m/z 870.0 (M+H + ). 
     Step 4: 
     Preparation of (2R,3S,4R,5R)-4-((4-methoxybenzyl)oxy)-5-(6-(tritylamino)-9H-purin-9-yl)-2-((trityloxy)methyl)tetrahydrofuran-3-ol (i11): To a solution of compound i10 (98 mg, 0.113 mmol) in DCM (3 mL) at −20° C. was added glacial AcOH (0.15 mL) followed by NaBH 4  (13 mg, 0.34 mmol). After 1 h the reaction mixture was quenched with 5% brine (20 mL) and extracted with EtOAc (25 mL). The organic phase was separated and dried (Na 2 SO 4 ), the drying agent filtered off and the filtrate concentrated in vacuo to a white solid. The crude solid (3S:3R ratio 7:1) was slurried in hot MeOH (3 mL, warmed to 50° C.) with DCM (˜0.5 mL) added dropwise and the suspension cooled. The mother liquor was decanted off and the solid was dried in vacuo (63 mg, 3S:3R ratio 13:1). Recrystallization from MeOH:DCM (4 mL, v/v 5:1) gave compound i11 as a single diastereomer (ratio 50:1):  1 H NMR (400 MHz, CDCl 3 ) δ 7.90 (s, 1H), 7.74 (s, 1H), 7.48-7.13 (m, 32H), 6.95-6.84 (m, 2H), 5.80 (s, 1H), 4.68 (d, J 11.3 Hz, 1H), 4.49 (d, J 11.3 Hz, 1H), 4.36 (s, 1H), 4.33-4.27 (m, 1H), 4.23 (d, J 3 Hz, 1H), 3.83 (s, 3H), 3.59-3.52 (m, 2H); LCMS (Method H) Rt 1.76 mins; m/z 872.2 (M+H) + . 
     Step 5: 
     Preparation of 9-((2R,3S,4R,5R)-4-fluoro-3-((4-methoxybenzyl)oxy)-5-((trityloxy)methyl)tetrahydro-furan-2-yl)-N-trityl-9H-purin-6-amine (i12): To a solution of compound i11 (240 mg, 0.275 mmol) in anhydrous DCM (15 mL) at 0° C. was added anhydrous pyridine (0.223 mL, 2.75 mmol). After 5 min, diethylaminosulfur trifluoride (DAST, 0.182 mL, 1.38 mmol) was added dropwise. After 5 min, the cooling bath was removed and the reaction stirred for 4.5 h. The reaction mixture was diluted with chloroform (20 mL), dry silica gel was added, and the mixture concentrated in vacuo before adding toluene (20 mL) and concentrating to dryness in vacuo. The crude material was purified by chromatography on silica gel (gradient elution 10-50% EtOAc/heptane) to give the desired compound i12 as a white solid (121 mg):  1 H NMR (400 MHz, CDCl 3 ) δ 7.93 (s, 1H), 7.82 (s, 1H), 7.42-7.20 (m, 30H), 7.13-7.05 (m, 3H), 6.74 (d, J 8.3 Hz, 2H), 6.09-6.05 (m, 1H), 5.15-5.06 (m, 1H), 5.00 (dd, J54.4, and 4.4 Hz, 1H), 4.60-4.50 (m, 2H), 4.49-4.39 (m, 1H), 3.77 (s, 3H), 3.51-3.38 (m, 1H), 3.32 (dd, J=10.6, 4.0 Hz, 1H);  19 F NMR (376.4 MHz, CDCl 3 ) δ −198.09; LCMS (Method I) Rt 1.27 mins; m/z 874.5 (M+H) + . 
     Step 6: 
     Preparation of (2R,3S,4S,5R)-2-(6-amino-9H-purin-9-yl)-4-fluoro-5-(hydroxymethyl)tetrahydrofuran-3-ol (i13): To a solution of compound i12 (70 mg, 0.080 mmol) in DCM (1 mL) was added TFA (0.5 mL, 6.49 mmol). After 45 min the reaction mixture was diluted with MeOH (10 mL) and concentrated in vacuo. The crude material was dissolved in MeOH (10 mL) and TEA (0.1 mL) was added before silica gel was added and the suspension concentrated in vacuo. The crude material was purified by chromatography on silica gel (gradient elution 0-10% MeOH/DCM) to give the desired compound i13 as a white solid (21 mg) containing TEA. TFA salt and used as is:  1 H NMR (400 MHz, Methanol-d 4 ) δ 8.33 (s, 1H), 8.21 (s, 1H), 6.02 (d, J7.9 Hz, 1H), 5.12 (dd, J 54.5, 4.3 Hz, 1H), 4.96 (ddd, J 25.1, 8.0, 4.3 Hz, 1H), 4.44 (dt, J 27.6, 2.5 Hz, 1H), 3.94-3.69 (m, 2H);  19 F NMR (376.4 MHz, Methanol-d 4 ) δ −200.02; LCMS (Method G) Rt 0.51 mins; m/z 270.1 (M+H) + . 
     Step 7: 
     Preparation of N-(9-((2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-9H-purin-6-yl)benzamide (i14): To compound i13 (3.88 g, 14.41 mmol) in pyridine (65 mL) at 0° C. was added benzoyl chloride (8.36 mL, 72.1 mmol) slowly followed by TMSCl (9.21 mL, 72.1 mmol). The reaction mixture was stirred while warming to rt for 4 h. After another 1 h the solution was quenched with water (35 mL), followed by conc. NH 4 OH (17 mL) after 5 min resulting in a pale tan solid. The mixture was diluted with water (100 mL) and extracted with MeTHF (3×75 mL). The combined organic phases were dried (Na 2 SO 4 ), the drying agent filtered off and the filtrate concentrated in vacuo to a tan semi-solid crude material, which was purified by chromatography on silica gel (gradient elution 0-20% MeOH/DCM) to give the desired compound i14 (2.75 g):  1 H NMR (400 MHz, CDCl 3 ) δ 8.78 (s, 1H), 8.09 (s, 1H), 8.08-8.01 (m, 2H), 7.66 (t, J=7.4 Hz, 1H), 7.57 (t, J=7.5 Hz, 2H), 6.13 (br s, 1H), 5.92 (d, J=7.9 Hz, 1H), 5.41-5.11 (m, 2H), 4.60 (d, J=28.4 Hz, 1H), 4.13-3.98 (m, 2H), 3.86 (d, J=13.0 Hz, 1H). 19F NMR (376.4 MHz, CDCl 3 ) δ −199.36; LCMS (Method G) Rt 0.72 mins; m/z 374.2 (M+H) + . 
     Step 8: 
     Preparation of N-(9-((2R,3S,4S,5R)-5-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)-9H-purin-6-yl)benzamide (i6): To compound i14 (2.73 g, 10.14 mmol) in pyridine (55 mL) was added DMTCI (4.12 g, 12.17 mmol) in one portion. The reaction was stirred at rt for 72 h before the yellowish solution was quenched by addition of MeOH (20 mL) and then concentrated in vacuo to a semi-solid following addition of toluene (2×50 mL) to azeotrope residual pyridine. The resulting material was dissolved in DCM (100 mL), washed with sat. NaHCO 3  (100 mL), brine then dried (Na 2 SO 4 ). The drying agent was filtered off and the filtrate evaporated in vacuo. The resulting residue was purified by chromatography on silica gel (gradient elution 0-10% MeOH/DCM with 0.04% TEA) to give compound i6 as a white solid (3.70 g):  1 H NMR (400 MHz, CDCl 3 ) δ 9.16 (s, 1H), 8.64 (s, 1H), 8.23 (s, 1H), 7.99 (d, J7.5 Hz, 2H), 7.59 (t, J7.4 Hz, 1H), 7.48 (t, J7.6 Hz, 2H), 7.41-7.31 (m, 3H), 7.31-7.11 (m, 7H), 6.79 (d, J8.9 Hz, 4H), 6.16 (d, J7.3 Hz, 1H), 5.77 (br s, 1H), 5.27-5.10 (m, 2H), 4.53 (dt, J28.0 Hz, 3.4 Hz, 1H), 3.77 (s, 6H), 3.51 (dd, J 10.7, 3.7 Hz, 1H), 3.34 (dd, J 10.7, 3.3 Hz, 1H);  19 F NMR (376.4 MHz, CDCl 3 ) δ −197.5;  13 C NMR (101 MHz, CDCl 3 ) δ 164.66, 158.64, 158.62, 152.60, 151.43, 149.34, 144.22, 141.66, 135.29, 135.13, 133.40, 132.93, 129.96, 128.87, 127.99, 127.93, 127.86, 127.07, 122.65, 113.26, 93.85, 92.02, 87.56 (d, J 144 Hz), 83.56 (d, J 23 Hz), 77.30, 74.63 (d, J 16 Hz), 62.82 (d, J 11 Hz), 55.26; LCMS (Method C) Rt 2.72 mins; m/z 676.3 (M+H) + . 
     Note: The LCMS or HRMS data in this example, and where indicated in the following examples, were recorded using the indicated methods as follows. In all instances, masses reported are those of the protonated parent ions unless indicated otherwise. 
     Method A: LCMS data were recorded using a Waters System: Micromass ZQ mass spectrometer; Column: Sunfire C18 3.5 micron, 3.0×30 mm; gradient: 40-98% MeCN in water with 0.05% TFA over a 2.0 min period; flow rate 2 mL/min; column temperature 40° C.). 
     Method B: LCMS were recorded using a Waters System: Micromass SQ mass spectrometer; Column: Acquity UPLC BEH C18 1.7 micron, 2.1×30 mm; gradient 1% to 30% MeCN to 3.20 min then gradient: 30-98% MeCN in water with 5 mM NH 4 OH over a 1.55 min period before returning to 1% MeCN at 5.19 min-total run time 5.2 min; flow rate 1 mL/min; column temperature 50° C. 
     Method C: LCMS were recorded using a Waters System: Micromass SQ mass spectrometer; Column: Acquity UPLC BEH C18 1.7 micron, 2.1×50 mm; gradient: 2-98% MeCN in water+5 mM NH 4 OH over a 4.40 min period isocratic for 0.65 min before returning to 2% MeCN at 5.19 min−total run time 5.2 min; flow rate 1 mL/min; column temperature 50° C. 
     Method E: HRMS data were recorded using a Waters System: Acquity G2 Xevo QT of mass spectrometer; Column: Acquity BEH 1.7 micron, 2.1×50 mm; gradient: 40-98% MeCN in water with 0.1% Formic acid over a 3.4 min period, isocratic 98% MeCN for 1.75 mins returning to 40% at 5.2 mins; flow rate 1 mL/min; column temperature 50° C. 
     Method G: LCMS data were recorded using a Waters System: Micromass SQ mass spectrometer; Column: Acquity UPLC BEH C18 1.7 micron, 2.1×30 mm; gradient 1% to 30% MeCN to 1.20 mins then gradient: 30-98% MeCN in water with 5 mM NH 4 OAc over a 0.55 min period before returning to 1% MeCN at 2.19 mins—total run time 2.2 mins; flow rate 1 mL/min; column temperature 50° C. 
     Method H: LCMS data were recorded using a Waters System: Micromass SQ mass spectrometer; Column: Acquity UPLC BEH C18 1.7 micron, 2.1×30 mm; gradient 2% to 98% MeCN to 1.76 mins then isocratic to 2.00 mins and then returning to 2% MeCN using gradient to 2.20 mins in water with 0.1% Formic acid; flow rate 1 mL/min; column temperature 50° C. 
     Method I: LCMS data were recorded using a Waters System: Micromass SQ mass spectrometer; Column: Acquity UPLC BEH C18 1.7 micron, 2.1×30 mm; gradient 40% to 98% MeCN to 1.40 mins then isocratic to 2.05 mins and then returning to 40% MeCN using gradient to 2.20 mins in water with 0.1% Formic acid; flow rate 1 mL/min; column temperature 50° C. 
     Given the synthetic methods described above, and the synthetic methods described in WO2016/145102, WO2014/093936, WO2017/027646, WO2017/027645, WO2015/185565, WO2016/096174, WO2014/189805, US2015158886, WO2017011622, WO2017004499 and WO2007070598 the compounds listed in Tables 1-4 can be readily made. 
     Linker-Drug Moiety (L-(D) m ) 
     Linker 
     As used herein, a “linker” is any chemical moiety that is capable of linking an antibody, antibody fragment (e.g., antigen binding fragments) or functional equivalent to another moiety, such as a drug moiety, (e.g. a cyclic dinucleotide or cyclic dinucleoside), which binds to Stimulator of Interferon Genes (STING) receptor. 
     Linkers of the immunoconjugates of the invention may comprise one or more cleavage elements and in certain embodiments the linkers of the immunoconjugates of the invention comprise two or more cleavage elements, wherein each cleavage element is independently selected from a self-immolative spacer and a group that is susceptible to cleavage (such as a group which is susceptible to acid-induced cleavage, peptidase-induced cleavage, esterase-induced cleavage, glycosidase induced cleavage, phosphodiesterase induced cleavage, phosphatase induced cleavage, protease induced cleavage, lipase induced cleavage or disulfide bond cleavage). 
     In some aspects, the linker is a procharged linker, a hydrophilic linker, or a dicarboxylic acid based linker. 
     Acid-labile linkers are linkers cleavable at acidic pH. For example, certain intracellular compartments, such as endosomes and lysosomes, have an acidic pH (pH 4-5), and provide conditions suitable to cleave acid-labile linkers. 
     Some linkers can be cleaved by peptidases, i.e., peptidase cleavable linkers. Only certain peptides are readily cleaved inside or outside cells, see e.g., Trout et al., 79 Proc. Natl. Acad. Sci. USA, 626-629 (1982) and Umemoto et al. 43 Int. J. Cancer, 677-684 (1989). Furthermore, peptides are composed of α-amino acids and peptidic bonds, which chemically are amide bonds between the carboxylate of one amino acid and the amino group of a second amino acid. Other amide bonds, such as the bond between a carboxylate and the ε-amino group of lysine, are understood not to be peptidic bonds and are considered non-cleavable. 
     Some linkers can be cleaved by esterases, i.e., esterase cleavable linkers. Again, only certain esters can be cleaved by esterases present inside or outside of cells. Esters are formed by the condensation of a carboxylic acid and an alcohol. Simple esters are esters produced with simple alcohols, such as aliphatic alcohols, and small cyclic and small aromatic alcohols. 
     Cleavable linkers, such as those containing a hydrazone, a disulfide, and a dipeptide (e.g. Val-Cit), are well known in the art, and can be used. See, e.g., Ducry, et al.,  Bioconjugate Chem . vol. 21, 5-13 (2010). 
     In addition, cleavable linkers containing a glucuronidase-cleavable moiety, are well known in the art, and can be used. See, e.g., Ducry, et al.,  Bioconjugate Chem ., vol. 21, 5-13 (2010). 
     For the immunoconjugates of the invention comprising a cleavable linker, the linker is substantially stable in vivo until the immunoconjugate binds to or enters a cell, at which point either intracellular enzymes or intracellular chemical conditions (pH, reduction capacity) cleave the linker to free the Drug moiety. 
     Procharged linkers are derived from charged cross-linking reagents that retain their charge after incorporation into an antibody drug conjugate. Examples of procharged linkers can be found in US 2009/0274713. 
     The linker (L) can be attached to the antibody, antigen binding fragment or their functional equivalent at any suitable available position on the antibody, antigen binding fragment or their functional equivalent: typically, linker (L) is attached to an available amino nitrogen atom (i.e., a primary or secondary amine, rather than an amide) or a hydroxylic oxygen atom, or to an available sulfhydryl, such as on a cysteine. 
     The linker (L) of the immunoconjugates of the invention can be divalent, where the linker is used to link only one drug moiety per linker to an antibody, antigen binding moiety or functional equivalent, or the linker (L) of the immunoconjugates of the invention can be trivalent and is able to link two drug moieties per linker to an antibody, antigen binding moiety or functional equivalent. In addition, the linker (L) of in the immunoconjugates of the invention can also polyvalent and is able to link multiple drug moieties per linker to an antibody, antigen binding moiety or functional equivalent. 
     The linker (L) of the immunoconjugates of the invention is a linking moiety comprising one or more linker components. Some preferred linkers and linker components are described herein. 
     A linker component of linker (L) of the immunoconjugates of the invention can be, for example,
         a) an alkylene group: —(CH 2 ) n — (where in this instance is n is 1-18);   b) an alkenyl group;   c) an alkynyl group;   d) an ethylene glycol unit: —CH 2 CH 2 O—;   e) an polyethylene glycol unit: (—CH 2 CH 2 O—) x  (where x in this instance is 2-20);   f) —O—;   g) —S—;   h) a carbonyl: —C(═O)—;   i) an ester: —C(═O)—O— or —O—C(═O)—;   j) a carbonate: —OC(═O)O—;   k) an amine: —NH—;   l) an amides: —C(═O)—NH—, —NH—C(═O)— or —C(═O)N(C 1-6 alkyl)-;   m) a carbamate: —OC(═O)NH— or —NHC(═O)O—;   n) a urea: —NHC(═O)NH—;   o) an alkylene substituted with one or more groups independently selected from carboxy, sulfonate, hydroxyl, amine, amino acid, saccharide, phosphate and phosphonate);   p) an C 1 -C 10 alkylene in which one or more methylene groups is replace by one or more —S—, —NH— or —O— moieties;   q) a ring systems having two available points of attachment such as a divalent ring selected from phenyl (including 1,2-1,3- and 1,4-di-substituted phenyls), a C 5 -C 6  heteroaryl, a C 3 -C 8  cycloalkyl (including 1,1-disubstituted cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and 1,4-disubstituted cyclohexyl), and a C 4 -C 8  heterocycloalkyl;   r) a residue of an amino acid selected from alanine (Ala), cysteine (Cys), aspartic acid (Asp), glutamic acid (Glu), phenylalanine (Phe), glycine (Gly), histidine (His), isoleucine (Ile), lysine (Lys), leucine (Leu),methionine (Met), asparagine (Asn), proline (Pro), glutamine (Gln), arginine (Arg), serine (Ser), threonine (Thr), valine (Val), tryptophan (Trp), tyrosine (Tyr), citrulline (Cit), norvaline (Nva), norleucune (Nle), selenocysteine (Sec), pyrrolysine (Pyl), homoserine, homocysteine, and desmethyl pyrrolysine;
           a combination of 2 or more amino acid residues where each residue is independently selected from a residue of an amino acid selected from alanine (Ala), cysteine (Cys), aspartic acid (Asp), glutamic acid (Glu), phenylalanine (Phe), glycine (Gly), histidine (His), isoleucine (Ile), lysine (Lys), leucine (Leu),methionine (Met), asparagine (Asn), proline (Pro), glutamine (Gln), arginine (Arg), serine (Ser), threonine (Thr), valine (Val), tryptophan (Trp), tyrosine (Tyr), citrulline (Cit), norvaline (Nva), norleucune (Nle), selenocysteine (Sec), pyrrolysine (Pyl), homoserine, homocysteine, and desmethyl pyrrolysine, for example Val-Cit; Cit-Val; Ala-Ala; Ala-Cit; Cit-Ala; Asn-Cit; Cit-Asn; Cit-Cit; Val-Glu; Glu-Val; Ser-Cit; Cit-Ser; Lys-Cit; Cit-Lys; Asp-Cit; Cit-Asp; Ala-Val; Val-Ala; Phe-Lys; Lys-Phe; Val-Lys; Lys-Val; Ala-Lys; Lys-Ala; Phe-Cit; Cit-Phe; Leu-Cit; Cit-Leu; Ile-Cit; Cit-Ile; Phe-Arg; Arg-Phe; Cit-Trp; and Trp-Cit;   
           and   s) a self-immolative spacer, wherein the self-immolative spacer comprises
           i. one or more protecting (triggering) groups which are susceptible to acid-induced cleavage, peptidase-induced cleavage, esterase-induced cleavage, glycosidase induced cleavage, phosphodiesterase induced cleavage, phosphatase induced cleavage, protease induced cleavage, lipase induced cleavage or disulfide bond cleavage   and   ii. one or more groups which can undergo 1,4-elimination, 1,6-elimination, 1,8-elimination, 1,6-cyclization elimination, 1,5-cyclization elimination, 1,3-cyclization elimination, intramolecular 5-exo-trig or 6-exo-trig cyclization,   
           Non-limiting examples of such self-immolative spacer include:       

     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
         
         
           
             where:
           PG is a protecting (triggering) group;   X a  is O, NH or S;   X b  is O, NH, NCH 3  or S;   X c  is O or NH;   Y a  is CH 2 , O or NH;   Y b  is a bond, CH 2 , O or NH, and LG is a leaving group such as a Drug moiety (D) of the immunoconjugates of the invention.   
         
             Additional non-limiting examples of such self-immolative spacers are described n Angew. Chem. Int. Ed. 2015, 54, 7492-7509. 
             By way of example only, certain self-immolative spacers used in the immunoconjugates of the invention are 
           
         
       
    
     
       
         
         
             
             
         
       
     
     In addition, a linker component can be a chemical moiety which is readily formed by reaction between two reactive groups. Non-limiting examples of such chemical moieties are given in Table 5. 
     
       
         
           
               
               
               
             
               
                 TABLE 5 
               
               
                   
               
               
                 Reactive Group 
                 Reactive Group 
                   
               
               
                 1 
                 2 
                 Chemical Moiety 
               
               
                   
               
             
            
               
                 a thiol 
                 a thiol 
                 —S—S— 
               
               
                   
               
               
                 a thiol 
                 a maleimide 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 a thiol 
                 a haloacetamide 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 an azide 
                 an alkyne 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 an azide 
                 a triaryl phosphine 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 an azide 
                 a cyclooctyne 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 an azide 
                 an oxanobornadiene 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 a triaryl phosphine 
                 an azide 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 an oxanobornadiene 
                 an azide 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 an alkyne 
                 an azide 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 a cyclooctyne 
                 azide 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 a cyclooctene 
                 a diaryl tetrazine 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 a diaryl tetrazine 
                 a cyclooctene 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 a monoaryl tetrazine 
                 a norbornene 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 a norbornene 
                 a monoarl tetrazine 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 an aldehyde 
                 a hydroxylamine 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 an aldehyde 
                 a hydrazine 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 an aldehyde 
                 NH 2 —NH—C(═O)— 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 a ketone 
                 a hydroxylamine 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 a ketone 
                 a hydrazine 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 a ketone 
                 NH 2 —NH—C(═O)— 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 a hydroxylamine 
                 an aldehyde 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 a hydroxylamine 
                 a ketone 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 a hydrazine 
                 an aldehyde 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 a hydrazine 
                 a ketone 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 NH 2 —NH—C(═O)— 
                 an aldehyde 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 NH 2 —NH—C(═O)— 
                 a ketone 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 a haloacetamide 
                 a thiol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 a maleimide 
                 a thiol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 a vinyl sulfone 
                 a thiol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 a thiol 
                 a vinyl sulfone 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 an aziridine 
                 a thiol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 a thiol 
                 an aziridine 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 hydroxylamine 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 hydroxylamine 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 —NH 2 , 
                 amide 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                   
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                   
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                   
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                   
               
               
                   
               
               
                 —NH 2 , 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 amide 
               
               
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
               
               
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
               
               
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
               
               
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
               
               
                   
               
               
                 CoA or CoA analogue 
                 Serine residue 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 pyridyldithiol 
                 thiol 
                 disulfide 
               
               
                   
               
            
           
         
       
         
         where: R 32  in Table 5 is H, C 1-4  alkyl, phenyl, pyrimidine or pyridine; R 35  in Table 5 is H, C 1-6 alkyl, phenyl or C 1-4 alkyl substituted with 1 to 3 —OH groups; each R 36  in Table 5 is independently selected from H, C 1-6 alkyl, fluoro, benzyloxy substituted with —C(═O)OH, benzyl substituted with —C(═O)OH, C 1-4 alkoxy substituted with —C(═O)OH and C 1-4 alkyl substituted with —C(═O)OH; R 37  in Table 5 is independently selected from H, phenyl and pyridine; n in Table 5 is 0, 1, 2 or 3; R 13  in Table 5 is H or methyl; R 50  in Table 5 is H or nitro; and R 14  in Table 5 is H, —CH 3  or phenyl. 
       
    
     In some embodiments, a linker component of linker, L, of the immunoconjugates of the invention is a group formed upon reaction of a reactive functional group with a side chain of an amino acid residue commonly used for conjugation, e.g., the thiol of a cysteine residue, or the free —NH 2  of a lysine residue. In other embodiments a linker component of linker, L, of the immunoconjugates of the invention is a group formed upon reaction of a reactive functional group with a side chain of an amino acid residue of an non-naturally occurring amino acid, such as para-acetyl Phe or para-azido-Phe. In other embodiments a linker component of linker, L, of the immunoconjugates of the invention is a group formed upon reaction of a reactive functional group with a side chain of an amino acid residue which has been engineered into the antibody, antigen binding fragment or their functional equivalent, e.g. the thiol of a cysteine residue, the hydroxyl of a serine residue, the pyrroline of a pyrrolysine residue or the pyrroline of a desmethyl pyrrolysine residue engineered into an antibody. See e.g., Ou, et al., PNAS 108(26), 10437-42 (2011). 
     A linker component formed by reaction with the thiol of a cysteine residue of the antibody, antigen binding fragment or their functional equivalent includes, but are not limited to, 
     
       
         
         
             
             
         
       
     
     A linker components formed by reaction with the amine of a lysine residue of the antibody, antigen binding fragment or their functional equivalent include, but are not limited to, 
     
       
         
         
             
             
         
       
     
     wherein each p is 1-10, and each R is independently H or C1-4 alkyl (preferably methyl). 
     A linker component formed by reaction with a pyrrolysine residue or desmethyl pyrrolysine residue includes, but are not limited to, 
     
       
         
         
             
             
         
       
     
     wherein R 13  is H or methyl, and R 14  is H, methyl or phenyl. 
     In some embodiments, a linker component of linker, L, of immunoconjugates of the invention is 
     
       
         
         
             
             
         
       
     
     which is formed upon reaction of a hydroxylamine and a 
     
       
         
         
             
             
         
       
     
     moiety, where the 
     
       
         
         
             
             
         
       
     
     moiety is formed by reduction of an interchain disulfide bridge of the antibody and re-bridging using a 1,3-dihaloacetone (e.g. 1,3-dichloroacetone, 1,3-dibromoacetone, 1,3-diiodoacetone) and bissulfonate esters of 1, 3-dihydroxyacetone. In some embodiments, a linker component of linker, L, of immunoconjugates of the invention is 
     
       
         
         
             
             
         
       
     
     which is formed upon reaction of a hydrazine and a 
     
       
         
         
             
             
         
       
     
     moiety, where the 
     
       
         
         
             
             
         
       
     
     moiety is formed by reduction of an interchain disulfide bridge of the antibody and re-bridging using a 1,3-dihaloacetone (e.g. 1,3-dichloroacetone, 1,3-dibromoacetone, 1,3-diiodoacetone) and bissulfonate esters of 1, 3-dihydroxyacetone. 
     In some embodiments, a linker component of linker, L, of immunoconjugates of the invention is selected from the groups shown in Table 6 below: 
     
       
         
           
               
             
               
                 TABLE 6 
               
               
                   
               
             
            
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 each R 12  is independently selected from H and C 1 -C 6 alkyl 
               
               
                 R 13  is H or methyl; 
               
               
                 R 14  is H, —CH 3  or phenyl; 
               
               
                 each R 25  is independently selected from H or C 1-4  alkyl; 
               
               
                 each R 18  is independently selected from a C 1 -C 6 alkyl, a C 1 -C 6 alkyl which is substituted with azido and a C 1 -C 6 alkyl which is substituted with 1 to 5 hydroxyl; 
               
               
                 I is 1, 2, 3, 4, 5 or 6; 
               
               
                 R 26  is 
               
               
                                                                                                                                                                                                                                                                             
R 32  is independently selected from H, C 1-4  alkyl, phenyl, pyrimidine and pyridine; 
               
               
                                                     
R 33  is independently selected from 
               
               
                                                                                                                             
R 34  is independently selected from H, C 1-4  alkyl, and C 1-6  haloalkyl. 
               
            
           
         
       
     
     The linker, L, in the immunoconjugates of the invention typically contain two or more linker components, which may be selected for convenience in assembly of the conjugate, or they may be selected to impact properties of the conjugate. 
     Linkers of the immunoconjugates of the invention comprise one or more cleavage elements and in certain embodiments the linkers of the immunoconjugates of the invention comprise two or more cleavage elements. In certain embodiments one of the cleavage elements is directly attached to a Drug moiety which, after the cleavage process, allows for release of a Drug moiety which does not comprise a fragment of the cleaved linker. By way of example, the Linker-Drug Moiety (-(L-(D) m )), wherein m is 1, of the immunoconjugates of the invention is designed to have one of the following structures: 
     
       
         
         
             
             
         
       
     
     wherein:
         Lc is a linker component and each Lc is independently selected from a linker component described herein;   x is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20;   y is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20;   p is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;   D is a Drug moiety described herein;   and each cleavage element (C E ) is independently selected from a self-immolative spacer and a group that is susceptible to cleavage (such as a group which is susceptible to acid-induced cleavage, peptidase-induced cleavage, esterase-induced cleavage, glycosidase induced cleavage, phosphodiesterase induced cleavage, phosphatase induced cleavage, protease induced cleavage, lipase induced cleavage or disulfide bond cleavage).       

     In one embodiment of the immunconjugates disclosed herein the Linker (L) of the Linker-Drug Moiety (-(L-(D) m )), wherein m is 1, has a structure selected from: 
     
       
         
         
             
             
         
       
     
     wherein:
 
Lc is a linker component and each Lc is independently selected from a linker component as disclosed herein;
 
x is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20;
 
y is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20;
 
p is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;
         and each cleavage element (C E ) is independently selected from a self-immolative spacer and a group that is susceptible to cleavage selected from acid-induced cleavage, peptidase-induced cleavage, esterase-induced cleavage, glycosidase induced cleavage, phosphodiesterase induced cleavage, phosphatase induced cleavage, protease induced cleavage, lipase induced cleavage or disulfide bond cleavage.
 
The presence of a non-cleavable linker fragment attached directly to a Drug moiety described herein is observed to decrease the activity of the Drug moiety as tested in a hSTING wt assay and THP1-dual assay (see below for description of assays and Table 7 for results), therefore such linker designs allow for the release of active Drug moieties.
 
hSTING Wt Assay:
       

     HEK-293T cells were reverse transfected with a mixture of human STING (accession BC047779 with Arg mutation introduced at position 232 to make the clone into human STING wild type) and a 5xISRE-mIFNb-GL4 plasmid (five interferon stimulated response elements and a minimal mouse interferon beta promoter driving expression of the firefly luciferase GL4). Cells were transfected using FuGENE transfection reagent (3:1 FuGENE:DNA ratio) by adding the FuGENE:DNA mix to HEK-293T cells in suspension and plating into 384 well plates. Cells were incubated overnight and treated with compounds. After 9-14 hours, plates were read by adding BrightGlo reagent (Promega) and reading on an Envision plate reader. The fold change over background was calculated and normalized to the fold-change induced by 2′3′-cGAMP at 50 uM. Plates were run in triplicate. EC50 values were calculated as described for the IP-10 secretion assay. 
     THP1-Dual Assay: 
     THP1-Dual cells were purchased from Invivogen. THP1-Dual cells were plated in 384 well plates in 20 uL of tissue culture media and incubated overnight. Compounds were added the next day and incubated 16-24 hours. Lucia reporter signal was read out by adding Quantiluc reagent (Invivogen) followed by reading on an Envision plate reader. The fold change over background was calculated and normalized to the fold-change induced by 2′3′-cGAMP at 50 uM. Plates were run in triplicate. EC50 values were calculated as described for the IP-10 secretion assay. 
     THP1-Dual/STING-KO Assay 
     Guide RNA (gRNA) oligo (TCCATCCATCCCGTGTCCCA (SEQ ID NO: 931)) for human STING was cloned into Lentivirus vector pNGx_LV_g003 and transduced into THP1-Dual_Cas9 cells. FACS sorted single clones were then cultured in 96 well cell culture plate. Each single well also contains 500 THP1-Dual parental cells as supporting cells. After 30 days 1 ug/ml puromycin was added to each well to eliminate supporting cells. Each individual THP1-Dual/STING-KO clone was tested using western blotting and NGS to confirm loss of STING expression and non-sense nucleotide insertion/deletion in both alleles. Six confirmed clones were then pooled and tested with cGAMP, T1-1, T1-2, using the methods described in the THP1-Dual assay above. 
     
       
         
           
               
               
               
               
               
             
               
                 TABLE 7 
               
               
                   
               
               
                   
                   
                   
                   
                 THP1 
               
               
                   
                   
                   
                 THP1 
                 Dual 
               
               
                   
                   
                 hSTING 
                 Dual 384 
                 STING 
               
               
                 Compound 
                 Structure 
                 wt (uM) 
                 (uM) 
                 KO (uM) 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 T1-1 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 0.294 
                 0.462 
                 &gt;50 
               
               
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 &gt;25 
                 ND 
                 ND 
               
               
                   
               
               
                 T1-2 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 4.48 
                 1.99 
                 &gt;50 
               
               
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 &gt;25 
                 ND 
               
               
                   
               
            
           
         
       
     
     Certain aspects and examples of the linkers and linker components of the immunoconjugates of the invention are provided in the following listing of enumerated embodiments. It will be recognized that features specified in each embodiment may be combined with other specified features to provide further embodiments of the present invention. 
     Embodiment 70 
     A linker component of linker, L, or combinations thereof, of immunoconjugates of the invention is selected from 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Embodiment 71 
     A linker, L selected from:
         —**C(═O)O(CH 2 ) m NR 11 C(═O)(CH 2 ) m —; —**C(═O)O(CH 2 ) m NR 11 C(═O)(CH 2 ),O(CH 2 ) m —; —**C(═O)O(CH 2 ) m NR 11 C(═O)X 1 X 2 C(═O)(CH 2 ) m —; —**C(═O)OC(R 12 ) 2 (CH 2 ) m NR 11 C(═O)X 1 X 2 C(═O)(CH 2 ) m —; —**C(═O)O(CH 2 ) m NR 11 C(═O)X 1 X 2 C(═O)(CH 2 ) m O(CH 2 ) m —; —**C(═O)O(CH 2 ) m NR 11 C(═O)X 1 X 2 C(═O)(CH 2 ) m O(CH 2 ) m C(═O)—; —**C(═O)O(CH 2 ) m NR 11 C(═O)X 4 C(═O)NR 11 (CH 2 ) m NR 11 C(═O)(CH 2 ) m O(CH 2 ) m —; —**C(═O)O(CH 2 ) m NR 11 C(═O)X 6 C(═O)(CH 2 ) m NR 11 C(═O)(CH 2 ) m —; —**C(═O)X 4 C(═O)NR 11 (CH 2 ) m NR 11 C(═O)(CH 2 ) m O(CH 2 ) m —; —**C(═O)(CH 2 ) m NR 11 C(═O)X 1 X 2 C(═O)(CH 2 ) m —; —**C(═O)O(CH 2 ) m X 6 C(═O)X 1 X 2 C(═O)(CH 2 ) m —; —**C(═O)(CH 2 ) m NR 11 C(═O)((CH 2 ) m O) n (CH 2 ) m —; —**C(═O)O(CH 2 ) m X 6 C(═O)(CH 2 ) m —; —**C(═O)O(CH 2 ) m X 6 C(═O)(CH 2 ) m O(CH 2 ) m —; —**C(═O)O(CH 2 ) m X 6 C(═O)X 1 X 2 C(═O)(CH 2 ) m —; —**C(═O)O(CH 2 ) m X 6 C(═O)X 1 X 2 C(═O)(CH 2 ) m O(CH 2 ) m —; —**C(═O)O(CH 2 ) m X 6 C(═O)X 1 X 2 C(═O)(CH 2 ) m O(CH 2 ) m C(═O)—; —**C(═O)O(CH 2 ) m X 6 C(═O)X 4 C(═O)NR 11 (CH 2 ) m NR 11 C(═O)(CH 2 ) m O(CH 2 ) m —; —**C(═O)X 4 C(═O)X 6 (CH 2 ) m NR 11 C(═O)(CH 2 ) m O(CH 2 ) m —; —**C(═O) (CH 2 ) m X 6 C(═O)X 1 X 2 C(═O) (CH 2 ) m —; —**C(═O)O((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 6 C(═O)(CH 2 ) m —; —**C(═O)O((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 6 C(═O)(CH 2 ) m NR 11 C(═O)(CH 2 ) m —; —**C(═O)O((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 C(═O)(CH 2 ) m X 3 (CH 2 ) m —; —**C(═O)O((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 C(═O)((CH 2 ) m O) n (CH 2 ) m —; —**C(═O)O((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)(CH 2 ) m —; —**C(═O)O((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)(CH 2 ) m X 3 (CH 2 ) m —; —**C(═O)O((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O))X 5 C(═O)((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —; —**C(═O)O((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 C(═O)(CH 2 ) m NR 11 C(═O)((CH 2 ) m O) n (CH 2 ) m —; —**C(═O)O((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 C(═O)(CH 2 ) m NR 11 C(═O)((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —; —**C(═O)O((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 (CH 2 ) m X 3 (CH 2 ) m —; —**C(═O)O((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 ((CH 2 ) m O) n (CH 2 ) m —; —**C(═O)O((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 ((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)(CH 2 ) m —; —**C(═O)O((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 ((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)(CH 2 ) m X 3 (CH 2 ) m —; —**C(═O)O((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 ((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —; —**C(═O)O((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 (CH 2 ) m NR 11 ((CH 2 ) m O) n (CH 2 ) m —; —**C(═O)O((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 C(═O)(CH 2 ) m NR 11 ((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —; —**C(═O)O((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 (CH 2 ) m —; —**C(═O)O((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 C(═O)((CH 2 ) m O) n (CH 2 ) m —; —**C(═O)O((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 (CH 2 ) m X 3 (CH 2 ) m —; —**C(═O)O(CH 2 ) m —; —**C(═O)O((CH 2 ) m O) n (CH 2 ) m —; —**C(═O)O(CH 2 ) m NR 11 (CH 2 ) m —; —**C(═O)O(CH 2 ) m NR 11 (CH 2 ) m C(═O)X 2 X 1 C(═O)—; —**C(═O)O(CH 2 ) m X 3 (CH 2 ) m —; —**C(═O)O((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —; —**C(═O)O((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)(CH 2 ) m —; —**C(═O)O(CH 2 ) m NR 11 C(═O(CH 2 ) m X 3 (CH 2 ) m —; —**C(═O)O((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)(CH 2 ) m X 3 (CH 2 ) m —; —**C(═O)O((CH 2 ) m O) n X 3 (CH 2 ) m —; —**C(═O)O((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —; —**C(═O)O((CH 2 ) m O) n (CH 2 ) m C(═O)NR 11 (CH 2 ) m —; —**C(═O)O(CH 2 ) m C(R 12 ) 2 —; —**C(═O)OCH 2 ) m C(R 12 ) 2 SS(CH 2 ) m NR 11 C(═O)(CH 2 ) m —, and —**C(═O)O(CH 2 ) m C(═O)NR 11 (CH 2 ) m —, where the ** of L indicates point of attachment to the drug moiety (D);   wherein:   X 1  is       

     
       
         
         
             
             
         
       
     
     where the * of X 1  indicates the point of attachment to X 2 ;
         X 2  is selected from       

     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     where the * of X 2  indicates the point of attachment to X 1 ;
         X 3  is       

     
       
         
         
             
             
         
       
         
         
           
             X 4  is —O(CH 2 ) n SSC(R 12 ) 2 (CH 2 ) n — or —(CH 2 ) n C(R 12 ) 2 SS(CH 2 ) n O—; 
             X 5  is 
           
         
       
    
     
       
         
         
             
             
         
       
     
     where the ** of X 5  indicates orientation toward the Drug moiety;
         X 6  is       

     
       
         
         
             
             
         
       
     
     or, where the ** of X 6  indicates orientation toward the Drug moiety;
         each R 11  is independently selected from H and C 1 -C 6 alkyl;   each R 12  is independently selected from H and C 1 -C 6 alkyl;   each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, and   each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 and 18.       

     Embodiment 72 
     A linker, L selected from:
         —**C(═O)(CH 2 ) m —; —**C(═O)((CH 2 ) m O) n (CH 2 ) m —; —**C(═O)(CH 2 ) m NR 11 (CH 2 ) m —; —**C(═O)(CH 2 ) m NR 11 (CH 2 ) m C(═O)X 2 X 1 C(═O)—; —**C(═O) ( CH 2 ) m X 3 (CH 2 ) m —; —**C(═O)((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —; —**C(═O)(CH 2 ) m NR 11 C(═O)(CH 2 ) m —; —**C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)(CH 2 ) m —; —**C(═O)(CH 2 ) m NR 11 C(═O(CH 2 ) m X 3 (CH 2 ) m —; —**C(═O)((CH 2 ) m O) n (CH 2 ) m NR C(═O)(CH 2 ) m X 3 (CH 2 ) m —; —**C(═O)((CH 2 ) m O) n X 3 (CH 2 ) m —; —**C(═O)((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —; —**C(═O)((CH 2 ) m O) n (CH 2 ) m C(═O)NR 11 (CH 2 ) m —; —**C(═O)(CH 2 ) m C(R 12 ) 2 —; —**C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 C(═O)(CH 2 ) m —; —**C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 C(═O)(CH 2 ) m NR 11 C(═O)(CH 2 ) m —; —**C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 C(═O)(CH 2 ) m X 3 (CH 2 ) m —; —**C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 C(═O)((CH 2 ) m O) n (CH 2 ) m —; —**C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)(CH 2 ) m —; —**C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)(CH 2 ) m X 3 (CH 2 ) m —; —**C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O))X 5 C(═O)((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —; —**C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 C(═O)(CH 2 ) m NR 11 C(═O)((CH 2 ) m O) n (CH 2 ) m —; —**C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 C(═O)(CH 2 ) m NR 11 C(═O)((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —; —**C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 (CH 2 ) m X 3 (CH 2 ) m —; —**C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 ((CH 2 ) m O) n (CH 2 ) m —; —**C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 ((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)(CH 2 ) m —; —**C(═O)((CH 2 ) m O) n (CH 2 ) m NR 1l C(═O)X 5 ((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)(CH 2 ) m X 3 (CH 2 ) m —; —**C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 ((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —; —**C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 (CH 2 ) m NR 11 ((CH 2 ) m O) n (CH 2 ) m —; —**C(═O)((CH 2 ) m O) n (CH 2 ) m NR 1 C(═O)X 5 C(═O)(CH 2 ) m NR 11 ((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —; —**C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 (CH 2 ) m —; —**C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 C(═O)((CH 2 ) m O) n (CH 2 ) m —; —**C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 (CH 2 ) m X 3 (CH 2 ) m —; —**C(═O)(CH 2 ) m C(R 12 ) 2 SS(CH 2 ) m NR 11 C(═O)(CH 2 ) m —, and —**C(═O)(CH 2 ) m C(═O)NR 11 (CH 2 ) m —,
           where the ** of L indicates point of attachment to the drug moiety (D), and
               X 1 , X 2 , X 3 , X q , Xs, R 11 , R 12 , n and m are as defined in Embodiment 63.   
               
               

     Embodiment 73 
     A linker, L selected from:
         —**C(═O)X 1 X 2 C(═O)(CH 2 ) m —; —**C(═O)X 1 X 2 C(═O)(CH 2 ) m NR 11 C(═O)(CH 2 ) m —; —**C(═O)X 1 X 2 C(═O)(CH 2 ) m X 3 (CH 2 ) m —; —**C(═O)X 1 X 2 C(═O)((CH 2 ) m O) n (CH 2 ) m —; —**C(═O)X 1 X 2 C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)(CH 2 ) m —; —**C(═O)X 1 X 2 C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)(CH 2 ) m X 3 (CH 2 ) m —; —**C(═O)X 1 X 2 C(═O)((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —; —**C(═O)X 1 X 2 C(═O)(CH 2 ) m NR 11 C(═O)((CH 2 ) m O) n (CH 2 ) m —; —**C(═O)X 1 X 2 C(═O)(CH 2 ) m NR 11 C(═O)((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —; —**C(═O)X 1 X 2 (CH 2 ) m X 3 (CH 2 ) m —; —**C(═O)X 1 X 2 ((CH 2 ) m O) n (CH 2 ) m —; —**C(═O)X 1 X 2 ((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)(CH 2 ) m —; —**C(═O)X 1 X 2 ((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)(CH 2 ) m X 3 (CH 2 ) m —; —**C(═O)X 1 X 2 ((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —; —**C(═O)X 1 X 2 (CH 2 ) m NR 11 ((CH 2 ) m O) n (CH 2 ) m —; —**C(═O)X 1 X 2 C(═O)(CH 2 ) m NR 11 ((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —; —**C(═O)NR 11 (CH 2 ) m —; —C(═O)NR 11 (CH 2 ) m X 3 (CH 2 ) m —; —**C(═O)NR 11 (CH 2 ) m NR 11 C(═O)X 1 X 2 C(═O)(CH 2 ) m —; —**C(═O)NR 11 (CH 2 ) m NR 11 C(═O)O(CH 2 ) m —; —**C(═O)NR 11  (CH 2 ) m NR 11 C(═O)X 1 X 2 —; —**C(═O)NR 11  (CH 2 ) m NR 11 C(═O)X 5 —; —**C(═O)NR 11 (CH 2 ) m NR 11 C(═O)(CH 2 ) m X 5 (CH 2 ) m —; —**C(═O)X 1 C(═O)NR 11 (CH 2 ) m X 5 (CH 2 ) m —; —**C(═O)NR 11  (CH 2 ) m NR 11 C(═O)(CH 2 ) m —; —**C(═O)NR 11 (CH 2 ) m NR 11 C(═O)(CH 2 ) m O(CH 2 ) m —; —**C(═O)NR 11 (CH 2 ) m NR 11 C(═O)X 1 X 2 C(═O)(CH 2 ) m O(CH 2 ) m —; —**C(═O)NR 11 (CH 2 ) m NR 11 C(═O)X 1 X 2 C(═O) (CH 2 ) m O(CH 2 ) m C(═O)—; —**C(═O)NR 11 (CH 2 ) m NR 11 C(═O)X 4 C(═O)NR 11 (CH 2 ) m NR 11 C(═O)(CH 2 ) m O(CH 2 ) m —; —**C(═O)NR 11 (CH 2 ) m NR 11 C(═O)X 1 X 2 C(═O)(CH 2 ) m —; —**C(═O)NR 11 (CH 2 ) m NR 11 C(═O)X 5 C(═O)(CH 2 ) m —; —**C(═O)NR 11 (CH 2 ) m NR 11 C(═O)X 5 C(═O)(CH 2 ) m NR 11 C(═O)(CH 2 ) m —; —**C(═O)NR 11 (CH 2 ) m NR 11 C(═O)X 5 C(═O)(CH 2 ) m X 3 (CH 2 ) m —; —**C(═O)NR 11 (CH 2 ) m NR 11 C(═O)X 5 C(═O)((CH 2 ) m O) n (CH 2 ) m —; —**C(═O)NR 11 (CH 2 ) m NR 11 C(═O)X 5 C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)(CH 2 ) m —; —**C(═O)NR 11 (CH 2 ) m NR 11 C(═O)X 5 C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)(CH 2 ) m X 3 (CH 2 ) m —; —**C(═O)NR 11 (CH 2 ) m NR 11 C(═O)X 5 C(═O)((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —; —**C(═O)NR 11 (CH 2 ) m NR 11 C(═O)X 5 C(═O)(CH 2 ) m NR 11 C(═O)((CH 2 ) m O) n (CH 2 ) m —; —**C(═O)NR 11 (CH 2 ) m NR 11 C(═O)X 5 C(═O)(CH 2 ) m NR 11 C(═O)((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m ; —**C(═O)NR 11 (CH 2 ) m NR 11 C(═O)X 5 (CH 2 ) m X 3 (CH 2 ) m —; —**C(═O)NR 11 (CH 2 ) m NR 11 C(═O)X 5 ((CH 2 ) m O) n (CH 2 ) m —; —**C(═O)NR 11 (CH 2 ) m NR 11 C(═O)X 5 ((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)(CH 2 ) m —; —**C(═O)NR 11 (CH 2 ) m NR 11 C(═O)X 5 ((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)(CH 2 ) m X 3 (CH 2 ) m —; —**C(═O)NR 11 (CH 2 ) m NR 11 C(═O)X 5 ((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —; —**C(═O)NR 11 (CH 2 ) m NR 11 C(═O)X 5 (CH 2 ) m NR 11  ((CH 2 ) m O) n (CH 2 ) m —; —**C(═O)NR 11 (CH 2 ) m NR 11 C(═O)X 5 C(═O)(CH 2 ) m NR 11  ((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —; —**C(═O)NR 11 (CH 2 ) m NR 11 C(═O)X 5 (CH 2 ) m —; —**C(═O)NR 11  (CH 2 ) m NR 11 C(═O)X 5 C(═O)((CH 2 ) m O) n (CH 2 ) m —; —**C(═O)NR 11 (CH 2 ) m NR 11 C(═O)X 5 (CH 2 ) m X 3 (CH 2 ) m —; —**C(═O)X 1 C(═O)NR 11  (CH 2 ) m NR 11 C(═O)(CH 2 ) m —; —**C(═O)X 1 C(═O)NR 11 (CH 2 ) m X 3 (CH 2 ) m —; —**C(═O)NR 11  (CH 2 ) m NR 11 C(═O)(CH 2 ) m —; —**C(═O)NR 11 (CH 2 ) m NR 11 C(═O)(CH 2 ) m X 3 (CH 2 ) m —; —**C(═O)NR 11  (CH 2 ) m NR 11 C(═O)—; —**C(═O)X 1 X 2 (CH 2 ) m —; —**C(═O)X 1 X 2 C(═O)((CH 2 ) m O) n (CH 2 ) m —; —**C(═O)X 1 X 2 (CH 2 ) m X 3 (CH 2 ) m —; —**C(═O)NR 11  (CH 2 ) m X 3 (CH 2 ) m —; —**C(═O)NR 11 ((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —; —**C(═O)X 1 X 2 C(═O)((CH 2 ) m O) n (CH 2 ) m ; —**C(═O)X 1 X 2 C(═O)(CH 2 ) m —; —**C(═O)X 1 C(═O)(CH 2 ) m NR 11 C(═O)(CH 2 ) m —, and —**C(═O)X 1 C(═O)(CH 2 ) m NR 11 C(═O)((CH 2 ) m O) n (CH 2 ) m —,
           where the ** of L indicates point of attachment to the drug moiety (D), and X 1 , X 2 , X 3 , X 4 , X 5 ,   R 11 , R 12 , n and m are as defined in Embodiment 63.   
               

     Embodiment 74 
     A linker, L selected from
         —**C(═O)O(CH 2 ) m NR 11 C(═O)(CH 2 ) m —; —**C(═O)O(CH 2 ) m NR 11 C(═O)(CH 2 ) m O(CH 2 ) m —, —**C(═O)O(CH 2 ) m NR 11 C(═O)X 1 X 2 C(═O)(CH 2 ) m —; —**C(═O)OC(R 2 ) 2 (CH 2 ) m NR 11 C(═O)X 1 X 2 C(═O)(CH 2 ) m —; —**C(═O)O(CH 2 ) m NR 11 C(═O)X 1 X 2 C(═O)(CH 2 ) m O(CH 2 ) m —; —**C(═O)O(CH 2 ) m NR 11 C(═O)X 1 X 2 C(═O)(CH 2 ) m O(CH 2 ) m C(═O)—; —**C(═O)O(CH 2 ) m NR 11 C(═O)X 4 C(═O)NR 11 (CH 2 ) m NR 11 C(═O)(CH 2 ) m O(CH 2 ) m —; —**C(═O)O(CH 2 ) m NR 11 C(═O)X 5 C(═O)(CH 2 ) m NR 11 C(═O)(CH 2 ) m —; —**C(═O)O(CH 2 ) m X 6 C(═O)X 1 X 2 C(═O)((CH 2 ) m O) n (CH 2 ) m C(═O)—; **—(CH 2 ) m NR 11 C(═O)X 1 X 2 C(═O)(CH 2 ) m —, —**(CH 2 ) m (CHOH)(CH 2 ) m NR 11 C(═O)X 1 X 2 C(═O)(CH 2 ) m ; —**C(═O)X(C(═O)(CH) m NR 11 C(═O)X 1 X 2 C(═O)(CH); —**C(═O)X 4 C(═O)NR 11 (CH 2 ) m NR 11 C(═O)(CH 2 ) m O(CH 2 ) m —; —**C(═O)(CH 2 ) m NR 11 C(═O)X 1 X 2 C(═O)(CH 2 ) m —; —**(CH 2 ) m NR 11 C(═O)X 1 X 2 C(═O)(CH 2 ) m —; —C(═O)O(CH 2 ) m X 6 C(═O)X 1 X 2 C(═O)(CH 2 ) m —**, or —C(═O)(CH 2 ) m NR 11 C(═O)((CH 2 ) m O) n (CH 2 ) m —**;
           where the ** of L indicates point of attachment to the drug moiety (D), and X 1 , X 2 , X 4 , R 11 ,   R 12 , n and m are as defined in Embodiment 63.   
               

     Embodiment 75 
     A linker, L selected from: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     where the ** indicates the point of attachment to the drug moiety (D). 
     In one aspect, the Linker-Drug moiety of the immunoconjugates of the invention comprises one or more Drug moieties (D) as described herein. 
     In one aspect, the Linker-Drug moiety of the immunoconjugates of the invention comprises one or more Drug moieties (D), wherein the Drug moiety (D) is a compound which binds to Stimulator of Interferon Genes (STING) receptor and which comprises one or more reactive moieties capable of forming a covalent bond with a linker (L). 
     In one aspect, the Linker-Drug moiety of the immunoconjugates of the invention comprises one or more Drug moieties (D), wherein the Drug moiety (D) is a compound which binds to Stimulator of Interferon Genes (STING) receptor and which comprises one or more reactive moieties capable of forming a covalent bond with a linker (L), wherein linker (L) is a cleavable linker. 
     In one aspect, the Linker-Drug moiety of the immunoconjugates of the invention comprises one or more Drug moieties (D), wherein the Drug moiety (D) is a dinucleotide which binds to Stimulator of Interferon Genes (STING) receptor and which comprises one or more reactive moieties capable of forming a covalent bond with one or more linker(s) (L). 
     In one aspect, the Linker-Drug moiety of the immunoconjugates of the invention, comprises one or more Drug moieties (D), wherein the Drug moiety (D) is a dinucleotide which binds to Stimulator of Interferon Genes (STING) receptor and which comprises one or more reactive moieties capable of forming a covalent bond with one or more linker(s) (L), wherein linker (L) is a cleavable linker. 
     In one aspect, the Linker-Drug moiety of the immunoconjugates of the invention comprises one or more Drug moieties (D), wherein the Drug moiety (D) is a cyclic dinucleotide which binds to Stimulator of Interferon Genes (STING) receptor and which comprises one or more reactive moieties capable of forming a covalent bond with one or more linker(s) (L). 
     In one aspect, the Linker-Drug moiety of the immunoconjugates of the invention, comprises one or more Drug moieties (D), wherein the Drug moiety (D) is a cyclic dinucleotide which binds to Stimulator of Interferon Genes (STING) receptor and which comprises one or more reactive moieties capable of forming a covalent bond with one or more linker(s) (L), wherein linker (L) is a cleavable linker. 
     In one aspect the Linker-Drug moiety of the invention is a compound having the structure of Formula (A), Formula (B), Formula (C), Formula (D), Formula (E) or Formula (F) or stereoisomers or pharmaceutically acceptable salts thereof, wherein:
         a) one or more linkers is attached to one or more sugar moieties of Formula (A), Formula (B), Formula (C), Formula (D), Formula (E) or Formula (F), or   b) one or more linkers is attached to one or more R 1 , R 1a  and R 1b  groups of Formula (A), Formula (B), Formula (C), Formula (D), Formula (E) or Formula (F), or   c) one or more linkers is attached to one or more sugar moieties of Formula (A), Formula (B), Formula (C), Formula (D), Formula (E) or Formula (F) and one or more linkers is attached to one or more R 1 , R 1a  and R 1b  groups of Formula (A), Formula (B), Formula (C), Formula (D), Formula (E) or Formula (F).       

     Certain aspects and examples of the Linker-Drug moiety of the invention are provided in the following listing of additional, enumerated embodiments. It will be recognized that features specified in each embodiment may be combined with other specified features to provide further embodiments of the present invention. 
     Embodiment 76 
     A compound having the structure of Formula (A), Formula (B), Formula (C), Formula (D), Formula (E) or Formula (F), or stereoisomers or pharmaceutically acceptable salts thereof, 
     wherein:
         each G 1  is independently selected from       

     
       
         
         
             
             
         
       
     
     where the * of G 1  indicates the point of attachment to —CR 8 R 9 —;
         X A  is C(═O)—, —C(═S)— or —C(═NR 11 )— and each Z 1  is NR 12 ;   X B  is C, and each Z 2  is N; G 2  is       

     
       
         
         
             
             
         
       
     
     where the * of G 2  indicates the point of attachment to —CR 8a R 9a —;
         X C  is C(═O)—, —C(═S)— or —C(═NR 11 )— and each Z 3  is NR 12 ;   X D  is C, and each Z 4  is N;   Y 1  is —O—, —S—, —S(═O)—, —SO 2 —, —CH 2 —, or —CF 2 —;   Y 2  is —O—, —S—, —S(═O)—, —SO 2 —, —CH 2 —, or —CF 2 —;   Y 3  is OH, O − , OR 10 , N(R 10 ) 2 , SeH, Se − , BH 3 , SH or S − ;   Y 4  is OH, O − , OR 10 , N(R 10 ) 2 , SeH, Se − , BH 3 , SH or S − ;   Y 5  is —CH 2 —, —NH—, —O— or —S;   Y 6  is —CH 2 —, —NH—, —O— or —S;   Y 7  is O or S;   Y 8  is O or S;   Y 9  is —CH 2 —, —NH—, —O— or —S;   Y 10  is —CH 2 —, —NH—, —O— or —S;   Y 11  is —O—, —S—, —S(═O)—, —SO 2 —, —CH 2 —, or —CF 2 —;   q is 1, 2 or 3;   R 1  is a partially saturated or aromatic monocyclic heterocyclyl or partially saturated or aromatic fused bicyclic heterocyclyl containing from 5-10 ring members selected from carbon atoms and 1 to 5 heteroatoms, and each heteroatoms is independently selected from O, N or S, or a tautomer thereof, wherein R 1  is substituted with 0, 1, 2, 3 or 4 substituents independently selected from —NHL 1 R 15 , F, Cl, Br, OH, SH, NH 2 , D, CD 3 , C 1 -C 6 alkyl, C 1 -C 6 alkoxyalkyl, C 1 -C 6 hydroxyalkyl, C 3 -C 8 cycloalkyl, a 3 to 6 membered heterocyclyl having 1 to 2 heteroatoms independently selected from O, N and S, —O(C 1 -C 6 alkyl), —O(C 3 -C 8 cycloalkyl), —S(C 1 -C 6 alkyl), —S(C 1 -C 6 aminoalkyl), —S(C 1 -C 6 hydroxyalkyl), —S(C 3 -C 8 cycloalkyl), —NH(C 1 -C 6 alkyl), —NH(C 3 -C 8 cycloalkyl), —N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 alkyl) (C 3 -C 8 cycloalkyl), —CN, —P(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —(CH 2 ) 1-10 C(═O)OH, —CH═CH(CH 2 ) 1-10 C(═O)OH, —NHC(O)(C 1 -C 6 alkyl), —NHC(O)(C 3 -C 8 cycloalkyl), —NHC(O)(phenyl), and —N(C 3 -C 8 cycloalkyl) 2 ;   R 1a  is a partially saturated or aromatic monocyclic heterocyclyl or partially saturated or aromatic fused bicyclic heterocyclyl containing from 5-10 ring members selected from carbon atoms and 1 to 5 heteroatoms, and each heteroatoms is independently selected from O, N or S, or a tautomer thereof, wherein R 1a  is substituted with 0, 1, 2, 3 or 4 substituents independently selected from —NHL 1 R 15 , F, Cl, Br, OH, SH, NH 2 , D, CD 3 , C 1 -C 6 alkyl, C 1 -C 6 alkoxyalkyl, C 1 -C 6 hydroxyalkyl, C 3 -C 8 cycloalkyl, a 3 to 6 membered heterocyclyl having 1 to 2 heteroatoms independently selected from O, N and S, —O(C 1 -C 6 alkyl), —O(C 3 -C 8 cycloalkyl), —S(C 1 -C 6 alkyl), —S(C 1 -C 6 aminoalkyl), —S(C 1 -C 6 hydroxyalkyl), —S(C 3 -C 8 cycloalkyl), —NH(C 1 -C 6 alkyl), —NH(C 3 -C 8 cycloalkyl), —N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 alkyl) (C 3 -C 8 cycloalkyl), —CN, —P(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —(CH 2 ) 1-10 C(═O)OH, —CH═CH(CH 2 ) 1-10 C(═O)OH, —NHC(O)(C 1 -C 6 alkyl), —NHC(O)(C 3 -C 8 cycloalkyl), —NHC(O)(phenyl), and —N(C 3 -C 8 cycloalkyl) 2 ;   R 1b  is a partially saturated or aromatic monocyclic heterocyclyl or partially saturated or aromatic fused bicyclic heterocyclyl containing from 5-10 ring members selected from carbon atoms and 1 to 5 heteroatoms, and each heteroatoms is independently selected from O, N or S, or a tautomer thereof, wherein R 1b  is substituted with 0, 1, 2, 3 or 4 substituents independently selected from —NHL 1 R 15 , F, Cl, Br, OH, SH, NH 2 , D, CD 3 , C 1 -C 6 alkyl, C 1 -C 6 alkoxyalkyl, C 1 -C 6 hydroxyalkyl, C 3 -C 8 cycloalkyl, a 3 to 6 membered heterocyclyl having 1 to 2 heteroatoms independently selected from O, N and S, —O(C 1 -C 6 alkyl), —O(C 3 -C 8 cycloalkyl), —S(C 1 -C 6 alkyl), —S(C 1 -C 6 aminoalkyl), —S(C 1 -C 6 hydroxyalkyl), —S(C 3 -C 8 cycloalkyl), —NH(C 1 -C 6 alkyl), —NH(C 3 -C 8 cycloalkyl), —N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 alkyl) (C 3 -C 8 cycloalkyl), —CN, —P(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —(CH 2 ) 1-10 C(═O)OH, —CH═CH(CH 2 ) 1-10 C(═O)OH, —NHC(O)(C 1 -C 6 alkyl), —NHC(O)(C 3 -C 8 cycloalkyl), —NHC(O)(phenyl), and —N(C 3 -C 8 cycloalkyl) 2 ;   each R 2  is independently selected from the group consisting of H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 2  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 2  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;   each R 3  is independently selected from the group consisting of —OL 1 R 15 , H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 3  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 3  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;   each R 4  is independently selected from the group consisting of —OL 1 R 15 , H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 4  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 4  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;   each R 5  is independently selected from the group consisting of —OL 1 R 15 , H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 5  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 5  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;   each R 6  is independently selected from the group consisting of H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 6  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 6  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;   each R 7  is independently selected from the group consisting of —OL 1 R 15 , H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 7  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 7  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;   each R 8  is independently selected from the group consisting of H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 8  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 8  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;   each R 9  is independently selected from the group consisting of H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 9  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 9  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;   R 2a  is selected from the group consisting of H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 2a  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 2a  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3      R 3a  is selected from the group consisting of —OL 1 R 15 , H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 3a  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 3a  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;   R 4a  is selected from the group consisting of —OL 1 R 15 , H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 4a  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 4a  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;   R 5a  is selected from the group consisting of —OL 1 R 15 , H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 5a  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 5a  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;   R 6a  is selected from the group consisting of H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 6a  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 6a  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;   R 7a  is selected from the group consisting of —OL 1 R 15 , H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 7a  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 7a  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;   R 8a  is selected from the group consisting of H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 8a  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 8  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;   R 9a  is selected from the group consisting of H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 9a  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 9a  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;   each R 10  is independently selected from the group consisting of H, C 1 -C 12 alkyl, —(CH 2 CH 2 O) n CH 2 CH 2 C(═O)OC 1 -C 6 alkyl, and       

     
       
         
         
             
             
         
       
     
     wherein the C 1 -C 12 alkyl of R 10  is substituted by 0, 1, 2 or 3 substituents independently selected from —OH, C 1 -C 12 alkoxy, —S—C(═O)C 1 -C 6 alkyl and C(O)OC 1 -C 6 alkyl;
         each R 11  is independently selected from H and C 1 -C 6 alkyl;   each R 12  is independently selected from H and C 1 -C 6 alkyl;   optionally R 3  and R 6  are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, —O—C 2 -C 6 alkynylene, such that when R 3  and R 6  are connected, the O is bound at the R 3  position   optionally R 3a  and R 6a , are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, —O—C 2 -C 6 alkynylene, such that when R 3a  and R 6a  are connected, the O is bound at the R 3a  position;   optionally R 2  and R 3  are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, —O—C 2 -C 6 alkynylene, such that when R 2  and R 3  are connected, the O is bound at the R 3  position;   optionally R 2a  and R 3a , are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, —O—C 2 -C 6 alkynylene, such that when R 2a  and R 3a  are connected, the O is bound at the R 3a  position;   optionally R 4  and R 3  are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, —O—C 2 -C 6 alkynylene, such that when R 4  and R 3  are connected, the O is bound at the R 3  position;   optionally R 4a  and R 3a , are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, —O—C 2 -C 6 alkynylene, such that when R 4a  and R 3a  are connected, the O is bound at the R 3a  position;   optionally R 5  and R 6  are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, —O—C 2 -C 6 alkynylene, such that when R 5  and R 6  are connected, the O is bound at the R 5  position;   optionally R 5a  and R 6a , are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, —O—C 2 -C 6 alkynylene, such that when R 5a  and R 6a  are connected, the O is bound at the R 5a  position;   optionally R 5  and R 7  are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, —O—C 2 -C 6 alkynylene, such that when R 5  and R 7  are connected, the O is bound at the R 5  position;   optionally R 5a  and R 7a , are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, —O—C 2 -C 6 alkynylene, such that when R 5a  and R 7a  are connected, the O is bound at the R 5a  position;   optionally R 8  and R 9  are connected to form a C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, and   optionally R 8a  and R 9a  are connected to form a C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene,   L 1  is a linker;   R 15  is a reactive group selected from any one of the groups RG1 in Table 5;
 
and provided at least one of R 1 , R 1a  or R 1b  is substituted with —NHL 1 R 15 , or at least one of R 3 , R 4 , R 5 , R 7 , R 3a , R 4a , R 5a  or R 7a  is —OL 1 R 15 .
       

     Embodiment 77 
     A compound of Embodiment 76, wherein L 1  is a linker comprising one or more cleavage elements. 
     Embodiment 78 
     A compound of Formula (A-1), Formula (B-1), Formula (C-1), Formula (D-1), Formula (E-1) or Formula (F-1), or stereoisomers or pharmaceutically acceptable salts thereof, wherein R 1 , R 1a , R 1b , R 2 , R 2a , R 3 , R 3a , R 4 , R 4a , R 5 , R 5a , R 6 , R 6a , R 7 , R 7a , R 8 , R 8a , R 9 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , Y 8 , Y 9 , Y 10  and Y 11  are as described in Embodiment 76, and provided at least one of R 1 , R 1a  or R 1b  is substituted with —NHL 1 R 15 , or at least one of R 3 , R 4 , R 5 , R 7 , R 3a , R 4a , R 5a  or R 7a  is —OL 1 R 15 . 
     Embodiment 79 
     A compound of Formula (A), Formula (B), Formula (C), Formula (D), Formula (E), Formula (F), Formula (A-1), Formula (B-1), Formula (C-1), Formula (D-1), Formula (E-1) or Formula (F-1), wherein R 1  is pyrimidine or purine nucleic acid base or analogue thereof, R 1a  is a pyrimidine or purine nucleic acid base or analogue thereof and R 1b  is a pyrimidine or purine nucleic acid base or analogue thereof, each of which is substituted as described in R 1 , R 1a  and R 1b  in Embodiment 76. 
     Embodiment 80 
     A compound of Formula (A-2), Formula (B-2), Formula (C-2), Formula (D-2), Formula (E-2) or Formula (F-2), wherein R 1 , R 1a , R 1b , R 2 , R 2a , R 3 , R 3a , R 4 , R 4a , R 5 , R 5a R 6 , R 6a , R 7 , R 7a , R 8 , R 8a , R 9 , R 9a , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , Y 8 , Y 9 , Y 10  and Y 11  are as defined in Embodiment 76, and provided at least one of R 1 , R 1a  or R 1b  is substituted with —NHL 1 R 15 , or at least one of R 3 , R 4 , R 5 , R 7 , R 3a , R 4a , R 5a  or R 7a  is —OL 1 R 15 . 
     Embodiment 81 
     A compound of Formula (A), Formula (A-1) or Formula (A-2) of any one of Embodiments 76 to 80, wherein:
         R 2  and R 2a  are H;   one of R 3  and R 4  is H and the other is selected from the group consisting of —OL 1 R 15 , H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 3  or R 4  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 3  or R 4  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;   R 7  and R 7a  are H;   R 6  and R 6a  are H;   R 8 , R 9 , R 8a  and R 9a  are independently H or C 1 -C 6 alkyl, and   one of R 3a  and R 4a  is H and the other is selected from the group consisting of —OL 1 R 15 , H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 3a  and R 4a  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 3a  or R 4a  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ,   and provided at least one of R 1  or R 1a  is substituted with —NHL 1 R 15 , or at least one of R 3 , R 4 , R 3a  or R 4a  is —OL 1 R 15 .       

     Embodiment 82 
     A compound of Formula (A), Formula (A-1) or Formula (A-2) of any one of Embodiments 76 to 81, wherein:
         Y 1  and Y 2  are O, CH 2  or S;   Y 5  and Y 6  are O or S;   Y 7  and Y 8  are O or S;   Y 9  and Y 10  are O or S;   R 2 , R 2a , R 6 , R 6a , R 7  and R 7a  are H   one of R 3a  and R 4a  is H and the other is —OL 1 R 15 , H, OH or F;   one of R 3  and R 4  is H and the other is —OL 1 R 15 , H, OH or F; and   R 8a , R 9a , R 8  and R 9  are independently selected from H or C 1 -C 6 alkyl,   and provided at least one of R 1  or R 1a  is substituted with —NHL 1 R 15 , or at least one of R 3 , R 4 , R 3a  or R 4a  is —OL 1 R 15 .       

     Embodiment 83 
     A compound of Formula (B), Formula (B-1) or Formula (B-2) of any one of Embodiments 76 to 80, wherein:
         R 2  and R 2a  are H;   one of R 3a  and R 4a  is H and the other is selected from the group consisting of —OL 1 R 15 , H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 3a  and R 4a  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 3a  or R 4a  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;   R 7a  and R 6a  are H;   R 6  and R 4  are H;   R 8 , R 9 , R 8a  and R 9a  are independently H or C 1 -C 6 alkyl, and   one of R 5  and R 7  is H and the other is selected from the group consisting of —OL 1 R 15 , H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 5  and R 7  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 5  or R 7  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 , and provided at least one of R 1  or R 1a  is substituted with —NHL 1 R 15 , or at least one of R 5 , R 7 , R 3a  or R 4a  is —OL 1 R 15 .       

     Embodiment 84 
     A compound of Formula (B), Formula (B-1) or Formula (B-2) of any one of Embodiments 76 to 80 or 83, wherein:
         Y 1  and Y 2  are O, CH 2  or S;   Y 3  is OH, O − , OR 10 , N(R 10 ) 2 , SH or S − ;   Y 4  is OH, O − , OR 10 , N(R 10 ) 2 , SH or S − ;   Y 5  and Y 6  are O or S;   Y 7  and Y 8  are O or S;   Y 9  and Y 10  are O or S;   R 2 , R 2a , R 7a , R 6a , R 6  and R 4  are H;   one of R 3a  and R 4a  is H and the other is —OL 1 R 15 , H, OH or F;   one of R 5  and R 7  is H and the other is —OL 1 R 15 , H, OH or F, and   R 8a , R 9a , R 8  and R 9  are independently selected from H or C 1 -C 6 alkyl,   and provided at least one of R 1  or R 1a  is substituted with —NHL 1 R 15 , or at least one of R 5 , R 7 , R 3a  or R 4a  is —OL 1 R 15 .       

     Embodiment 85 
     A compound of Formula (C), Formula (C-1) or Formula (C-2) of any one of Embodiments 76 to 80, wherein:
         R 2  and R 2a  are H;   one of R 3  and R 4  is H and the other is selected from the group consisting of —OL 1 R 15 , H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 3  and R 4  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 3  or R 4  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;   R 4a  and R 6a  are H;   R 6  and R 7  are H;   R 8 , R 9 , R 8a  and R 9a  are independently H or C 1 -C 6 alkyl;   one of R 5a  and R 7a  is H and the other is selected from the group consisting of —OL 1 R 15 , H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 5a  and R 7a  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 5a  or R 7a  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ,   and provided at least one of R 1  or R 1a  is substituted with —NHL 1 R 15 , or at least one of R 5a R 7a , R 3  or R 4  is —OL 1 R 15 .       

     Embodiment 86 
     A compound of Formula (C), Formula (C-1) or Formula (C-2) of any one of Embodiments 76 to 80 or 85, wherein:
         Y 1  and Y 2  are O, CH 2  or S;   Y 3  is OH, O − , OR 10 , N(R 10 ) 2 , SH or S − ;   Y 4  is OH, O − , OR 10 , N(R 10 ) 2 , SH or S − ;   Y 5  and Y 6  are O or S;   Y 7  and Y 8  are O or S;   Y 9  and Y 10  are O or S;   R 2 , R 2a , R 4a , R 6a , R 6  and R 7  are H;   one of R 3  and R 4  is H and the other is —OL 1 R 15 , H, OH or F;   one of R 5a  and R 7a  is H and the other is —OL 1 R 15 , H, OH or F, and   R 8a , R 9a , R 8  and R 9  are independently selected from H or C 1 -C 6 alkyl,   and provided at least one of R 1  or R 1a  is substituted with —NHL 1 R 15 , or at least one of R 5a R 7a , R 3  or R 4  is —OL 1 R 15 .       

     Embodiment 87 
     A compound of Formula (D), Formula (D-1) or Formula (D-2) of any one of Embodiments 76 to 80, wherein:
         R 2  and R 2a  are H;   one of R 5a  and R 7a  is H and the other is selected from the group consisting of —OL 1 R 15 , H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 5a  and R 7a  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 5a  or R 7a  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;   R 4a  and R 6a  are H;   R 6  and R 4  are H;   R 8 , R 9 , R 8a  and R 9a  are independently H or C 1 -C 6 alkyl, and   one of R 5  and R 7  is H and the other is selected from the group consisting of —OL 1 R 15 , H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 5  and R 7  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 5  or R 7  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 , and provided at least one of R 1  or R 1a  is substituted with —NHL 1 R 15 , or at least one of R 5a R 7a , R 5  or R 7  is —OL 1 R 15 .       

     Embodiment 88 
     A compound of Formula (D), Formula (D-1) or Formula (D-2) of any one of Embodiments 76 to 80 or 87, wherein:
         Y 1  and Y 2  are O, CH 2  or S;   Y 3  is OH, O − , OR 10 , N(R 10 ) 2 , SH or S − ;   Y 4  is OH, O − , OR 10 , N(R 10 ) 2 , SH or S − ;   Y 5  and Y 6  are O or S;   Y 7  and Y 8  are O or S;   Y 9  and Y 10  are O or S;   R 2 , R 2a , R 4a , R 6a , R 6  and R 4  are H;   one of R 5a , R 7a  is H and the other is —OL 1 R 15 , OH or F;   one of R 5  and R 7  is H and the other is —OL 1 R 15 , H, OH or F, and   R 8 , R 9 , R 8a  and R 9a  are independently H or C 1 -C 6 alkyl,   and provided at least one of R 1  or R 1a  is substituted with —NHL 1 R 15 , or at least one of R 5a R 7a , R 5  or R 7  is —OL 1 R 15 .       

     Embodiment 89 
     A compound of Formula (E), Formula (E-1) or Formula (E-2) of any one of Embodiments 76 to 80, wherein:
         R 2  and R 2a  are H;   R 6  and R 6a  are H;   R 7a  is H;   R 8 , R 9 , R 8a  and R 9a  are independently H or C 1 -C 6 alkyl, and   one of R 3a  and R 4a  is H and the other is selected from the group consisting of —OL 1 R 15 , H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 3a  and R 4a  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 3a  or R 4a  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;   one of R 3  and R 4  is H and the other is selected from the group consisting of —OL 1 R 15 , H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 3  and R 4  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 3  or R 4  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 , and   one of R 5  and R 7  is H and the other is selected from the group consisting of —OL 1 R 15 , H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 5  and R 7  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 5  or R 7  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ,   and provided at least one of R 1  or R 1a  is substituted with —NHL 1 R 15 , or at least one of R 3a R 4a , R 3 , R 4 , R 5  or R 7  is —OL 1 R 15 .       

     Embodiment 90 
     A compound of Formula (E), Formula (E-1) or Formula (E-2) of any one of Embodiments 76 to 80 or 89, wherein:
         Y 1  and Y 2  are O, CH 2  or S;   Y 3  is OH, O − , OR 10 , N(R 10 ) 2 , SH or S − ;   Y 5  is O or S;   Y 7  and Y 8  are O or S;   Y 9  and Y 10  are O or S;   R 2 , R 2a , R 5a , R 6a , R 6  and R 7a  are H;   one of R 3a , R 4a  is H and the other is —OL 1 R 15 , H, OH, OCH 3  or F;   one of R 3 , R 4  is H and the other is —OL 1 R 15 , H, OH, OCH 3  or F;   one of R 5  and R 7  is H and the other is —OL 1 R 15 , —OL 1 R 15 , H, OH, OCH 3  or F, and   R 8 , R 9 , R 8a  and R 9a  are independently H or C 1 -C 6 alkyl,   and provided at least one of R 1  or R 1a  is substituted with —NHL 1 R 15 , or at least one of R 3a R 4a , R 3 , R 4 , R 5  or R 7  is —OL 1 R 15 .       

     Embodiment 91 
     A compound of Formula (F), Formula (F-1) or Formula (F-2) of any one of Embodiments 76 to 80, wherein:
         R 2  and R 2a  are H;   each R 6  and R 6a  are H;   each R 7a  and R 7  are H;   R 8 , R 9 , R 8a  and R 9a  are independently H or C 1 -C 6 alkyl, and   one of R 3a  and R 4a  is H and the other is selected from the group consisting of —OL 1 R 15 , H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 3a  and R 4a  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 3a  or R 4a  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;   one of R 3  and R 4  is H and the other is selected from the group consisting of —OL 1 R 15 , H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 3  and R 4  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 3  or R 4  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 , and   R 5  is selected from the group consisting of —OL 1 R 15 , H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 5  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 5  is substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ,   and provided at least one of R 1 , R 1a  or R 1b  is substituted with —NHL 1 R 15 , or at least one of R 3a , R 4a , R 3 , R 4 , R 5  or R 7  is —OL 1 R 15 .       

     Embodiment 92 
     A compound of Formula (F), Formula (F-1) or Formula (F-2) of any one of Embodiments 76 to 80 or 91, wherein:
         Y 1  and Y 2  are O, CH 2  or S;   each Y 3  is OH, O − , OR 10 , N(R 10 ) 2 , SH or S − ;   each Y 5  is O or S;   each Y 7  is independently are O or S;   each Y 9  is independently O or S;   Y 1  is O, CH 2  or S;   R 2 , R 2a , R 6 , R 6a , R 6 , R 7  and R 7a  are H;   one of R 3a , R 4a  is H and the other is —OL 1 R 15 , H, OH, OCH 3  or F;   one of R 3 , R 4  is H and the other is —OL 1 R 15 , H, OH, OCH 3  or F;   R 5  is —OL 1 R 15 , H, OH, OCH 3  or F, and   R 8 , R 9 , R 8a  and R 9a  are independently H or C 1 -C 6 alkyl,   and provided at least one of R 1 , R 1a  or R 1b  is substituted with —NHL 1 R 15 , or at least one of R 3a , R 4a , R 3 , R 4 , R 5  or R 7  is —OL 1 R 15 .       

     Embodiment 93 
     A compound of any one of Embodiments 76 to 92 wherein:
         R 1  is       

     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
         
         
           
             
               
                 wherein: R 1  is substituted with 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, OH, SH, NH 2 , D, CD 3 , C 1 -C 6 alkyl, C 1 -C 6 alkoxyalkyl, C 1 -C 6 hydroxyalkyl, O 3 —C 8 cycloalkyl, a 3 to 6 membered heterocyclyl having 1 to 2 heteroatoms independently selected from O, N and S, —O(C 1 -C 6 alkyl), —O(C 3 -C 8 cycloalkyl), —S(C 1 -C 6 alkyl), —S(C 1 -C 6 aminoalkyl), —S(C 1 -C 6 hydroxyalkyl), —S(C 3 -C 8 cycloalkyl), —NH(C 1 -C 6 alkyl), —NH(C 3 -C 8 cycloalkyl), —N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 alkyl) (C 3 -C 8 cycloalkyl), —ON, —P(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —(CH 2 ) 1-10 C(═O)OH, —CH═CH(CH 2 ) 1-10 C(═O)OH, —NHC(O)(C 1 -C 6 alkyl), —NHC(O)(C 3 -C 8 cycloalkyl), —NHC(O)(phenyl), and —N(C 3 -C 8 cycloalkyl) 2 , and 
                 each R 20  is independently selected from H and L 1 R 15 ; 
               
             
             R 1a  is 
           
         
       
    
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
         
         
           
             
               
                 wherein: R 1a  is substituted with 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, OH, SH, NH 2 , D, CD 3 , C 1 -C 6 alkyl, C 1 -C 6 alkoxyalkyl, C 1 -C 6 hydroxyalkyl, C 3 -C 8 cycloalkyl, a 3 to 6 membered heterocyclyl having 1 to 2 heteroatoms independently selected from O, N and S, —O(C 1 -C 6 alkyl), —O(C 3 -C 8 cycloalkyl), —S(C 1 -C 6 alkyl), —S(C 1 -C 6 aminoalkyl), —S(C 1 -C 6 hydroxyalkyl), —S(C 3 -C 8 cycloalkyl), —NH(C 1 -C 6 alkyl), —NH(C 3 -C 8 cycloalkyl), —N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 alkyl) (C 3 -C 8 cycloalkyl), —CN, —P(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —(CH 2 ) 1-10 C(═O)OH, —CH═CH(CH 2 ) 1-10 C(═O)OH, —NHC(O)(C 1 -C 6 alkyl), —NHC(O)(C 3 -C 8 cycloalkyl), —NHC(O)(phenyl), and —N(C 3 -C 8 cycloalkyl) 2 , 
                 and 
                 each R 21  is independently selected from H and L 1 R 15 ; 
               
             
             and 
             R 1  is 
           
         
       
    
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
         
         
           
             
               
                 wherein: R 1b  is substituted with 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, OH, SH, NH 2 , D, CD 3 , C 1 -C 6 alkyl, C 1 -C 6 alkoxyalkyl, C 1 -C 6 hydroxyalkyl, C 3 -C 8 cycloalkyl, a 3 to 6 membered heterocyclyl having 1 to 2 heteroatoms independently selected from O, N and S, —O(C 1 -C 6 alkyl), —O(C 3 -C 8 cycloalkyl), —S(C 1 -C 6 alkyl), —S(C 1 -C 6 aminoalkyl), —S(C 1 -C 6 hydroxyalkyl), —S(C 3 -C 8 cycloalkyl), —NH(C 1 -C 6 alkyl), —NH(C 3 -C 8 cycloalkyl), —N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 alkyl) (C 3 -C 8 cycloalkyl), —CN, —P(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —(CH 2 ) 1-10 C(═O)OH, —CH═CH(CH 2 ) 1-10 C(═O)OH, —NHC(O)(C 1 -C 6 alkyl), —NHC(O)(C 3 -C 8 cycloalkyl), —NHC(O)(phenyl), and —N(C 3 -C 8 cycloalkyl) 2 , 
                 and 
                 each R 21  is independently selected from H and L 1 R 15 . 
               
             
           
         
       
    
     Embodiment 94 
     A compound of Formula (A-3), Formula (B-3), Formula (C-3), Formula (D-3), Formula (E-3) or Formula (F-3), wherein:
         Y 1  is —O—, —S—, —S(═O)—, —SO 2 —, —CH 2 —, or —CF 2 —;   Y 2  is —O—, —S—, —S(═O)—, —SO 2 —, —CH 2 —, or —CF 2 —;   Y 11  is —O—, —S—, —S(═O)—, —SO 2 —, —CH 2 —, or —CF 2 —;   Y 3  is OH, O − , OR 10 , N(R 10 ) 2 , SH or S − ;   Y 4  is OH, O − , OR 10 , N(R 10 ) 2 , SH or S − ;   Y 7  is O or S;   Y 8  is O or S;   R 1  is       

     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
         
         
           
             
               
                 wherein: R 1  is substituted with 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, OH, SH, NH 2 , D, CD 3 , C 1 -C 6 alkyl, C 1 -C 6 alkoxyalkyl, C 1 -C 6 hydroxyalkyl, C 3 -C 8 cycloalkyl, a 3 to 6 membered heterocyclyl having 1 to 2 heteroatoms independently selected from O, N and S, —O(C 1 -C 6 alkyl), —O(C 3 -C 8 cycloalkyl), —S(C 1 -C 6 alkyl), —S(C 1 -C 6 aminoalkyl), —S(C 1 -C 6 hydroxyalkyl), —S(C 3 -C 8 cycloalkyl), —NH(C 1 -C 6 alkyl), —NH(C 3 -C 8 cycloalkyl), —N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 alkyl) (C 3 -C 8 cycloalkyl), —CN, —P(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —(CH 2 ) 1-10 C(═O)OH, —CH═CH(CH 2 ) 1-10 C(═O)OH, —NHC(O)(C 1 -C 6 alkyl), —NHC(O)(C 3 -C 8 cycloalkyl), —NHC(O)(phenyl), and —N(C 3 -C 8 cycloalkyl) 2 , 
                 and 
                 each R 20  is independently selected from H and L 1 R 15 ; 
               
             
             R 1a  is 
           
         
       
    
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
         
         
           
             
               
                 wherein: R 1a  is substituted with 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, OH, SH, NH 2 , D, CD 3 , C 1 -C 6 alkyl, C 1 -C 6 alkoxyalkyl, C 1 -C 6 hydroxyalkyl, C 3 -C 8 cycloalkyl, a 3 to 6 membered heterocyclyl having 1 to 2 heteroatoms independently selected from O, N and S, —O(C 1 -C 6 alkyl), —O(C 3 -C 8 cycloalkyl), —S(C 1 -C 6 alkyl), —S(C 1 -C 6 aminoalkyl), —S(C 1 -C 6 hydroxyalkyl), —S(C 3 -C 8 cycloalkyl), —NH(C 1 -C 6 alkyl), —NH(C 3 -C 8 cycloalkyl), —N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 alkyl) (C 3 -C 8 cycloalkyl), —CN, —P(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —(CH 2 ) 1-10 C(═O)OH, —CH═CH(CH 2 ) 1-10 C(═O)OH, —NHC(O)(C 1 -C 6 alkyl), —NHC(O)(C 3 -C 8 cycloalkyl), —NHC(O)(phenyl), and —N(C 3 -C 8 cycloalkyl) 2 , 
                 and 
                 each R 21  is independently selected from H and L 1 R 15 ; 
               
             
             and 
             R 1b  is 
           
         
       
    
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
         
         
           
             
               
                 wherein: R 1b  is substituted with 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, OH, SH, NH 2 , D, CD3, C 1 -C 6 alkyl, C 1 -C 6 alkoxyalkyl, C 1 -C 6 hydroxyalkyl, C 3 -C 8 cycloalkyl, a 3 to 6 membered heterocyclyl having 1 to 2 heteroatoms independently selected from O, N and S, —O(C 1 -C 6 alkyl), —O(C 3 -C 8 cycloalkyl), —S(C 1 -C 6 alkyl), —S(C 1 -C 6 aminoalkyl), —S(C 1 -C 6 hydroxyalkyl), —S(C 3 -C 8 cycloalkyl), —NH(C 1 -C 6 alkyl), —NH(C 3 -C 8 cycloalkyl), —N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 alkyl) (C 3 -C 8 cycloalkyl), —CN, —P(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —(CH 2 ) 1-10 C(═O)OH, —CH═CH(CH 2 ) 1-10 C(═O)OH, —NHC(O)(C 1 -C 6 alkyl), —NHC(O)(C 3 -C 8 cycloalkyl), —NHC(O)(phenyl), and —N(C 3 -C 8 cycloalkyl) 2 , 
                 and 
                 each R 21  is independently selected from H and L 1 R 15 ; 
               
             
             each R 2  is independently selected from the group consisting of H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 2  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 2  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ; 
             each R 3  is independently selected from the group consisting of —OL 1 R 15 , H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 3  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 3  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ; 
             each R 4  is independently selected from the group consisting of —OL 1 R 15 , H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 4  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 4  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ; 
             each R 5  is independently selected from the group consisting of —OL 1 R 15 , H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 5  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 5  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ; 
             each R 6  is independently selected from the group consisting of H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 6  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 6  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ; 
             each R 7  is independently selected from the group consisting of —OL 1 R 15 , H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 7  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 7  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ; 
             R 2a  is selected from the group consisting of H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 2a  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 2a  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3    
             R 3a  is selected from the group consisting of —OL 1 R 15 , H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 3a  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 3a  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ; 
             R 4a  is selected from the group consisting of —OL 1 R 15 , H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 4a  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 4a  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ; 
             R 5a  is selected from the group consisting of —OL 1 R 15 , H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 5a  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 5a  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ; 
             R 6a  is selected from the group consisting of H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 6a  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 6a  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ; 
             R 7a  is selected from the group consisting of —OL 1 R 15 , H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 7a  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 7a  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ; 
             each R 10  is independently selected from the group consisting of H, C 1 -C 12 alkyl, —(CH 2 CH 2 O) n CH 2 CH 2 C(═O)OC 1 -C 6 alkyl, and 
           
         
       
    
     
       
         
         
             
             
         
       
     
     wherein the C 1 -C 12 alkyl of R 10  is substituted by 0, 1, 2 or 3 substituents independently selected from —OH, C 1 -C 12 alkoxy, —S—C(═O)C 1 -C 6 alkyl and C(O)OC 1 -C 6 alkyl;
         optionally R 3  and R 6  are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, —O—C 2 -C 6 alkynylene, such that when R 3  and R 6  are connected, the O is bound at the R 3  position   optionally R 3a  and R 6a , are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, —O—C 2 -C 6 alkynylene, such that when R 3a  and R 6a  are connected, the O is bound at the R 3a  position;   optionally R 2  and R 3  are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, —O—C 2 -C 6 alkynylene, such that when R 2  and R 3  are connected, the O is bound at the R 3  position;   optionally R 2a  and R 3a , are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, —O—C 2 -C 6 alkynylene, such that when R 2a  and R 3a  are connected, the O is bound at the R 3a  position;   optionally R 4  and R 3  are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, —O—C 2 -C 6 alkynylene, such that when R 4  and R 3  are connected, the O is bound at the R 3  position;   optionally R 4a  and R 3a , are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, —O—C 2 -C 6 alkynylene, such that when R 4a  and R 3a  are connected, the O is bound at the R 3a  position;   optionally R 5  and R 6  are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, —O—C 2 -C 6 alkynylene, such that when R 5  and R 6  are connected, the O is bound at the R 5  position;   optionally R 5a  and R 6a , are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, —O—C 2 -C 6 alkynylene, such that when R 5a  and R 6a  are connected, the O is bound at the R 5a  position;   optionally R 5  and R 7  are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, —O—C 2 -C 6 alkynylene, such that when R 5  and R 7  are connected, the O is bound at the R 5  position, and   optionally R 5a  and R 7a , are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, —O—C 2 -C 6 alkynylene, such that when R 5a  and R 7a  are connected, the O is bound at the R 5a  position;   L 1  is —C(═O)O(CH 2 ) m NR 11 C(═O)(CH 2 ) m —**; —C(═O)O(CH 2 ) m NR 11 C(═O)(CH 2 ) m O(CH 2 ) m —**; —C(═O)O(CH 2 ) m NR 11 C(═O)X 1 X 2 C(═O)(CH 2 ) m —**; —C(═O)OC(R 12 ) 2 (CH 2 ) m NR 11 C(═O)X 1 X 2 C(═O)(CH 2 ) m —**; —C(═O)O(CH 2 ) m NR 11 C(═O)X 1 X 2 C(═O)X 2 C)(CH 2 ) m O)(CH 2 ) m —**; —C(═O)O(CH 2 ) m NR 11 C(═O)X 1 X 2 C(═O)X 2 C)(CH 2 ) m O)(CH 2 ) m C(═O)—**; —C(═O)O(CH 2 ) m NR 11 C(═O)X 4 C(═O)NR 11 (CH 2 ) m NR 11 C(═O)(CH 2 ) m O(CH 2 ) m —**; —C(═O)O(CH 2 ) m NR 11 C(═O)X 5 C═O)X C (═O)(CH 2 ) m NR 11 C(═O)(CH 2 ) m —**; —C(═O)X 4 C(═O)NR(CH 2 ) m NR 11 C(═O)(CH 2 ) m O(CH 2 ) m —**; —C(═O)(CH 2 ) m NR 11 C(═O)X 1 X 2 C(═O)(CH 2 ) m —**; —C(═O)(CH 2 ) m NR 11 C(═O)X 2 C(═O)(CH 2 ) m —**; —C(═O)O(CH 2 ) m X 6 C(═O)X 1 X 2 C(═O) (CH 2 ) m —**, —C(═O)(CH 2 ) m NR 11 C(═O)((CH 2 ) m O) n (CH 2 ) m —**, —C(═O)O(CH 2 ) m X 6 C(═O)(CH 2 ) m —**, —C(═O)O(CH 2 ) m X 6 C(═O)(CH 2 ) m O(CH 2 ) m —**, —C(═O)O(CH 2 ) m X 6 C(═O)X 1 X 2 C(═O) (CH 2 ) m —**, —C(═O)O(CH 2 ) m X 6 C(═O)X 1 X 2 C(═O) (CH 2 ) m O(CH 2 ) m —**, —C(═O)O(CH 2 ) m X 6 C(═O)X 1 X 2 C(═O)(CH 2 ) m O(CH 2 ) m C(═O)—**, —C(═O)O(CH 2 ) m X 6 C(═O)X 4 C(═O)NR 11 (CH 2 ) m NR 11 C(═O)(CH 2 ) m O(CH 2 ) m —**, —C(═O)X 4 C(═O)X 6 (CH 2 ) m NR 11 C(═O)(CH 2 ) m O(CH 2 ) m —**, —C(═O)(CH 2 ) m X 6 C(═O)X 1 X 2 C(═O)(CH 2 ) m —**, —C(═O)O((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 C(═O)(CH 2 ) m —**; —C(═O)O((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 C(═O)(CH 2 ) m NR 11 C(═O)(CH 2 ) m —**; —C(═O)O((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 C(═O)(CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)O((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 C(═O)((CH 2 ) m O) n (CH 2 ) m —**; —C(═O)O((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)(CH 2 ) m —**; —C(═O)O((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)(CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)O((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O))X 5 C(═O)((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)O((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 C(═O)(CH 2 ) m NR 11 C(═O)((CH 2 ) m O) n (CH 2 ) m —**; —C(═O)O((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 C(═O)(CH 2 ) m NR 11 C(═O)((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)O((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 (CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)O((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 ((CH 2 ) m O) n (CH 2 ) m —**; —C(═O)O((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 ((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)(CH 2 ) m-**; —C(═O)O((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 ((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)(CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)O((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 ((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)O((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 (CH 2 ) m NR 11  ((CH 2 ) m O) n (CH 2 ) m —**; —C(═O)O((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 C(═O)(CH 2 ) m NR 11  ((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)O((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 (CH 2 ) m —**; —C(═O)O((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 C(═O)((CH 2 ) m O) n (CH 2 ) m —**; —C(═O)O((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 (CH 2 ) m X 3 (CH 2 ) m —**; C(═O)O(CH 2 ) m —**; —C(═O)O((CH 2 ) m O) n (CH 2 ) m —**; C(═O)O(CH 2 ) m NR 11 (CH 2 ) m —**; —C(═O)O(CH 2 ) m NR 11  (CH 2 ) m C(═O)X 2 X 1 C(═O)—**; —C(═O)O(CH 2 ) m X 3 (CH 2 ) m —**; C(═O)O(H 2 ) m X 6 C(═O)X 1 X 2 O(═O)((CH 2 ) m O) n (CH 2 ) m **; —C(═O)O((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)O((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)(CH 2 ) m —**; —C(═O)O(CH 2 ) m NR 11 C(═O(CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)O((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)(CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)O((CH 2 ) m O) n X 3 (CH 2 ) m —**; C(═O)O((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)O((CH 2 ) m O) n (CH 2 ) m C(═O)NR 11 (CH 2 ) m —**; C(═O)O(CH 2 ) m C(R 12 ) 2 —**; —C(═O)OCH 2 ) m C(R 12 ) 2 SS(CH 2 ) m NR 11 C(═O)(CH 2 ) m —**; —C(═O)O(CH 2 ) m C(═O)NR 11 (CH 2 ) m —**; C(═O)(CH 2 ) m —**; C(═O)((CH 2 ) m O) n (CH 2 ) m —**; —C(═O)(CH 2 ) m NR 11 (CH 2 ) m —**; C(═O)(CH 2 ) m NR 11 (CH 2 ) m C(═O)X 2 X C (═O)**; —C(═O)(CH 2 ) m X 3 (CH 2 ) m —**; C(═O)((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)(CH 2 ) m NR 11 C(═O)(CH 2 ) m —**; C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)(CH 2 ) m —**; —C(═O)(CH 2 ) m NR 11 C(═O(CH 2 ) m X 3 (CH 2 ) m —**; (CH 2 ) m NR 11 C(═O)X 1 X 2 C(═O)(CH 2 ) m —**; —(CH 2 ) m (CHOH)(CH 2 ) m NR 11 C(═O)X 1 X 2 C(═O)(CH 2 ) m **; —C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)(CH 2 ) m X 3 (CH 2 ) m —**; C(═O)((CH 2 ) m O) n X 3 (CH 2 ) m **; —C(═O)((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —**; C(═O)((CH 2 ) m O) n (CH 2 ) m C(═O)NR 11  (CH 2 ) m —**; —C(═O)(CH 2 ) m C(R 12 ) 2 —**; C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 C(═O)(CH 2 ) m —**; —C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 C(═O)(CH 2 ) m NR 11 C(═O)(CH 2 ) m —**; —C(═O)((CH 2 ) m O) n  (CH 2 ) m NR 11 C(═O)X 5 C(═O)(CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 C(═O)((CH 2 ) m O) n (CH 2 ) m —**; —C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)(CH 2 ) m —**; —C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)(CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O))X 5 C(═O)((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m **; —C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 C(═O)(CH 2 ) m NR 11 C(═O)((CH 2 ) m O) n (CH 2 ) m —**; —C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 C(═O)(CH 2 ) m NR 11 C(═O)((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 (CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 ((CH 2 ) m O) n (CH 2 ) m —**; —C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 ((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)(CH 2 ) m —**; —C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 ((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)(CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 ((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 (CH 2 ) m NR 11 ((CH 2 ) m O) n (CH 2 ) m —**; —C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 C(═O)(CH 2 ) m NR 11 ((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 (CH 2 ) m —**; —C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 C(═O)((CH 2 ) m O) n (CH 2 ) m —**; —C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 (CH 2 ) m X 3 (CH 2 ) m —**. —C(═O)(CH 2 ) m C(R 12 ) 2 SS(CH 2 ) m NR 11 C(═O)(CH 2 ) m —**; C(═O)(CH 2 ) m C(═O)NR 11  (CH 2 ) m —**; —C(═O)X 1 X 2 C(═O)(CH 2 ) m —**; C(═O)X 1 X 2 C(═O)(CH 2 ) m NR 11 C(═O)(CH 2 ) m —**; —C(═O)X 1 X 2 C(═O)(CH 2 ) m X 3 (CH 2 ) m —**; C(═O)X 1 X 2 C(═O)((CH 2 ) m O) n (CH 2 ) m —**; —C(═O)X 1 X 2 C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)(CH 2 ) m —**; —C(═O)X 1 X 2 C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O) (CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)X 1 X 2 C(═O)((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)X 1 X 2 C(═O)(CH 2 ) m NR 11 C(═O) ((CH 2 ) m O) n (CH 2 ) m —**; —C(═O)X 1 X 2 C(═O)(CH 2 ) m NR 11 C(═O) ((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)X 1 X 2 (CH 2 ) m X 3 (CH 2 ) m —**; C(═O)X 1 X 2 ((CH 2 ) m O) n (CH 2 ) m —**; —C(═O)X 1 X 2 ((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)(CH 2 ) m —**; —C(═O)X 1 X 2 ((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)(CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)X 1 X 2 ((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)X 1 X 2 (CH 2 ) m NR 11  ((CH 2 ) m O) n (CH 2 ) m —**; —C(═O)X 1 X 2 C(═O)(CH 2 ) m NR 11 ((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)NR 11 (CH 2 ) m —**; C(═O)NR 11 (CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)NR 11  (CH 2 ) m NR 11 C(═O)X 1 X 2 C(═O)(CH 2 ) m —**; —C(═O)NR 11  (CH 2 ) m NR 11 C(═O)O(CH 2 ) m —**; C(═O)NR 11 (CH 2 ) m NR 11 C(═O)X 1 X 2 —**; —C(═O)NR 11 (CH 2 ) m NR 11 C(═O)X 5 ; —C(═O)NR 11  (CH 2 ) m NR 11 C(═O)(CH 2 ) m X 5 (CH 2 ) m **; —C(═O)X 1 C(═O)NR 11  (CH 2 ) m X 5 (CH 2 ) m —**; —C(═O)X 6 C(═O)(CH 2 ) m NR 11 C(═O)X 1 X 2 C(═O)(CH 2 ) m —** C(═O)NR 11 (CH 2 ) m NR 11 C(═O)(CH 2 ) m —**; C(═O)NR 11 (CH 2 ) m NR 11 C(═O)(CH 2 ) m O(CH 2 ) m —**; —C(═O)NR 11  (CH 2 ) m NR 11 C(═O)X 1 X 2 C(═O)(CH 2 ) m O(CH 2 ) m —**; —C(═O)NR 11  (CH 2 ) m NR 11 C(═O)X 1 X 2 C(═O)(CH 2 ) m O(CH 2 ) m C(═O)—**; —C(═O)NR 11  (CH 2 ) m NR 11 C(═O)X 4 C(═O)NR 11  (CH 2 ) m NR 11 C(═O)(CH 2 ) m O(CH 2 ) m —**; —C(═O)NR 11 (CH 2 ) m NR 11 C(═O)X 1 X 2 C(═O)(CH 2 ) m —**; —C(═O)NR 11  (CH 2 ) m NR 11 C(═O)X 5 C(═O)(CH 2 ) m —**; —C(═O)NR 11  (CH 2 ) m NR 11 C(═O)X 5 C(═O)(CH 2 ) m NR 11 C(═O)(CH 2 ) m —**; —C(═O)NR 11  (CH 2 ) m NR 11 C(═O)X 5 C(═O)(CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)NR 11  (CH 2 ) m NR 11 C(═O)X 5 C(═O)((CH 2 ) m O) n (CH 2 ) m —**; —C(═O)NR 11  (CH 2 ) m NR 11 C(═O)X 5 C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)(CH 2 ) m —**; —C(═O)NR 11  (CH 2 ) m NR 11 C(═O)X 5 C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)(CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)NR 11 (CH 2 ) m NR 11 C(═O)X 5 C(═O)((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)NR 11  (CH 2 ) m NR 11 C(═O)X 5 C(═O)(CH 2 ) m NR 11 C(═O)((CH 2 ) m O) n (CH 2 ) m —**; —C(═O)NR 11  (CH 2 ) m NR 11 C(═O)X 5 C(═O)(CH 2 ) m NR 11 C(═O)((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)NR 11  (CH 2 ) m NR 11 C(═O)X 5 (CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)NR 11  (CH 2 ) m NR 11 C(═O)X 5 ((CH 2 ) m O) n (CH 2 ) m —**; —C(═O)NR 11  (CH 2 ) m NR 11 C(═O)X 5 ((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)(CH 2 ) m —**; —C(═O)NR 11  (CH 2 ) m NR 11 C(═O)X 5 ((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)(CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)NR 11  (CH 2 ) m NR 11 C(═O)X 5 ((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)NR 11  (CH 2 ) m NR 11 C(═O)X 5 (CH 2 ) m NR 11 ((CH 2 ) m O) n (CH 2 ) m **; —C(═O)NR 11  (CH 2 ) m NR 11 C(═O)X 5 C(═O)(CH 2 ) m NR 11  ((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)NR 11 (CH 2 ) m NR 11 C(═O)X 5 (CH 2 ) m —**; —C(═O)NR 11  (CH 2 ) m NR 11 C(═O)X 5 C(═O)((CH 2 ) m O) n (CH 2 ) m —**. —C(═O)NR 11 (CH 2 ) m NR 11 C(═O)X 5 (CH 2 ) m X(CH 2 ) m —**; —C(═O)X 1 C(═O)NR 11  (CH 2 ) m NR 11 C(═O)(CH 2 ) m —**; —C(═O)X 1 C(═O)NR 11 (CH 2 ) m X(CH 2 ) m —**; C(═O)NR 11 (CH 2 ) m NR 11 C(═O)(CH 2 ) m —**; —C(═O)NR 11  (CH 2 ) m NR 11 C(═O)(CH 2 ) m X 3 (CH 2 ) m —**; C(═O)NR 11 (CH 2 ) m NR 11 C(═O)—**; —C(═O)X 1 X 2 (CH 2 ) m —**; C(═O)X 1 X 2 C(═O)((CH 2 ) m O) n (CH 2 ) m —**; —C(═O)X 1 X 2 (CH 2 ) m X 3 (CH 2 ) m —**; C(═O)NR 11  (CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)NR 11  ((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —**; C(═O)X 1 X 2 C(═O)((CH 2 ) m O) n (CH 2 ) m —**; —C(═O)X 1 X 2 C(═O)(CH 2 ) m —**; —C(═O)X 1 C(═O)(CH 2 ) m NR 11 C(═O)(CH 2 ) m —**; and —C(═O)X 1 C(═O)(CH 2 ) m NR 11 C(═O)((CH 2 ) m O) n (CH 2 ) m **;
           where the ** of L, indicates the point of attachment to R 15 ;   
           R 15  is       

     
       
         
         
             
             
         
       
     
     —ONH 2 , —NH 2 , 
     
       
         
         
             
             
         
       
     
     —N 3 , 
     
       
         
         
             
             
         
       
     
     —SH, —SR 12 , —SSR 17 , —S(═O) 2 (CH═CH 2 ), —(CH 2 ) 2 S(═O) 2 (CH═CH 2 ), —NHS(═O) 2 (CH═CH 2 ), —NHC(═O)CH 2 Br, —NHC(═O)CH 2 I, 
     
       
         
         
             
             
         
       
         
         
           
             X 1  is 
           
         
       
    
     
       
         
         
             
             
         
       
     
     where the * of X 1  indicates the point of attachment to X 2 ;
         X 2  is selected from       

     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     where the * of X 2  indicates the point of attachment to X 1 ;
         X 3  is       

     
       
         
         
             
             
         
       
         
         
           
             X 4  is —O(CH 2 ) n SSC(R 12 ) 2 (CH 2 ) n — or —(CH 2 ) n C(R 12 ) 2 SS(CH 2 ) n O—; 
             X 5  is 
           
         
       
    
     
       
         
         
             
             
         
       
     
     where the ** of X 5  indicates orientation toward R 15 ;
         X 6  is       

     
       
         
         
             
             
         
       
     
     or, where the ** of X 6  indicates orientation toward R 15 ;
         R 17  is 2-pyridyl or 4-pyridyl;   each R 11  is independently selected from H and C 1 -C 6 alkyl;   each R 12  is independently selected from H and C 1 -C 6 alkyl;   each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; and   each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 and 18.   each R 110  is independently selected from H, C 1 -C 6 alkyl, F, Cl, and —OH;   each R 111  is independently selected from H, C 1 -C 6 alkyl, F, Cl, —NH 2 , —OCH 3 , —OCH 2 CH 3 , —N(CH 3 ) 2 , —CN, —NO 2  and —OH;   each R 112  is independently selected from H, C 1-6 alkyl, fluoro, benzyloxy substituted with —C(═O)OH, benzyl substituted with —C(═O)OH, C 1-4 alkoxy substituted with —C(═O)OH and C 1-4 alkyl substituted with —C(═O)OH;
 
and provided at least one of R 20  or R 21  is —NHL 1 R 15  or is substituted with —NHL 1 R 15 , or at least one of R 3 , R 4 , R 5 , R 7 , R 3a , R 4a , R 5a  or R 7a  is —OL 1 R 15 .
       

     Embodiment 95 
     A compound of Formula (A-4), or a pharmaceutically acceptable salt thereof, wherein: R 1 , R 1a , R 3 , R 3a , R 6 , R 6a , Y 3  and Y 4  are as defined in Embodiment 94. 
     Embodiment 96 
     A compound of Formula (A-4a), Formula A-4b), Formula A-4c) or Formula A-4d), or a pharmaceutically acceptable salt thereof, wherein:
         R 1 , R 1a , R 3 , R 3a , R 6  and R 66a  are as defined in Embodiment 94;   Y 3  is OR 9 , N(R 10 ) 2 , SH or S − , and   Y 4  is OR 9 , N(R 10 ) 2 , SH or S − .       

     Embodiment 97 
     A compound of Formula (A-4e), Formula (A-4f), Formula (A-4 g), Formula (A-4h), Formula (A-4i), Formula (A-4j), Formula (A-4k), Formula (A-41), Formula (A-4m), Formula (A-4n), Formula (A-4o) or Formula (A-4p), or a pharmaceutically acceptable salt thereof, wherein:
         R 1 , R 1a , R 3 , R 3a , R 6  and R 6a  are as defined in Embodiment 94;   Y 3  is OR 9 , N(R 10 ) 2 , SH or S − , and   Y 4  is OR 9 , N(R 10 ) 2 , SH or S − .       

     Embodiment 98 
     A compound of Formula (B-4), or a pharmaceutically acceptable salt thereof, wherein: R 1 , R 1a , R 3a , R 5 , R 6a , Y 3  and Y 4  are as defined in Embodiment 94. 
     Embodiment 99 
     A compound of Formula (B-4a), Formula (B-4b), Formula (B-4c) or Formula (B-4d), or a pharmaceutically acceptable salt thereof, wherein:
         R 1 , R 1a , R 3a , R 5  and R 6a  are as defined in Embodiment 94;   Y 3  is OR 9 , N(R 10 ) 2 , SH or S − , and   Y 4  is OR 9 , N(R 10 ) 2 , SH or S − .       

     Embodiment 100 
     A compound of Formula (B-4e), Formula (B-4f), Formula (B-4 g) or Formula (B-4h), or a pharmaceutically acceptable salt thereof, wherein:
         R 1 , R 1a  and R 5  are as defined in Embodiment 94;   Y 3  is OR 10 , N(R 10 ) 2 , SH or S − , and   Y 4  is OR 10 , N(R 10 ) 2 , SH or S − .       

     Embodiment 101 
     A compound of Formula (C-4), or a pharmaceutically acceptable salt thereof, wherein: R 1 , R 1a , R 3 , R 5a , R 6 , Y 3  and Y 4  are as defined in Embodiment 94. 
     Embodiment 102 
     A compound of Formula (C-4a), Formula (C-4b), Formula (C-4c) or Formula (C-4d), or a pharmaceutically acceptable salt thereof, wherein:
         R 1 , R 1a , R 3 , R 5a  and R 6  are as defined in Embodiment 94;   Y 3  is OR 10 , N(R 10 ) 2 , SH or S − , and   Y 4  is OR 10 , N(R 10 ) 2 , SH or S − .       

     Embodiment 103 
     A compound of Formula (C-4e), Formula (C-4f), Formula (C-4 g) or Formula (C-4h), or a pharmaceutically acceptable salt thereof, wherein:
         R 1 , R 1a  and R 5a  are as defined in Embodiment 94;   Y 3  is OR 10 , N(R 10 ) 2 , SH or S − , and   Y 4  is OR 10 , N(R 10 ) 2 , SH or S − .       

     Embodiment 104 
     A compound of Formula (D-4), or a pharmaceutically acceptable salt thereof, wherein: R 1 , R 1a , R 5 , R 5a , Y 3  and Y 4  are as defined in Embodiment 94. 
     Embodiment 105 
     A compound of of Formula (D-4a), Formula (D-4b), Formula (D-4c) or Formula (D-4d), or a pharmaceutically acceptable salt thereof, wherein:
         R 1 , R 1a , R 5  and R 5a  are as defined in Embodiment 94;   Y 3  is OR 10 , N(R 10 ) 2 , SH or S − , and   Y 4  is OR 10 , N(R 10 ) 2 , SH or S − .       

     Embodiment 106 
     A compound of Formula (E-4), or a pharmaceutically acceptable salt thereof, wherein: R 1 , R 1a , R 3 , R 3a , R 4 , R 4a , R 5  and R 7  are as defined in Embodiment 94. 
     Embodiment 107 
     A compound of Formula (E-4a) or Formula (E-4b), or a pharmaceutically acceptable salt thereof, wherein:
         R 1 , R 3 , R 3a , R 4 , R 4a , R 5  and R 7  are as defined in Embodiment 94;   and   Y 3  is OR 10 , N(R 10 ) 2 , SH or S − .       

     Embodiment 108 
     A compound of Formula (F-4), or a pharmaceutically acceptable salt thereof, wherein: R 1 , R 1a , R 1b , R 3 , R 3a , R 4 , R 4a , R 5  and R 7  are as defined in Embodiment 94. 
     Embodiment 109 
     The compound of Formula (F-4a), Formula (F-4b), Formula (F-4c), or Formula (F-4d), or a pharmaceutically acceptable salt thereof, wherein:
         R 1 , R 1a , R 1b , R 3 , R 3a , R 4 , R 4a , R 5  and R 7  are as defined in Embodiment 94;   and   each Y 3  is independently selected from OR 10 , N(R 10 ) 2 , SH and S − .       

     Embodiment 110 
     The compound of any one of Embodiments 76 to 109, wherein R 1  is 
     
       
         
         
             
             
         
       
     
     Embodiment 111 
     The compound of any one of Embodiments 76 to 109, wherein R 1a  is 
     
       
         
         
             
             
         
       
     
     Embodiment 112 
     The compound of any one of Embodiments 76 to 109, wherein R 1b  is 
     
       
         
         
             
             
         
       
     
     Embodiment 113 
     The compound of any one of Embodiments 76 to 109, wherein R 1  is 
     
       
         
         
             
             
         
       
     
     Embodiment 114 
     The compound of any one of Embodiments 76 to 109, wherein R 1a  is 
     
       
         
         
             
             
         
       
     
     Embodiment 115 
     The compound of any one of Embodiments 76 to 109, wherein R 1b  is 
     
       
         
         
             
             
         
       
     
     Embodiment 116 
     The compound of any one of Embodiments 76 to 109, wherein R 1  is 
     
       
         
         
             
             
         
       
     
     wherein R 20  is -L 1 R 15 . 
     Embodiment 117 
     The compound of any one of Embodiments 76 to 109, wherein R 1a  is 
     
       
         
         
             
             
         
       
     
     wherein R 21  is -L 1 R 5 . 
     Embodiment 118 
     The compound of any one of Embodiments 76 to 109, wherein R 1b  is 
     
       
         
         
             
             
         
       
     
     wherein R 21  is -L 1 R 15    
     Embodiment 119 
     The compound of any one of Embodiments 76 to 109, wherein R 1  is 
     
       
         
         
             
             
         
       
     
     wherein R 20  is -L 1 R 15 . 
     Embodiment 120 
     The compound of any one of Embodiments 76 to 109, wherein R 1a  is 
     
       
         
         
             
             
         
       
     
     wherein R 21  is -L 1 R 15 . 
     Embodiment 121 
     The compound of any one of Embodiments 76 to 109, wherein R 1b  is 
     
       
         
         
             
             
         
       
     
     wherein R 21  is -L 1 R 15 . 
     Embodiment 122 
     The compound of any one of Embodiments 76 to 109, wherein R 1  is 
     
       
         
         
             
             
         
       
     
     and R 1a  is 
     
       
         
         
             
             
         
       
     
     wherein R 20  is L 1 R 15  and R 21  is H. 
     Embodiment 123 
     The compound of any one of Embodiments 76 to 109, wherein R 1  is 
     
       
         
         
             
             
         
       
     
     and R 1a  is 
     
       
         
         
             
             
         
       
     
     wherein R 20  is H and R 21  is L 1 R 15 . 
     Embodiment 124 
     The compound of any one of Embodiments 76 to 109, wherein R 1  is 
     
       
         
         
             
             
         
       
     
     and R 1a  is 
     
       
         
         
             
             
         
       
     
     wherein R 20  is L 1 R 15  and R 21  is L 1 R 15    
     Embodiment 125 
     The compound of any one of Embodiments 76 to 109, wherein R 1  is 
     
       
         
         
             
             
         
       
     
     and R 1a  is 
     
       
         
         
             
             
         
       
     
     wherein R 20  is L 1 R 15  and R 21  is H. 
     Embodiment 126 
     The compound of any one of Embodiments 76 to 109, wherein R 1  is 
     
       
         
         
             
             
         
       
     
     and R 1a  is 
     
       
         
         
             
             
         
       
     
     wherein R 20  is H and R 21  is L 1 R 15 . 
     Embodiment 127 
     The compound of any one of Embodiments 76 to 109, wherein R 1  is 
     
       
         
         
             
             
         
       
     
     and R 1a  is 
     
       
         
         
             
             
         
       
     
     wherein R 20  is L 1 R 15  and R 21  is L 1 R 15    
     Embodiment 128 
     The compound of any one of Embodiments 76 to 109, wherein R 1  is 
     
       
         
         
             
             
         
       
     
     and R 1a  is 
     
       
         
         
             
             
         
       
     
     wherein R 20  is H and R 21  is L 1 R 15    
     Embodiment 129 
     The compound of any one of Embodiments 76 to 109, wherein R 1  is 
     
       
         
         
             
             
         
       
     
     and R 1a  is 
     
       
         
         
             
             
         
       
     
     wherein R 20  is L 1 R 15  and R 21  is H. 
     Embodiment 130 
     The compound of any one of Embodiments 76 to 109, wherein R 1  is 
     
       
         
         
             
             
         
       
     
     and R 1a  is 
     
       
         
         
             
             
         
       
     
     wherein R 20  is L 1 R 15  and R 21  is L 1 R 15 . 
     Embodiment 131 
     The compound of any one of Embodiments 76 to 109, wherein R 1  is 
     
       
         
         
             
             
         
       
     
     and R 1a  is 
     
       
         
         
             
             
         
       
     
     wherein R 20  is H and R 21  is L 1 R 15 . 
     Embodiment 132 
     The compound of any one of Embodiments 76 to 109, wherein R 1  is 
     
       
         
         
             
             
         
       
     
     and R 1a  is 
     
       
         
         
             
             
         
       
     
     wherein R 20  is L 1 R 5  and R 21  is H. 
     Embodiment 133 
     The compound of any one of Embodiments 76 to 109, wherein R 1  is 
     
       
         
         
             
             
         
       
     
     and R 1a  is 
     
       
         
         
             
             
         
       
     
     wherein R 20  is L 1 R 15  and R 21  is L 1 R 15    
     Embodiment 134 
     The compound of any one of Embodiments 76 to 109, wherein R 1  is 
     
       
         
         
             
             
         
       
     
     and R 1a  is 
     
       
         
         
             
             
         
       
     
     wherein R 20  is L 1 R 15  and R 21  is H. 
     Embodiment 135 
     The compound of any one of Embodiments 76 to 109, wherein R 1  is 
     
       
         
         
             
             
         
       
     
     and R 1a  is 
     
       
         
         
             
             
         
       
     
     wherein R 20  is H and R 21  is L 1 R 15 . 
     Embodiment 136 
     The compound of any one of Embodiments 76 to 109, wherein R 1  is 
     
       
         
         
             
             
         
       
     
     and R 1a  is 
     
       
         
         
             
             
         
       
     
     wherein R 20  is L 1 R 15  and R 21  is L 1 R 15    
     Embodiment 137 
     The compound of any one of Embodiments 76 to 109, wherein R 1  is 
     
       
         
         
             
             
         
       
     
     R 1b  is 
     
       
         
         
             
             
         
       
     
     and R 1a  is 
     
       
         
         
             
             
         
       
     
     wherein R 20  is L 1 R 5  and each R 21  is H. 
     Embodiment 138 
     The compound of any one of Embodiments 76 to 109, wherein R 1  is 
     
       
         
         
             
             
         
       
     
     R 1b  is 
     
       
         
         
             
             
         
       
     
     and R 1a  is 
     
       
         
         
             
             
         
       
     
     wherein R 20  is H, R 21  of Rib is L 1 R 15  and R 21  of R 1a  is H. 
     Embodiment 139 
     The compound of any one of Embodiments 76 to 109, wherein R 1  is 
     
       
         
         
             
             
         
       
     
     R 1b  is 
     
       
         
         
             
             
         
       
     
     and R 1a  is 
     
       
         
         
             
             
         
       
     
     wherein R 20  is H, R 21  of Rib is H and R 21  of R 1a  is L 1 R 15 . 
     Embodiment 140 
     The compound of any one of Embodiments 76 to 109, wherein R 1a  is 
     
       
         
         
             
             
         
       
     
     wherein R 21  is H and one of R 3 , R 3a , R 5  or R 5a  is —OL 1 R 15 . 
     Embodiment 141 
     The compound of any one of Embodiments 76 to 109, wherein R 1b  is 
     
       
         
         
             
             
         
       
     
     wherein R 21  is H and one of R 3 , R 3a , R 5  or R 5a  is —OL 1 R 15 . 
     Embodiment 142 
     The compound of any one of Embodiments 76 to 109, wherein R 1  is 
     
       
         
         
             
             
         
       
     
     wherein R 20  is H and one of R 3 , R 3a , R 5  or R 5a  is —OL 1 R 15 . 
     Embodiment 143 
     The compound of any one of Embodiments 76 to 109, wherein R 1a  is 
     
       
         
         
             
             
         
       
     
     wherein R 21  is H and one of R 3 , R 3a , R 5  or R 5a  is —OL 1 R 15 . 
     Embodiment 144 
     The compound of any one of Embodiments 76 to 109, wherein R 1b  is 
     
       
         
         
             
             
         
       
     
     wherein R 21  is H and one of R 3 , R 3a , R 5  or R 5a  is —OL 1 R 15 . 
     Embodiment 145 
     The compound of any one of Embodiments 76 to 109, wherein R 1  is 
     
       
         
         
             
             
         
       
     
     and R 1a  is 
     
       
         
         
             
             
         
       
     
     wherein R 20  is H, R 21  is H and one of R 3 , R 3a , R 5  or R 5a  is —OL 1 R 15 . 
     Embodiment 146 
     The compound of any one of Embodiments 76 to 109, wherein R 1  is 
     
       
         
         
             
             
         
       
     
     and R 1a  is 
     
       
         
         
             
             
         
       
     
     wherein R 20  is H, R 21  is H and one of R 3 , R 3a , R 5  or R 5a  is —OL 1 R 15 . 
     Embodiment 147 
     The compound of any one of Embodiments 76 to 109, wherein R 1  is 
     
       
         
         
             
             
         
       
     
     and R 1a  is 
     
       
         
         
             
             
         
       
     
     wherein R 20  is H, R 21  is H and one of R 3 , R 3a , R 5  or R 5a  is —OL 1 R 15 . 
     Embodiment 148 
     The compound of any one of Embodiments 76 to 109, wherein R 1  is 
     
       
         
         
             
             
         
       
     
     and R 1a  is 
     
       
         
         
             
             
         
       
     
     wherein R 20  is H, R 21  is H and one of R 3 , R 3a , R 5  or R 5a  is —OL 1 R 15 . 
     Embodiment 149 
     The compound of any one of Embodiments 76 to 109, wherein R 1  is 
     
       
         
         
             
             
         
       
     
     and R 1  is 
     
       
         
         
             
             
         
       
     
     wherein R 20  is H, R 21  is H and one of R 3 , R 3a , R 5  or R 5a  is —OL 1 R 15 . 
     Embodiment 150 
     The compound of any one of Embodiments 76 to 109, wherein R 1  is 
     
       
         
         
             
             
         
       
     
     R 1b  is 
     
       
         
         
             
             
         
       
     
     and R 1a  is 
     
       
         
         
             
             
         
       
     
     wherein R 20  is H, each R 21  is H and one of R 3 , R 3a , R 5  or R 5a  is —OL 1 R 15 . 
     Embodiment 151 
     The compound of any one of Embodiments 76 to 150, wherein:
         Y 3  is OH, O − , SH or S − , and   Y 4  is OH, O − , SH or S − .       

     Embodiment 152 
     The compound of any one of Embodiments 76 to 150, wherein:
         Y 3  is OH or O − , and   Y 4  is OH or O − .       

     Embodiment 153 
     The compound of any one of Embodiments 76 to 150, wherein:
         Y 3  is SH or S − , and   Y 4  is OH or O − .       

     Embodiment 154 
     The compound of any one of Embodiments 76 to 150, wherein:
         Y 3  is OH or O − , and   Y 4  is SH or S − .       

     Embodiment 155 
     The compound of any one of Embodiments 76 to 150, wherein:
         Y 3  is SH or S − , and   Y 4  is SH or S − .       

     Embodiment 156 
     The compound of any one of Embodiments 76 to 139 or Embodiments 151 to 155, wherein: R 2 , R 2a , R 4 , R 4a , R 6 , R 6a , R 7  and R 7a  are each H. 
     Embodiment 157 
     The compound of any one of Embodiments 76 to 139 or Embodiments 151 to 155, wherein: R 3  is —OH, F or —NH 2 . 
     Embodiment 158 
     The compound of any one of Embodiments 76 to 139 or Embodiments 151 to 155, wherein: R 3  is —OH or F. 
     Embodiment 159 
     The compound of any one of Embodiments 76 to 139 or Embodiments 151 to 155, wherein: R 3a  is —OH, F or —NH 2 . 
     Embodiment 160 
     The compound of any one of Embodiments 76 to 139 or Embodiments 151 to 155, wherein: R 3a  is —OH or F. 
     Embodiment 161 
     The compound of any one of Embodiments 76 to 139 or Embodiments 151 to 155, wherein: R 5  is —OH, F or —NH 2 . 
     Embodiment 162 
     The compound of any one of Embodiments 76 to 139 or Embodiments 151 to 155, wherein: R 5  is —OH or F. 
     Embodiment 163 
     The compound of any one of Embodiments 76 to 139 or Embodiments 151 to 155, wherein: R 5a  is —OH, F or —NH 2 . 
     Embodiment 164 
     The compound of any one of Embodiments 76 to 139 or Embodiments 151 to 155, wherein: R 5a  is —OH or F. 
     Embodiment 165 
     The compound of any one of Embodiments 76 to 139 or Embodiments 151 to 155, wherein when present:
         R 2 , R 2a , R 4 , R 4a , R 6 , R 6a , R 7  and R 7a  are each H;   R 3  is —OH, and   R 3a  is F.       

     Embodiment 166 
     The compound of any one of Embodiments 76 to 139 or Embodiments 151 to 155, wherein when present:
         R 2 , R 2a , R 4 , R 4a , R 6 , R 6a , R 7  and R 7a  are each H;   R 3  is F, and   R 3a  is —OH.       

     Embodiment 167 
     The compound of any one of Embodiments 76 to 139 or Embodiments 151 to 155, wherein when present:
         R 2 , R 2a , R 4 , R 4a , R 6 , R 6a , R 7  and R 7a  are each H;   R 3  is F, and   R 3a  is F.       

     Embodiment 168 
     The compound of any one of Embodiments 76 to 139 or Embodiments 151 to 155, wherein when present:
         R 2 , R 2a , R 4 , R 4a , R 6 , R 6a , R 7  and R 7a  are each H;   R 3  is —OH, and   R 3a  is —OH.       

     Embodiment 169 
     The compound of any one of Embodiments 76 to 139 or Embodiments 151 to 155, wherein when present:
         R 2 , R 2a , R 4 , R 4a , R 6 , R 6a , R 7  and R 7a  are each H;   R 3a  is —OH, and   R 5  is F.       

     Embodiment 170 
     The compound of any one of Embodiments 76 to 139 or Embodiments 151 to 155, wherein when present:
         R 2 , R 2a , R 4 , R 4a , R 6 , R 6a , R 7  and R 7a  are each H;   R 3a  is F, and   R 5  is —OH.       

     Embodiment 171 
     The compound of any one of Embodiments 76 to 139 or Embodiments 151 to 155, wherein when present:
         R 2 , R 2a , R 4 , R 4a , R 6 , R 6a , R 7  and R 7a  are each H;   R 3a  is F, and   R 5  is F.       

     Embodiment 172 
     The compound of any one of Embodiments 76 to 139 or Embodiments 151 to 155, wherein when present:
         R 2 , R 2a , R 4 , R 4a , R 6 , R 6a , R 7  and R 7a  are each H;   R 3a  is —OH, and   R 5  is —OH.       

     Embodiment 173 
     The compound of any one of Embodiments 76 to 139 or Embodiments 151 to 155, wherein when present:
         R 2 , R 2a , R 4 , R 4a , R 6 , R 6a , R 7  and R 7a  are each H;   R 3  is —OH, and   R 5a  is F.       

     Embodiment 174 
     The compound of any one of Embodiments 76 to 139 or Embodiments 151 to 155, wherein when present:
         R 2 , R 2a , R 4 , R 4a , R 6 , R 6a , R 7  and R 7a  are each H;   R 3  is F, and   R 5a  is —OH.       

     Embodiment 175 
     The compound of any one of Embodiments 76 to 139 or Embodiments 151 to 155, wherein when present:
         R 2 , R 2a , R 4 , R 4a , R 6 , R 6a , R 7  and R 7a  are each H;   R 3  is F, and   R 5a  is F.       

     Embodiment 176 
     The compound of any one of Embodiments 76 to 139 or Embodiments 151 to 155, wherein when present:
         R 2 , R 2a , R 4 , R 4a , R 6 , R 6a , R 7  and R 7a  are each H;   R 3  is —OH, and   R 5a  is —OH.       

     Embodiment 177 
     The compound of any one of Embodiments 76 to 139 or Embodiments 151 to 155, wherein when present:
         R 2 , R 2a , R 4 , R 4a , R 6 , R 6a , R 7  and R 7a  are each H;   R 5  is —OH, and   R 5a  is F.       

     Embodiment 178 
     The compound of any one of Embodiments 76 to 139 or Embodiments 151 to 155, wherein when present:
         R 2 , R 2a , R 4 , R 4a , R 6 , R 6a , R 7  and R 7a  are each H;   R 5  is F, and   R 5a  is —OH.       

     Embodiment 179 
     The compound of any one of Embodiments 76 to 139 or Embodiments 151 to 155, wherein when present:
         R 2 , R 2a , R 4 , R 4a , R 6 , R 6a , R 7  and R 7a  are each H;   R 5  is F, and   R 5a  is F.       

     Embodiment 180 
     The compound of any one of Embodiments 76 to 139 or Embodiments 151 to 155, wherein when present:
         R 2 , R 2a , R 4 , R 4a , R 6 , R 6a , R 7  and R 7a  are each H;   R 5  is —OH, and   R 5a  is —OH.       

     Embodiment 181 
     The compound of any one of Embodiments 76 to 139 or Embodiments 151 to 155, wherein:
         R 3  is —OH or F;   R 3a  is —OH or F;   R 5  is —OH or F;   R 5a  is —OH or F;   R 6  is H, and   R 6a  is H.       

     Embodiment 182 
     The compound of any one of Embodiments 76 to 139 or Embodiments 151 to 155, wherein:
         R 3  is H, —OH or F;   R 3a  is H, —OCH 3 , —OH or F;   R 5  is —OH or F;   R 4 , R 4a , R 6 , R 6a , R 7 , R 7a  are H, and   R 6a  is H.       

     Embodiment 183 
     The compound of any one of Embodiments 76 to 182, wherein:
         L 1  is —C(═O)O(CH 2 ) m NR 11 C(═O)(CH 2 ) m —**; —C(═O)O(CH 2 ) m NR 11 C(═O)(CH 2 ) m O(CH 2 ) m —**; —C(═O)O(CH 2 ) m NR 11 C(═O)X 1 X 2 C(═O)(CH 2 ) m —**; —C(═O)OC(R 12 ) 2 (CH 2 ) m NR 11 C(═O)X 1 X 2 C(═O)(CH 2 ) m —**; —C(═O)O(CH 2 ) m NR 11 C(═O)X 2 C═O)X 2 C(═CH 2 )O(CH 2 ) m —**; —C(═O)O(CH 2 ) m NR 11 C(═O)X 1 X 2 C(═O)(CH 2 ) m O(CH 2 ) m C(═O)—**; —C(═O)O(CH 2 ) m NR 11 C(═O)X 4 C(═O)NR 11  (CH 2 ) m NR 11 C(═O)(CH 2 ) m O(CH 2 ) m —**; —C(═O)O(CH 2 ) m NR 11 C(═O)X 5 C(═O)(CH 2 ) m NR 11 C(═O)(CH 2 ) m —**; —C(═O)O(CH 2 ) m X 6 C(═O)X 1 X 2 C(═O)((CH 2 ) m O) n (CH 2 ) m **; —(CH 2 ) m NR 11 C(═O)X 1 X 2 C(═O)(CH 2 ) m —**; —(CH 2 ) m (CHOH)(CH 2 ) m NR 11 C(═O)X 1 X 2 C(═O)(CH 2 ) m **; —C(═O)X 6 C(═O)(CH 2 ) m NR 11 C(═O)X 1 X 2 C(═O) (CH 2 ) m —**; —C(═O)X 4 C(═O)NR 11 (CH 2 ) m NR 11 C(═O)(CH 2 ) m O(CH 2 ) m —**; —C(═O)(CH 2 ) m NR 11 C(═O)X 1 X 2 C(═O)(CH 2 ) m —**; —C(═O)O(CH 2 ) m X 6 C(═O)X 1 X 2 C(═O)(CH 2 ) m —**, or —C(═O)(CH 2 ) m NR 11 C(═O)((CH 2 ) m O) n (CH 2 ) m —**,   where the ** of L 1  indicates the point of attachment to R 15  and   where R 11 , R 12 , X 1 , X 2 , m and n are s defined in Embodiment 94.       

     Embodiment 184 
     The compound of any one of Embodiments 76 to 183, wherein:
         L 1  is       

     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Embodiment 185 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Embodiment 186 
     A compound of Formula (A) selected from: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Embodiment 187 
     A compound of Formula (B) selected from: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Methods of Conjugation 
     The present invention provides various methods of conjugating Linker-Drug moieties to antibodies or antibody fragments to produce antibody drug conjugates, also referred to as immunconjugates. 
     A general reaction scheme for the formation of immunostimmulator antibody conjugates of Formula (I) is shown in Scheme 1 below: 
     
       
         
         
             
             
         
       
     
     where: RG 2  is a reactive group which reacts with a compatible R 15  group to form a corresponding R 115  group (such groups are illustrated in Table 5). D, R 15 , L, Ab, y, m, n and R 115  are as defined herein. 
     Scheme 2 further illustrates this general approach wherein the antibody comprises reactive groups (RG 2 ) which react with an R 15  group (as defined herein) to covalently attach the Linker-Drug moiety to the antibody via an R 115  group (as defined herein). For illustrative purposes only Scheme 2 shows the antibody having four RG 2  groups. 
     
       
         
         
             
             
         
       
     
     In one aspect, Linker-Drug moieties are conjugated to antibodies via modified cysteine residues in the antibodies (see for example WO2014/124316). Scheme 3 illustrates this approach wherein a free thiol group generated from the engineered cysteine residues in the antibody react with an R 15  group (where R 15  is a maleimide) to covalently attach the Linker-Drug moiety to the antibody via an R 115  group (where R 115  is a succinimide ring). For illustrative purposes only Scheme 3 shows the antibody chaving four free thiol groups. 
     
       
         
         
             
             
         
       
     
     In another aspect, Linker-Drug moieties are conjugated to antibodies via lysine residues in the antibodies. Scheme 4 illustrates this approach wherein a free amine group from the lysine residues in the antibody react with an R 15  group (where R 15  is an NHS ester, a pentafluorophenyl or a tetrafluorophenyl) to covalently attach the Linker-Drug moiety to the antibody via an R 115  group (where R 115  is an amide). For illustrative purposes only Scheme 4 shows the antibody chaving four amine groups. 
     
       
         
         
             
             
         
       
     
     In another aspect, Linker-Drug moieties are conjugated to antibodies via formation of an oxime bridge at the naturally occurring disulfide bridges of an antibody. The oxime bridge is formed by initially creating a ketone bridge by reduction of an interchain disulfide bridge of the antibody and re-bridging using a 1,3-dihaloacetone (e.g. 1,3-dichloroacetone). Subsequent reaction with a Linker-Drug moiety comprising a hydroxyl amine thereby form an oxime linkage (oxime bridge) which attaches the Linker-Drug moiety to the antibody (see for example WO2014/083505). Scheme 5 illustrates this approach. 
     
       
         
         
             
             
         
       
     
     In yet another aspect, Linker-Drug moieties are conjugated to antibodies by inserting a peptide tag containing a serine residue, such as an S6, ybbR, or Al tag, into the sequence of an antibody as described in Bioconjugate Chemistry, 2015, 26, 2554-2562. These tags acts as a substrate for 4′-phosphopantetheinyl transferases (PPTase) enzymes wherein the PPTase posttranslationally modifies the serine residue to covalently attach a linker derived from coenzyme A (CoA) or from CoA analogues. The linker comprises a pendent ketone which is subsequently reacted with a Linker-Drug moiety comprising a hydroxyl amine thereby forming an oxime linkage which attaches the Linker-Drug moiety to the antibody. Scheme 6 illustrates this approach. 
     
       
         
         
             
             
         
       
     
     DC-SIGN Immunoconjugates of the Invention 
     The present invention provides DC-SIGN immunoconjugates, also referred to as antibody drug conjugates, where an anti-DC-SIGN antibody, or a functional fragment thereof, is coupled to an agonist of STING via a linker. The DC-SIGN immunoconjugates of the invention can deliver an effective dose of a STING agonist to DC-SIGN+ cells, such as dendritic cells (DCs) and/or macrophages. In some embodiments, the DC-SIGN immunoconjugates of the invention can deliver an effective dose of a STING agonist to tumor residing antigen presenting cells, such as tumor residing DCs and/or macrophages, whereby stimulates activation of the DC-SIGN expressing cells and triggers an immune response including tumor specific T cell activation, in the tumor. The DC-SIGN immunoconjugates can also deliver an effective dose of a STING agonist to lymphoid tissue resident and peripheral tissue resident DC-SIGN expressing cells, including dendritic cells and macrophages. Delivery of the DC-SIGN immunoconjugates to DC-SIGN expressing cells not located in the tumor also stimulates activation of the DC-SIGN expressing cells and triggers an immune response. 
     In one aspect, the anti-DC-SIGN antibodies, antigen binding fragments or their functional equivalents of the invention are linked, via covalent attachment by a linker, to one or more compounds that are agonists of Stimulator of Interferon Genes (STING) receptor. 
     In one aspect, the anti-DC-SIGN antibodies, antigen binding fragments or their functional equivalents of the invention are linked, via covalent attachment by a linker, to one or more compounds that are cyclic dinucleotides which bind to Stimulator of Interferon Genes (STING) receptor. 
     In one aspect, the anti-DC-SIGN antibodies, antigen binding fragments or their functional equivalents of the invention are linked, via covalent attachment by a linker, to one or more compounds that are cyclic dinucleotides which are agonists of Stimulator of Interferon Genes (STING) receptor. 
     In one aspect, the anti-DC-SIGN immunoconjugates of the invention comprises one or more Drug moieties (D) as described herein. 
     In one aspect, the anti-DC-SIGN immunoconjugates of the invention comprises one or more Drug moieties (D), wherein the Drug moiety (D) is a compound which binds to Stimulator of Interferon Genes (STING) receptor and which comprises one or more reactive moieties capable of forming a covalent bond with one or more linker(s) (L). 
     In one aspect, the anti-DC-SIGN immunoconjugates of the invention comprises one or more Drug moieties (D), wherein the Drug moiety (D) is a compound which binds to Stimulator of Interferon Genes (STING) receptor and which a comprises one or more reactive moieties capable of forming a covalent bond with one or more linker(s) (L), wherein linker (L) is a cleavable linker. 
     In one aspect, the anti-DC-SIGN immunoconjugates of the invention comprise one or more Drug moieties (D), wherein the Drug moiety (D) is a dinucleotide which binds to Stimulator of Interferon Genes (STING) receptor and which comprises one or more reactive moieties capable of forming a covalent bond with one or more linker(s) (L). 
     In one aspect, the anti-DC-SIGN immunoconjugates of the invention, comprises one or more Drug moieties (D), wherein the Drug moiety (D) is a dinucleotide which binds to Stimulator of Interferon Genes (STING) receptor and which comprises one or more reactive moieties capable of forming a covalent bond with one or more linker(s) (L), wherein linker (L) is a cleavable linker. 
     In one aspect, the anti-DC-SIGN immunoconjugates of the invention comprise one or more Drug moieties (D), wherein the Drug moiety (D) is a cyclic dinucleotide which binds to Stimulator of Interferon Genes (STING) receptor and which comprises one or more reactive moieties capable of forming a covalent bond with one or more linker(s) (L). 
     In one aspect, the anti-DC-SIGN immunoconjugates of the invention, comprise one or more Drug moieties (D), wherein the Drug moiety (D) is a cyclic dinucleotide which binds to Stimulator of Interferon Genes (STING) receptor and which comprises one or more reactive moieties capable of forming a covalent bond with one or more linker(s) (L), wherein linker (L) is a cleavable linker. 
     In one aspect, the invention provides an immunoconjugate of Formula (I): 
       Ab-(L-(D) m ) n   (Formula(I))
 
     wherein:
         Ab is an anti-DC-SIGN antibody or fragment thereof;   L is a linker comprising one or more cleavage elements;   D is a compound which binds to Stimulator of Interferon Genes (STING) receptor;   m is an integer from 1 to 8; and   n is an integer from 1-20.       

     In another aspect, the invention provides an immunoconjugate of Formula (II): 
       Ab-(L-D) n   (Formula(II))
 
     wherein:
         Ab is an anti-DC-SIGN antibody or fragment thereof;   L is a linker comprising one or more cleavage elements;   D is a compound which binds to Stimulator of Interferon Genes (STING) receptor;   and   n is an integer from 1-20.       

     In another aspect, the invention provides an immunoconjugate of Formula (I): 
       Ab-(L-(D) m ) n   (Formula (I)
 
     wherein:
         Ab is an anti-DC-SIGN antibody or fragment thereof;   L is a linker comprising two or more cleavage elements;   D is a compound which binds to Stimulator of Interferon Genes (STING) receptor;   m is an integer from 1 to 8; and   n is an integer from 1-20.       

     In an embodiment of Formula (I) or Formula (II), D is an agonist of Stimulator of Interferon Genes (STING) receptor. 
     In an embodiment of Formula (I) or Formula (II), D is a cyclic dinucleotides which bind to Stimulator of Interferon Genes (STING) receptor. 
     In an embodiment of Formula (I) or Formula (II), D is a cyclic dinucleotide which is an agonist of Stimulator of Interferon Genes (STING) receptor. 
     In one aspect, the DC-SIGN immunoconjugates of the invention comprise one or more Drug moieties (D) as described herein. 
     In one aspect, the DC-SIGN immunoconjugates of the invention comprises one or more Drug moieties (D), wherein the Drug moiety (D) is a compound which binds to Stimulator of Interferon Genes (STING) receptor and which comprises one or more reactive moieties capable of forming a covalent bond with a linker. 
     In one aspect, the DC-SIGN immunoconjugates of the invention comprises one or more Drug moieties (D), wherein the Drug moiety (D) is a compound which binds to Stimulator of Interferon Genes (STING) receptor and which a comprises one or more reactive moieties capable of forming a covalent bond with a linker, wherein linker (L) is a cleavable linker. 
     In one aspect, the DC-SIGN immunoconjugates of the invention comprises one or more Drug moieties (D), wherein the Drug moiety (D) is a dinucleotide which binds to Stimulator of Interferon Genes (STING) receptor and which comprises one or more reactive moieties capable of forming a covalent bond with a linker. 
     In one aspect, the DC-SIGN immunoconjugates of the invention, comprises one or more Drug moieties (D), wherein the Drug moiety (D) is a dinucleotide which binds to Stimulator of Interferon Genes (STING) receptor and which comprises one or more reactive moieties capable of forming a covalent bond with a linker, wherein linker (L) is a cleavable linker. 
     In one aspect, the DC-SIGN immunoconjugates of the invention comprise one or more Drug moieties (D), wherein the Drug moiety (D) is a cyclic dinucleotide which binds to Stimulator of Interferon Genes (STING) receptor and which comprises one or more reactive moieties capable of forming a covalent bond with a linker. 
     In one aspect, the DC-SIGN immunoconjugates of the invention, comprise one or more Drug moieties (D), wherein the Drug moiety (D) is a cyclic dinucleotide which binds to Stimulator of Interferon Genes (STING) receptor and which comprises one or more reactive moieties capable of forming a covalent bond with a linker, wherein linker (L) is a cleavable linker. 
     The term “cleavage product”, as used herein, refers to a drug moiety (D) linked to a fragment of the linker wherein the fragment comprises one or more linker components (Lc). The cleavage product is formed upon cleavage of Linker (L) from Ab-(L-(D) m ) n , wherein a fragment of the Linker (L) remains attached to the drug moiety (D). 
     In one embodiment, the DC-SIGN immunoconjugates of the invention comprise Formula (I): 
       Ab-(L-(D) m ) n   (Formula(I))
 
     wherein:
         Ab is an anti DC-SIGN antibody or a functional fragment thereof;   L is a linker comprising one or more cleavage elements;   D is a drug moiety] that has agonist activity against STING receptor;   m is an integer from 1 to 8; and   n is an integer from 1 to 20.       

     In one embodiment, the DC-SIGN immunoconjugates of the invention comprise Formula (I): 
       Ab-(L-(D) m ) n   (Formula(I))
 
     wherein:
         Ab is an anti DC-SIGN antibody or a functional fragment thereof;   L is a linker;   D is a drug moiety that binds to STING receptor;   m is an integer from 1 to 8; and   n is an integer from 1 to 20;
 
and wherein D, or a cleavage product thereof, that is released from the DC-SIGN immunoconjugate has STING agonist activity.
       

     In one embodiment, the DC-SIGN immunoconjugates of the invention comprise Formula (I): 
       Ab-(L-(D) m ) n   (Formula(I))
 
     wherein:
         Ab is an anti DC-SIGN antibody or a functional fragment thereof;   L is a linker;   D is a drug moiety that binds to STING receptor;   m is an integer from 1 to 8; and   n is an integer from 1 to 20;
 
wherein the DC-SIGN immunoconjugate delivers D, or a cleavage product thereof, to a cell targeted by the Ab, and wherein D, or the cleavage product thereof, has STING agonist activity.
       

     In one embodiment, the DC-SIGN immunoconjugates of the invention comprise Formula (I): 
       Ab-(L-(D) m ) n   (Formula (I))
 
     wherein:
         Ab is an anti DC-SIGN antibody or a functional fragment thereof;   L is a linker comprising one or more cleavage elements;   D is a drug moiety that binds to STING receptor;   m is an integer from 1 to 8; and   n is an integer from 1 to 20;
 
and wherein the DC-SIGN immunoconjugate releases D, or a cleavage product thereof, in a cell targeted by the Ab, and wherein D, or the cleavage product thereof, has STING agonist activity.
       

     In one embodiment, the DC-SIGN immunoconjugates of the invention comprise Formula (I): 
       Ab-(L-(D) m ) n   (Formula (I))
 
     wherein:
         Ab is an anti DC-SIGN antibody or a functional fragment thereof;   L is a linker comprising one or more cleavage elements;   D is a drug moiety that has agonist activity against STING receptor;   m is an integer from 1 to 8; and   n is an integer from 1 to 20;
 
wherein the DC-SIGN immunoconjugate releases D, or a cleavage product thereof, in a cell targeted by the Ab, and wherein D, or the cleavage product thereof, has STING agonist activity in the cell.
       

     In one embodiment, the DC-SIGN immunconjugates of the invention comprise Formula (I): 
       Ab-(L-(D) m ) n   (Formula (I))
 
     wherein:
         Ab is an anti-DC-SIGN antibody or a functional fragment thereof;   L is a linker comprising one or more cleavage elements;   D is a drug moiety that binds to STING receptor;   m is an integer from 1 to 8; and   n is an integer from 1 to 20;
 
wherein the DC-SIGN immunoconjugate specifically binds to DC-SIGN expressed on the cell surface and is internalized into the cell, and wherein D, or a cleavage product thereof, is cleaved from L and has STING agonist activity as determined by one or more STING agonist assays selected from: an interferon stimulation assay, a hSTING wt assay, a THP1-Dual assay, a TANK binding kinase 1 (TBK1) assay, or an interferon-γ-inducible protein (IP-10) secretion assay.
       

     In one aspect the DC-SIGN immunoconjugate of the invention, the DC-SIGN immunoconjugate is selected from the following; 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     wherein:
         each G 1  is independently selected from       

     
       
         
         
             
             
         
       
     
     where the * of G 1  indicates the point of attachment to —CR 8 R 9 —;
         X A  is C(═O)—, —C(═S)— or —C(═NR 1 )— and each Z 1  is NR 12 ;   X B  is C, and each Z 2  is N;   G 2  is       

     
       
         
         
             
             
         
       
     
     where the * of G 2  indicates the point of attachment to —CR 8a R 9a —;
         X C  is C(═O)—, —C(═S)— or —C(═NR 11 )— and each Z 3  is NR 12 ;   X D  is C, and each Z 4  is N;   Y 1  is —O—, —S—, —S(═O)—, —SO 2 —, —CH 2 —, or —CF 2 —;   Y 2  is —O—, —S—, —S(═O)—, —SO 2 —, —CH 2 —, or —CF 2 —;   Y 3  is OH, O − , OR 10 , N(R 10 ) 2 , SR 10 , SeH, Se − , BH 3 , SH or S − ;   Y 4  is OH, O − , OR 10 , N(R 10 ) 2 , SR 10 , SeH, Se − , BH 3 , SH or S − ;   Y 5  is —CH 2 —, —NH—, —O— or —S;   Y 6  is —CH 2 —, —NH—, —O— or —S;   Y 7  is O or S;   Y 8  is O or S;   Y 9  is —CH 2 —, —NH—, —O— or —S;   Y 10  is —CH 2 —, —NH—, —O— or —S;   Y 11  is —O—, —S—, —S(═O)—, —SO 2 —, —CH 2 —, or —CF 2 —;   q is 1, 2 or 3;   each R 1  is independently a partially saturated or aromatic monocyclic heterocyclyl or partially saturated or aromatic fused bicyclic heterocyclyl containing from 5-10 ring members selected from carbon atoms and 1 to 5 heteroatoms, and each heteroatoms is independently selected from O, N or S, or a tautomer thereof, wherein R 1  is substituted with 0, 1, 2, 3 or 4 substituents independently selected from —NHL 1 R 115 , F, Cl, Br, OH, SH, NH 2 , D, CD 3 , C 1 -C 6 alkyl, C 1 -C 6 alkoxyalkyl, C 1 -C 6 hydroxyalkyl, C 3 -C 8 cycloalkyl, a 3 to 6 membered heterocyclyl having 1 to 2 heteroatoms independently selected from O, N and S, —O(C 1 -C 6 alkyl), —O(C 3 -C 8 cycloalkyl), —S(C 1 -C 6 alkyl), —S(C 1 -C 6 aminoalkyl), —S(C 1 -C 6 hydroxyalkyl), —S(C 3 -C 8 cycloalkyl), —NH(C 1 -C 6 alkyl), —NH(C 3 -C 8 cycloalkyl), —N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 alkyl) (C 3 -C 8 cycloalkyl), —CN, —P(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —(CH 2 ) 1-10 C(═O)OH, —CH═CH(CH 2 ) 1-10 C(═O)OH, —NHC(O)(C 1 -C 6 alkyl), —NHC(O)(C 3 -C 8 cycloalkyl), —NHC(O)(phenyl), and —N(C 3 -C 8 cycloalkyl) 2 ;   each R 1a  is independently a partially saturated or aromatic monocyclic heterocyclyl or partially saturated or aromatic fused bicyclic heterocyclyl containing from 5-10 ring members selected from carbon atoms and 1 to 5 heteroatoms, and each heteroatoms is independently selected from O, N or S, or a tautomer thereof, wherein R 1a  is substituted with 0, 1, 2, 3 or 4 substituents independently selected from —NHL 1 R 115 , F, Cl, Br, OH, SH, NH 2 , D, CD 3 , C 1 -C 6 alkyl, C 1 -C 6 alkoxyalkyl, C 1 -C 6 hydroxyalkyl, C 3 -C 8 cycloalkyl, a 3 to 6 membered heterocyclyl having 1 to 2 heteroatoms independently selected from O, N and S, —O(C 1 -C 6 alkyl), —O(C 3 -C 8 cycloalkyl), —S(C 1 -C 6 alkyl), —S(C 1 -C 6 aminoalkyl), —S(C 1 -C 6 hydroxyalkyl), —S(C 3 -C 8 cycloalkyl), —NH(C 1 -C 6 alkyl), —NH(C 3 -C 8 cycloalkyl), —N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 alkyl) (C 3 -C 8 cycloalkyl), —CN, —P(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —(CH 2 ) 1-10 C(═O)OH, —CH═CH(CH 2 ) 1-10 C(═O)OH, —NHC(O)(C 1 -C 6 alkyl), —NHC(O)(C 3 -C 8 cycloalkyl), —NHC(O)(phenyl), and —N(C 3 -C 8 cycloalkyl) 2 ;   each R 1b  is independently a partially saturated or aromatic monocyclic heterocyclyl or partially saturated or aromatic fused bicyclic heterocyclyl containing from 5-10 ring members selected from carbon atoms and 1 to 5 heteroatoms, and each heteroatoms is independently selected from O, N or S, or a tautomer thereof, wherein R 1b  is substituted with 0, 1, 2, 3 or 4 substituents independently selected from —NHL 1 R 115 , F, Cl, Br, OH, SH, NH 2 , D, CD 3 , C 1 -C 6 alkyl, C 1 -C 6 alkoxyalkyl, C 1 -C 6 hydroxyalkyl, C 3 -C 8 cycloalkyl, a 3 to 6 membered heterocyclyl having 1 to 2 heteroatoms independently selected from O, N and S, —O(C 1 -C 6 alkyl), —O(C 3 -C 8 cycloalkyl), —S(C 1 -C 6 alkyl), —S(C 1 -C 6 aminoalkyl), —S(C 1 -C 6 hydroxyalkyl), —S(C 3 -C 8 cycloalkyl), —NH(C 1 -C 6 alkyl), —NH(C 3 -C 8 cycloalkyl), —N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 alkyl) (C 3 -C 8 cycloalkyl), —CN, —P(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —(CH 2 ) 1-10 C(═O)OH, —CH═CH(CH 2 ) 1-10 C(═O)OH, —NHC(O)(C 1 -C 6 alkyl), —NHC(O)(C 3 -C 8 cycloalkyl), —NHC(O)(phenyl), and —N(C 3 -C 8 cycloalkyl) 2 ;   each R 2  is independently selected from the group consisting of H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 2  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 2  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;   each R 3  is independently selected from the group consisting of —OL 1 R 115 , H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 3  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 3  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;   each R 4  is independently selected from the group consisting of —OL 1 R 115 , H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 4  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 4  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;   each R 5  is independently selected from the group consisting of —OL 1 R 115 , H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 5  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 5  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;   each R 6  is independently selected from the group consisting of H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 6  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 6  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;   each R 7  is independently selected from the group consisting of —OL 1 R 115 , H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 7  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 7  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;   each R 8  is independently selected from the group consisting of H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 8  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 8  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;   each R 9  is independently selected from the group consisting of H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 9  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 9  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;   each R 2a  is selected from the group consisting of H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 2a  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 2a  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3      each R 3a  is selected from the group consisting of —OL 1 R 115 , H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 3a  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 3a  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;   each R 4a  is selected from the group consisting of —OL 1 R 115 , H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 4a  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 4a  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;   each R 5a  is selected from the group consisting of —OL 1 R 115 , H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 5a  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 5a  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;   each R 6a  is selected from the group consisting of H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 6a  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 6a  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;   each R 7a  is selected from the group consisting of —OL 1 R 115 , H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 7a  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 7a  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;   each R 8a  is selected from the group consisting of H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 8a  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 8  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;   each R 9a  is selected from the group consisting of H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 9a  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 9a  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;   each R 10  is independently selected from the group consisting of H, C 1 -C 12 alkyl, C 1 -C 6 heteroalkyl, —(CH 2 CH 2 O) n CH 2 CH 2 C(═O)OC 1 -C 6 alkyl, and       

     
       
         
         
             
             
         
       
     
     wherein the C 1 -C 12 alkyl and C 1 -C 6 heteroalkyl of R 10  is substituted by 0, 1, 2 or 3 substituents independently selected from —OH, C 1 -C 12 alkoxy, —S—C(═O)C 1 -C 6 alkyl, halo, —CN, C 1 -C 12 alkyl, —O-aryl, _O-heteroaryl, —O-cycloalkyl, oxo, cycloalkyl, heterocyclyl, aryl, or heteroaryl, —OC(O)OC 1 -C 6 alkyland C(O)OC 1 -C 6 alkyl, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is substituted by 0, 1, 2 or 3 substituents independently selected from C 1 -C 12  alkyl, O—C 1 -C 12 alkyl, C 1 -C 12 heteroalkyl, halo, CN, OH, oxo, aryl, heteroaryl, O-aryl, O-heteroaryl, —C(═O)C 1 -C 12 alkyl, —OC(═O)C 1 -C 12 alkyl, —C(═O)OC 1 -C 12 alkyl, —OC(═O)OC 1 -C 12 alkyl, —C(═O)N(R 11 )—C 1 -C 12 alkyl, —N(R 11 )C(═O)—C 1 -C 12 alkyl; —OC(═O)N(R 11 )—C 1 -C 12 alkyl, —C(═O)-aryl, —C(═O)-heteroaryl, —OC(═O)-aryl, —C(═O)O-aryl, —OC(═O)-heteroaryl, —C(═O)O-heteroaryl, —C(═O)O-aryl, —C(═O)O-heteroaryl, —C(═O)N(R 11 )-aryl, —C(═O)N(R 11 )-heteroaryl, —N(R 11 )C(O)-aryl, —N(R 11 ) 2 C(O)-aryl, —N(R 11 )C(O)-heteroaryl, and S(O) 2 N(R 11 )-aryl;
         each R 11  is independently selected from H and C 1 -C 6 alkyl;   each R 12  is independently selected from H and C 1 -C 6 alkyl;   optionally R 3  and R 6  are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, —O—C 2 -C 6 alkynylene, such that when R 3  and R 6  are connected, the O is bound at the R 3  position   optionally R 3a  and R 6a , are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, —O—C 2 -C 6 alkynylene, such that when R 3a  and R 6a  are connected, the O is bound at the R 3a  position;   optionally R 2  and R 3  are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, —O—C 2 -C 6 alkynylene, such that when R 2  and R 3  are connected, the O is bound at the R 3  position;   optionally R 2a  and R 3a , are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, —O—C 2 -C 6 alkynylene, such that when R 2a  and R 3a  are connected, the O is bound at the R 3a  position;   optionally R 4  and R 3  are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, —O—C 2 -C 6 alkynylene, such that when R 4  and R 3  are connected, the O is bound at the R 3  position;   optionally R 4a  and R 3a , are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, —O—C 2 -C 6 alkynylene, such that when R 4a  and R 3a  are connected, the O is bound at the R 3a  position;   optionally R 5  and R 6  are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, —O—C 2 -C 6 alkynylene, such that when R 5  and R 6  are connected, the O is bound at the R 5  position;   optionally R 5a  and R 6a , are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, —O—C 2 -C 6 alkynylene, such that when R 5a  and R 6a  are connected, the O is bound at the R 5a  position;   optionally R 5  and R 7  are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, —O—C 2 -C 6 alkynylene, such that when R 5  and R 7  are connected, the O is bound at the R 5  position;   optionally R 5a  and R 7a , are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, —O—C 2 -C 6 alkynylene, such that when R 5a  and R 7a  are connected, the O is bound at the R 5a  position;   optionally R 8  and R 9  are connected to form a C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, and   optionally R 8a  and R 9a  are connected to form a C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene,   L 1  is a linker;   each R 115  is independently       

     
       
         
         
             
             
         
       
     
     —C(═O)—, —ON═***, —S—, —NHC(═O)CH 2 —***, —S(═O) 2 CH 2 CH 2 —***, —(CH 2 ) 2 S(═O) 2 CH 2 CH 2 —***, —NHS(═O) 2 CH 2 CH 2-** , —NHC(═O)CH 2 CH 2 —***, —CH 2 NHCH 2 CH 2 —***, —NHCH 2 CH 2 —***, 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     where the *** of R 115  indicates the point of attachment to Ab;
         R 13  is H or methyl;   R 14  is H, —CH 3  or phenyl;   each R 110  is independently selected from H, C 1 -C 6 alkyl, F, Cl, and —OH;   each R 111  is independently selected from H, C 1 -C 6 alkyl, F, Cl, —NH 2 , —OCH 3 , —OCH 2 CH 3 , —N(CH 3 ) 2 , —CN, —NO 2  and —OH;   each R 112  is independently selected from H, C 1-6 alkyl, fluoro, benzyloxy substituted with —C(═O)OH, benzyl substituted with —C(═O)OH, C 1-4 alkoxy substituted with —C(═O)OH and C 1-4 alkyl substituted with —C(═O)OH;   Ab is an anti-DC-SIGN antibody or fragment thereof; and   y is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10,   and provided at least one of R 1 , R 1a  or R 1b  is substituted with —NHL 1 R 115 , or at least one of R 3 , R 4 , R 5 , R 7 , R 3a , R 4a , R 5a  or R 7a  is —OL 1 R 115 .       

     Certain aspects and examples of the DC-SIGN Immunoconjugates of the invention are provided in the following listing of additional, enumerated embodiments. It will be recognized that features specified in each embodiment may be combined with other specified features to provide further embodiments of the present invention. 
     Embodiment 188 
     The DC-SIGN immunoconjugate of Formulas (AA-a to AA-f), Formulas (BB-a to BB-f), Formulas (CC-a to CC-f), Formulas (DD-a to DD-f), Formulas (EE-a to EE-h) or Formulas (FF-a to FF-k), or stereoisomers or pharmaceutically acceptable salts thereof, wherein L 1  is a linker comprising one or more cleavage elements; 
     Embodiment 189 
     A DC-SIGN immunoconjugate of Formulas (AA-a to AA-f), Formulas (BB-a to BB-f), Formulas (CC-a to CC-f), Formulas (DD-a to DD-f), Formulas (EE-a to EE-h) or Formulas (FF-a to FF-k), or stereoisomers or pharmaceutically acceptable salts thereof selected from: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     wherein y, Ab, R 1 , R 1a , R 1b , R 2 , R 2a , R 3 , R 3a , R 4 , R 4a , R 5 , R 5a , R 6 , R 6a , R 7 , R 7a , R 8 , R 8a , R 9 , R 9a , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , Y 8 , Y 9 , Y 10  and Y 11  are as defined above for immunoconjugates of Formulas (AA-a to AA-f), Formulas (BB-a to BB-f), Formulas (CC-a to CC-f), Formulas (DD-a to DD-f), Formulas (EE-a to EE-h) and Formulas (FF-a to FF-k), and provided at least one of R 1 , R 1a  or Rib is substituted with —NHL 1 R 115 , or at least one of R 3 , R 4 , R 5 , R 7 , R 3a , R 4a , R 5a  or R 7a  is —OL 1 R 115    
     Embodiment 190 
     The DC-SIGN immunoconjugate of Embodiment 146, wherein R 1  is pyrimidine or purine nucleic acid base or analogue thereof, R 1a  is pyrimidine or purine nucleic acid base or analogue thereof, and Rib is a pyrimidine or purine nucleic acid base or analogue thereof, each of which is substituted as described in R 1 , R 1a  or R 1b  for immunoconjugates of Formulas (AA-a to AA-f), Formulas (BB-a to BB-f), Formulas (CC-a to CC-f), Formulas (DD-a to DD-f), Formulas (EE-a to EE-h) and Formulas (FF-a to FF-k). 
     Embodiment 191 
     A DC-SIGN immunoconjugate of Embodiment 148 selected from: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     wherein y, Ab, R 1 , R 1a , R 1b , R 2 , R 2a , R 3 , R 3a , R 4 , R 4a , R 5 , R 5a , R 6 , R 6a , R 7 , R 7a , R 8 , R 8a , R 9 , R 9a , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , Y 8 , Y 9 , Y 10  and Y 11  are as defined above for immunoconjugates of Formulas (AA-a to AA-f), Formulas (BB-a to BB-f), Formulas (CC-a to CC-f), Formulas (DD-a to DD-f), Formulas (EE-a to EE-h) and Formulas (FF-a to FF-k), and provided at least one of R 1 , R 1a  or R 1b  is substituted with —NHL 1 R 115 , or at least one of R 3 , R 4 , R 5 , R 7 , R 3a , R 4a , R 5a  or R 7a  is —OL 1 R 115    
     Embodiment 192 
     The DC-SIGN immunoconjugate of Formula (AA-a to AA-f), Formula (AA-1a to AA-1f) or Formula (AA-2a to AA-2f), wherein
         R 2  and R 2a  are H;   one of R 3  and R 4  is H and the other is selected from the group consisting of —OL 1 R 115 , H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 3  or R 4  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 3  or R 4  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;   R 5  and R 5a  are H;   R 6  and R 6a  are H;   R 8 , R 9 , R 8a  and R 9a  are independently H or C 1 -C 6 alkyl, and   one of R 3a  and R 4a  is H and the other is selected from the group consisting of —OL 1 R 115 , H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 3a  and R 4a  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 3a  or R 4a  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 , and provided at least one of R 1  or R 1a  is substituted with —NHL 1 R 115 , or at least one of R 3 , R 4 , R 3a  or R 4a  is —OL 1 R 115 .       

     Embodiment 193 
     The DC-SIGN immunoconjugate of Formula (AA-a to AA-f), Formula (AA-1a to AA-1f) or Formula (AA-2a to AA-2f), wherein:
         Y 1  and Y 2  are O, CH 2  or S;   Y 3  is OH, O − , OR 10 , N(R 10 ) 2 , SH or S − ;   Y 4  is OH, O − , OR 10 , N(R 10 ) 2 , SH or S − ;   Y 5  and Y 6  are O or S;   Y 7  and Y 8  are O or S;   Y 9  and Y 10  are O or S;   R 2 , R 2a , R 6 , R 6a , R 5  and R 5a  are H   one of R 3a  and R 4a  is H and the other is —OL 1 R 115 , H, OH or F;   one of R 3  and R 4  is H and the other is —OL 1 R 115 , H, OH or F; and   R 8a , R 9a , R 8  and R 9  are independently selected from H or C 1 -C 6 alkyl,   and provided at least one of R 1  or R 1a  is substituted with —NHL 1 R 115 , or at least one of R 3 , R 4 , R 3a  or R 4a  is —OL 1 R 115          

     Embodiment 194 
     The DC-SIGN immunoconjugate of Formula (BB-a to BB-f), Formula (BB-1a to BB-1f) or Formula (BB-2a to BB-2f), wherein:
         R 2  and R 2a  are H;   one of R 3a  and R 4a  is H and the other is selected from the group consisting of —OL 1 R 115 , H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 3a  and R 4a  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 3a  or R 4a  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;   R 5a  and R 6a  are H;   R 6  and R 4  are H;   R 8 , R 9 , R 8a  and R 9a  are independently H or C 1 -C 6 alkyl, and   one of R 5  and R 7  is H and the other is selected from the group consisting of —OL 1 R 115 , H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 5  and R 7  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 5  or R 7  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ,   and provided at least one of R 1  or R 1a  is substituted with —NHL 1 R 115 , or at least one of R 5 , R 7 , R 3a  or R 4a  is —OL 1 R 115          

     Embodiment 195 
     The DC-SIGN immunoconjugate of Formula (BB-a to BB-f), Formula (BB-1a to BB-1f) or Formula (BB-2a to BB-2f), wherein:
         Y 1  and Y 2  are O, CH 2  or S;   Y 3  is OH, O − , OR 10 , N(R 10 ) 2 , SH or S − ;   Y 4  is OH, O − , OR 10 , N(R 10 ) 2 , SH or S − ;   Y 5  and Y 6  are O or S;   Y 7  and Y 8  are O or S;   Y 9  and Y 10  are O or S;   R 2 , R 2a , R 5a , R 6a , R 6  and R 4  are H;   one of R 3a  and R 4a  is H and the other is —OL 1 R 115 , H, OH or F;   one of R 5  and R 7  is H and the other is —OL 1 R 115 , H, OH or F, and   R 8a , R 9a , R 8  and R 9  are independently selected from H or C 1 -C 6 alkyl,   and provided at least one of R 1  or R 1a  is substituted with —NHL 1 R 115 , or at least one of R 5 , R 7 , R 3a  or R 4a  is —OL 1 R 115          

     Embodiment 196 
     A DC-SIGN immunoconjugate of Formula (CC-a to CC-f), Formula (CC-1a to CC-1f) or Formula (CC-2a to CC-2f), wherein:
         R 2  and R 2a  are H;   one of R 3  and R 4  is H and the other is selected from the group consisting of —OL 1 R 115 , H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 3  and R 4  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 3  or R 4  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;   R 4a  and R 6a  are H;   R 6  and R 5  are H;   R 8 , R 9 , R 8a  and R 9a  are independently H or C 1 -C 6 alkyl;   one of R 5a  and R 7a  is H and the other is selected from the group consisting of —OL 1 R 115 , H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 5a  and R 7a  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 5a  or R 7a  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ,   and provided at least one of R 1  or R 1a  is substituted with —NHL 1 R 115 , or at least one of R 5a , R 7a , R 3a  or R 4a  is —OL 1 R 115          

     Embodiment 197 
     A DC-SIGN immunoconjugate of Formula (CC-a to CC-f), Formula (CC-1a to CC-1f) or Formula (CC-2a to CC-2f), wherein:
         Y 1  and Y 2  are O, CH 2  or S;   Y 3  is OH, O − , OR 10 , N(R 10 ) 2 , SH or S − ;   Y 4  is OH, O − , OR 10 , N(R 10 ) 2 , SH or S − ;   Y 5  and Y 6  are O or S;   Y 7  and Y 8  are O or S;   Y 5  and Y 10  are O or S;   R 2 , R 2a , R 4a , R 6a , R 6  and R 5  are H;   one of R 3  and R 4  is H and the other is —OL 1 R 115 , H, OH or F;   one of R 5a  and R 7a  is H and the other is —OL 1 R 115 , H, OH or F, and   R 8a , R 9a , R 8  and R 9  are independently selected from H or C 1 -C 6 alkyl,   and provided at least one of R 1  or R 1a  is substituted with —NHL 1 R 115 , or at least one of R 5a , R 7a , R 3a  or R 4a  is —OL 1 R 115          

     Embodiment 198 
     A DC-SIGN immunoconjugate of Formula (DD-a to DD-f), Formula (DD-1a to DD-1f) or Formula (DD-2a to DD-2f), wherein:
         R 2  and R 2a  are H;   one of R 5a  and R 7a  is H and the other is selected from the group consisting of —OL 1 R 115 , H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 5a  and R 7a  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 5a  or R 7a  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;   R 4a  and R 6a  are H;   R 6  and R 4  are H;   R 8 , R 9 , R 8a  and R 9a  are independently H or C 1 -C 6 alkyl, and   one of R 5  and R 7  is H and the other is selected from the group consisting of —OL 1 R 115 , H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 5  and R 7  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 5  or R 7  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ,   and provided at least one of R 1  or R 1a  is substituted with —NHL 1 R 115 , or at least one of R 5a , R 7a , R 5  or R 7  is —OL 1 R 115          

     Embodiment 199 
     A DC-SIGN immunoconjugate of Formula (DD-a to DD-f), Formula (DD-1a to DD-1f) or Formula (DD-2a to DD-2f), wherein:
         Y 1  and Y 2  are O, CH 2  or S;   Y 3  is OH, O − , OR 10 , N(R 10 ) 2 , SH or S − ;   Y 4  is OH, O − , OR 10 , N(R 10 ) 2 , SH or S − ;   Y 5  and Y 6  are O or S;   Y 7  and Y 8  are O or S;   Y 9  and Y 10  are O or S;   R 2 , R 2a , R 4a , R 6a , R 6  and R 4  are H;   one of R 5a  and R 7a  is H and the other is —OL 1 R 115 , OH or F;   one of R 5  and R 7  is H and the other is —OL 1 R 115 , H, OH or F, and   R 8 , R 9 , R 8a  and R 9a  are independently H or C 1 -C 6 alkyl,   and provided at least one of R 1  or R 1a  is substituted with —NHL 1 R 115 , or at least one of R 5a , R 7a , R 5  or R 7  is —OL 1 R 115          

     Embodiment 200 
     A DC-SIGN immunoconjugate of Formula (EE-a to EE-h), Formula (EE-1a to EE-1h) or Formula (EE-2a to EE-2h), wherein: R 2  and R 2a  are H;
         R 6  and R 6a  are H;   R 7  is H;   R 8 , R 9 , R 8a  and R 9a  are independently H or C 1 -C 6 alkyl, and   one of R 3a  and R 4a  is H and the other is selected from the group consisting of —OL 1 R 115 , H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 3a  and R 4a  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 3a  or R 4a  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;   one of R 3  and R 4  is H and the other is selected from the group consisting of —OL 1 R 115 , H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 3  and R 4  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 3  or R 4  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 , and   one of R 5  and R 7  is H and the other is selected from the group consisting of —OL 1 R 115 , H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 5  and R 7  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 5  or R 7  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ,   and provided at least one of R 1  or R 1a  is substituted with —NHL 1 R 115 , or at least one of R 3a , R 4a , R 3 , R 4 , R 5  or R 7  is —OL 1 R 115 .       

     Embodiment 201 
     A DC-SIGN immunoconjugate of Formula (EE-a to EE-h), Formula (EE-1a to EE-1h) or Formula (EE-2a to EE-2h), wherein:
         Y 1  and Y 2  are O, CH 2  or S;   Y 3  is OH, O − , OR 10 , N(R 10 ) 2 , SH or S − ;   Y 5  is O or S;   Y 7  is O or S;   Y 9  is O or S;   R 2 , R 2a , R 5 , R 6a , R 6  and R 7  are H;   one of R 3a , R 4a  is H and the other is —OL 1 R 115 , H, OH, OCH 3  or F;   one of R 3 , R 4  is H and the other is —OL 1 R 115 , H, OH, OCH 3  or F;   one of R 5  and R 7  is H and the other is —OL 1 R 115 , H, OH, OCH 3  or F, and   R 8 , R 9 , R 8a  and R 9a  are independently H or C 1 -C 6 alkyl,   and provided at least one of R 1  or R 1a  is substituted with —NHL 1 R 115 , or at least one of R 3a , R 4a , R 3 , R 4 , R 5  or R 7  is —OL 1 R 115          

     Embodiment 202 
     A DC-SIGN immunoconjugate of Formula (FF-a to FF-k), Formula (FF-1a to FF-1 k) or Formula (FF-2a to FF-2k), wherein:
         R 2  and R 2a  are H;   each R 6  and R 6a  are H;   R 5a  and R 7  are H;   R 8 , R 9 , R 8a  and R 9a  are independently H or C 1 -C 6 alkyl, and   one of R 3a  and R 4a  is H and the other is selected from the group consisting of —OL 1 R 115 , H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 3a  and R 4a  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 3a  or R 4a  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ;   one of R 3  and R 4  is H and the other is selected from the group consisting of —OL 1 R 115 , H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 3  and R 4  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 3  or R 4  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 , and   R 5  is selected from the group consisting of —OL 1 R 115 , H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 5  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 5  is substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ,   and provided at least one of R 1 , R 1a  or R 1b  is substituted with —NHL 1 R 115 , or at least one of R 3a , R 4a , R 3 , R 4 , R 5  or R 7  is —OL 1 R 115          

     Embodiment 203 
     A DC-SIGN immunoconjugate of Formula (FF-a to FF-k), Formula (FF-1a to FF-1 k) or Formula (FF-2a to FF-2k), wherein:
         Y 1  and Y 2  are O, CH 2  or S;   each Y 3  is independently OH, O − , OR 10 , N(R 10 ) 2 , SH or S − ;   each Y 5  is independently O or S;   each Y 7  is independently O or S;   each Y 9  is independently O or S;   Y 11  is O, CH 2  or S;   R 2 , R 2a , R 6 , R 6a , R 5a , and R 7a  are H;   one of R 3a  and R 4a  is H and the other is —OL 1 R 115 , H, OH, OCH 3  or F;   one of R 3  and R 4  is H and the other is —OL 1 R 115 , H, OH, OCH 3  or F;   one of R 5  and R 7  is H and the other is —OL 1 R 115 , H, OH, OCH 3  or F, and   R 8 , R 9 , R 8a  and R 9a  are independently H or C 1 -C 6 alkyl,   and provided at least one of R 1 , R 1a  or R 1b  is substituted with —NHL 1 R 115 , or at least one of R 3a , R 4a , R 3 , R 4 , R 5  or R 7  is —OL 1 R 115          

     Embodiment 204 
     A DC-SIGN immunoconjugate of Formula (AA-a to AA-f), Formula (BB-a to BB-f), Formula (CC-a to CC-f), Formula (DD-a to DD-f), Formula (EE-a to EE-h), Formula (FF-a to FF-k) or an immunoconjugate of any one of Embodiments 146 to 161, wherein:
         R 1  is       

     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
         
         
           
             
               
                 wherein: R 1  is substituted with 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, OH, SH, NH 2 , D, CD 3 , C 1 -C 6 alkyl, C 1 -C 6 alkoxyalkyl, C 1 -C 6 hydroxyalkyl, C 3 -C 8 cycloalkyl, a 3 to 6 membered heterocyclyl having 1 to 2 heteroatoms independently selected from O, N and S, —O(C 1 -C 6 alkyl), —O(C 3 -C 8 cycloalkyl), —S(C 1 -C 6 alkyl), —S(C 1 -C 6 aminoalkyl), —S(C 1 -C 6 hydroxyalkyl), —S(C 3 -C 8 cycloalkyl), —NH(C 1 -C 6 alkyl), —NH(C 3 -C 8 cycloalkyl), —N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 alkyl) (C 3 -C 8 cycloalkyl), —CN, —P(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —(CH 2 ) 1-10 C(═O)OH, —CH═CH(CH 2 ) 1-10 C(═O)OH, —NHC(O)(C 1 -C 6 alkyl), —NHC(O)(C 3 -C 8 cycloalkyl), —NHC(O)(phenyl), and —N(C 3 -C 8 cycloalkyl) 2 ,
               and   each R 200  is independently selected from H and L 1 R 115 ;   
             
               
             
             R 1a  is 
           
         
       
    
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
         
         
           
             
               
                 wherein: R 1a  is substituted with 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, OH, SH, NH 2 , D, CD 3 , C 1 -C 6 alkyl, C 1 -C 6 alkoxyalkyl, C 1 -C 6 hydroxyalkyl, C 3 -C 8 cycloalkyl, a 3 to 6 membered heterocyclyl having 1 to 2 heteroatoms independently selected from O, N and S, —O(C 1 -C 6 alkyl), —O(C 3 -C 8 cycloalkyl), —S(C 1 -C 6 alkyl), —S(C 1 -C 6 aminoalkyl), —S(C 1 -C 6 hydroxyalkyl), —S(C 3 -C 8 cycloalkyl), —NH(C 1 -C 6 alkyl), —NH(C 3 -C 8 cycloalkyl), —N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 alkyl) (C 3 -C 8 cycloalkyl), —ON, —P(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —(CH 2 ) 1-10 C(═O)OH, —CH═CH(CH 2 ) 1-10 C(═O)OH, —NHC(O)(C 1 -C 6 alkyl), —NHC(O)(C 3 -C 8 cycloalkyl), —NHC(O)(phenyl), and —N(C 3 -C 8 cycloalkyl) 2 ,
               and   each R 210  is independently selected from H and L 1 R 115 ,   
             
               
             
             and 
             R 1b  is 
           
         
       
    
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
         
         
           
             
               
                 wherein: R 1b  is substituted with 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, OH, SH, NH 2 , D, CD 3 , C 1 -C 6 alkyl, C 1 -C 6 alkoxyalkyl, C 1 -C 6 hydroxyalkyl, C 3 -C 8 cycloalkyl, a 3 to 6 membered heterocyclyl having 1 to 2 heteroatoms independently selected from O, N and S, —O(C 1 -C 6 alkyl), —O(C 3 -C 8 cycloalkyl), —S(C 1 -C 6 alkyl), —S(C 1 -C 6 aminoalkyl), —S(C 1 -C 6 hydroxyalkyl), —S(C 3 -C 8 cycloalkyl), —NH(C 1 -C 6 alkyl), —NH(C 3 -C 8 cycloalkyl), —N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 alkyl) (C 3 -C 8 cycloalkyl), —CN, —P(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —(CH 2 ) 1-10 C(═O)OH, —CH═CH(CH 2 ) 1-10 C(═O)OH, —NHC(O)(C 1 -C 6 alkyl), —NHC(O)(C 3 -C 8 cycloalkyl), —NHC(O)(phenyl), and —N(C 3 -C 8 cycloalkyl) 2 ,
               and   each R 210  is independently selected from H and L 1 R 115      
             
               
             
           
         
       
    
     Embodiment 205 
     A DC-SIGN immunoconjugate selected from: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     wherein:
         Y 1  is —O—, —S—, —S(═O)—, —SO 2 —, —CH 2 —, or —CF 2 —;   Y 2  is —O—, —S—, —S(═O)—, —SO 2 —, —CH 2 —, or —CF 2 —;   Y 3  is OH, O − , OR 10 , N(R 10 ) 2 , SH or S − ;   Y 4  is OH, O − , OR 10 , N(R 10 ) 2 , SH or S − ;   Y 7  is O or S;   Y 8  is O or S;   Y 11  is —O—, —S—, —S(═O)—, —SO 2 —, —CH 2 —, or —CF 2 —;   R 1  is       

     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
         
         
           
             
               
                 wherein: R 1  is substituted with 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, OH, SH, NH 2 , D, CD 3 , C 1 -C 6 alkyl, C 1 -C 6 alkoxyalkyl, C 1 -C 6 hydroxyalkyl, C 3 -C 8 cycloalkyl, a 3 to 6 membered heterocyclyl having 1 to 2 heteroatoms independently selected from O, N and S, —O(C 1 -C 6 alkyl), —O(C 3 -C 8 cycloalkyl), —S(C 1 -C 6 alkyl), —S(C 1 -C 6 aminoalkyl), —S(C 1 -C 6 hydroxyalkyl), —S(C 3 -C 8 cycloalkyl), —NH(C 1 -C 6 alkyl), —NH(C 3 -C 8 cycloalkyl), —N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 alkyl) (C 3 -C 8 cycloalkyl), —CN, —P(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —(CH 2 ) 1-10 C(═O)OH, —CH═CH(CH 2 ) 1-10 C(═O)OH, —NHC(O)(C 1 -C 6 alkyl), —NHC(O)(C 3 -C 8 cycloalkyl), —NHC(O)(phenyl), and —N(C 3 -C 8 cycloalkyl) 2 , 
                 and 
                 each R 200  is independently selected from H and L 1 R 115    
               
             
             R 1a  is 
           
         
       
    
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
         
         
           
             
               
                 wherein: R 1a  is substituted with 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, OH, SH, NH 2 , D, CD 3 , C 1 -C 6 alkyl, C 1 -C 6 alkoxyalkyl, C 1 -C 6 hydroxyalkyl, C 3 -C 8 cycloalkyl, a 3 to 6 membered heterocyclyl having 1 to 2 heteroatoms independently selected from O, N and S, —O(C 1 -C 6 alkyl), —O(C 3 -C 8 cycloalkyl), —S(C 1 -C 6 alkyl), —S(C 1 -C 6 aminoalkyl), —S(C 1 -C 6 hydroxyalkyl), —S(C 3 -C 8 cycloalkyl), —NH(C 1 -C 6 alkyl), —NH(C 3 -C 8 cycloalkyl), —N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 alkyl) (C 3 -C 8 cycloalkyl), —CN, —P(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —(CH 2 ) 1-10 C(═O)OH, —CH═CH(CH 2 ) 1-10 C(═O)OH, —NHC(O)(C 1 -C 6 alkyl), —NHC(O)(C 3 -C 8 cycloalkyl), —NHC(O)(phenyl), and —N(C 3 -C 8 cycloalkyl) 2 , 
                 and 
                 each R 210  is independently selected from H and L 1 R 115 , 
               
             
             R 1b  is 
           
         
       
    
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
         
         
           
             
               
                 wherein: R 1b  is substituted with 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, OH, SH, NH 2 , D, CD 3 , C 1 -C 6 alkyl, C 1 -C 6 alkoxyalkyl, C 1 -C 6 hydroxyalkyl, C 3 -C 8 cycloalkyl, a 3 to 6 membered heterocyclyl having 1 to 2 heteroatoms independently selected from O, N and S, —O(C 1 -C 6 alkyl), —O(C 3 -C 8 cycloalkyl), —S(C 1 -C 6 alkyl), —S(C 1 -C 6 aminoalkyl), —S(C 1 -C 6 hydroxyalkyl), —S(C 3 -C 8 cycloalkyl), —NH(C 1 -C 6 alkyl), —NH(C 3 -C 8 cycloalkyl), —N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 alkyl) (C 3 -C 8 cycloalkyl), —CN, —P(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —(CH 2 ) 1-10 C(═O)OH, —CH═CH(CH 2 ) 1-10 C(═O)OH, —NHC(O)(C 1 -C 6 alkyl), —NHC(O)(C 3 -C 8 cycloalkyl), —NHC(O)(phenyl), and —N(C 3 -C 8 cycloalkyl) 2 , 
                 and 
                 each R 210  is independently selected from H and L 1 R 115 ; 
               
             
             each R 2  is independently selected from the group consisting of H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 2  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 2  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ; 
             each R 3  is independently selected from the group consisting of —OL 1 R 115 , H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 3  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 3  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ; 
             each R 4  is independently selected from the group consisting of —OL 1 R 115 , H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 4  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 4  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ; 
             each R 5  is independently selected from the group consisting of —OL 1 R 115 , H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 5  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 5  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ; 
             each R 6  is independently selected from the group consisting of H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 6  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 6  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ; 
             each R 7  is independently selected from the group consisting of —OL 1 R 115 , H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 7  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 7  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ; 
             R 2a  is selected from the group consisting of H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 2a  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 2a  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ; 
             R 3a  is selected from the group consisting of —OL 1 R 115 , H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 3a  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 3a  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ; 
             R 4a  is selected from the group consisting of —OL 1 R 115 , H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 4a  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 4a  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ; 
             R 5a  is selected from the group consisting of —OL 1 R 115 , H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 5a  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 5a  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ; 
             R 6a  is selected from the group consisting of H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 6a  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 6a  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ; 
             R 7a  is selected from the group consisting of —OL 1 R 115 , H, —OH, F, Cl, Br, I, D, CD 3 , CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OP(═O)(OH) 2 , —O(CH 2 ) 1-10 C(═O)OH, —O(CH 2 ) 1-10 P(═O)(OH) 2 , —OC(O)Ophenyl, —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)phenyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl, wherein the —OC(O)Ophenyl of R 7a  and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, —O(C 1 -C 6 alkyl), —O(C 2 -C 6 alkenyl), —O(C 2 -C 6 alkynyl), —OC(O)OC 1 -C 6 alkyl, —OC(O)OC 2 -C 6 alkenyl, —OC(O)OC 2 -C 6 alkynyl, —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl and —OC(O)C 2 -C 6 alkynyl of R 7a  are substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN, and N 3 ; 
             each R 10  is independently selected from the group consisting of H, C 1 -C 12 alkyl, —(CH 2 CH 2 O) n CH 2 CH 2 C(═O)OC 1 -C 6 alkyl, and 
           
         
       
    
     
       
         
         
             
             
         
       
     
     wherein the C 1 -C 12 alkyl of R 10  is substituted by 0, 1, 2 or 3 substituents independently selected from —OH, C 1 -C 12 alkoxy, —S—C(═O)C 1 -C 6 alkyl and C(O)OC 1 -C 6 alkyl;
         optionally R 3  and R 6  are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, —O—C 2 -C 6 alkynylene, such that when R 3  and R 6  are connected, the O is bound at the R 3  position   optionally R 3a  and R 6a , are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, —O—C 2 -C 6 alkynylene, such that when R 3a  and R 6a  are connected, the O is bound at the R 3a  position;   optionally R 2  and R 3  are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, —O—C 2 -C 6 alkynylene, such that when R 2  and R 3  are connected, the O is bound at the R 3  position;   optionally R 2a  and R 3a , are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, —O—C 2 -C 6 alkynylene, such that when R 2a  and R 3a  are connected, the O is bound at the R 3a  position;   optionally R 4  and R 3  are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, —O—C 2 -C 6 alkynylene, such that when R 4  and R 3  are connected, the O is bound at the R 3  position;   optionally R 4a  and R 3a , are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, —O—C 2 -C 6 alkynylene, such that when R 4a  and R 3a  are connected, the O is bound at the R 3a  position;   optionally R 5  and R 6  are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, —O—C 2 -C 6 alkynylene, such that when R 5  and R 6  are connected, the O is bound at the R 5  position;   optionally R 5a  and R 6a , are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, —O—C 2 -C 6 alkynylene, such that when R 5a  and R 6a  are connected, the O is bound at the R 5a  position;   optionally R 5  and R 7  are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, O 2 —C 6 alkynylene, —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, —O—C 2 -C 6 alkynylene, such that when R 5  and R 7  are connected, the 0 is bound at the R 5  position, and   optionally R 5a  and R 7a , are connected to form C 1 -C 6 alkylene, C 2 -C 6 alkenylene, O 2 —C 6 alkynylene, —O—C 1 -C 6 alkylene, —O—C 2 -C 6 alkenylene, —O—C 2 -C 6 alkynylene, such that when R 5a  and R 7a  are connected, the 0 is bound at the R 5a  position;   L 1  is —C(═O)O(CH 2 ) m NR 11 C(═O)(CH 2 ) m —**; C(═O)O(CH 2 ) m NR 11 C(═O)(CH 2 ) m O(CH 2 ) m —**; —C(═O)O(CH 2 ) m NR 11 C(═O)X 1 X 2 C(═O)(CH 2 )m-**; —C(═O)OC(R 12 ) 2 (CH 2 ) m NR 11 C(═O)X 1 X 2 C(═O)(CH 2 ) m —**; —C(═O)O(CH 2 ) m NR 11 C(═O)X 1 X 2 C(═O)(CH 2 ) m O(CH 2 ) m —**; —C(═O)O(CH 2 ) m NR 11 C(═O)X 1 X 2 C(═O)(CH 2 ) m O(CH 2 ) m C(═O)**; —C(═O)O(CH 2 ) m NR 11 C(═O)X 4 C(═O)NR 11 (CH 2 ) m NR 11 C(═O)(CH 2 ) m O(CH 2 ) m —**; —C(═O)O(CH 2 ) m NR 11 C(═O)X 5 C(═O)(CH 2 ) m NR 11 C(═O)(CH 2 ) m —**; —C(═O)X 4 C(═O)NR 11  (CH 2 ) m NR 11 C(═O)(CH 2 ) m O(CH 2 ) m —**; —C(═O)(CH 2 ) m NR 11 C(═O)X 1 X 2 C(═O)(CH 2 ) m —**; C(═O)(CH 2 ) m NR 11 C(═O)X 2 C(═O)(CH 2 ) m —**; —C(═O)O(CH 2 ) m X 6 C(═O)X 1 X 2 C(═O)(CH 2 ) m —**, —C(═O)(CH 2 ) m NR 11 C(═O)((CH 2 ) m O) n (CH 2 ) m —**, —C(═O)O(CH 2 ) m X 6 C(═O)(CH 2 ) m —**, —C(═O)O(CH 2 ) m X 6 C(═O)(CH 2 ) m O(CH 2 ) m —**, —C(═O)O(CH 2 ) m X 6 C(═O)X 1 X 2 C(═O)(CH 2 ) m —**, —C(═O)O(CH 2 ) m X 6 C(═O)X 1 X 2 C(═O)(CH 2 ) m O(CH 2 ) m —**, —C(═O)O(CH 2 ) m X 6 C(═O)X 1 X 2 C(═O)(CH 2 ) m O(CH 2 ) m C(═O)—**; —C(═O)O(CH 2 ) m X 6 C(═O)X 4 C(═O)NR 11  (CH 2 ) m NR 11 C(═O)(CH 2 ) m O(CH 2 ) m —**, —C(═O)X 4 C(═O)X 6 (CH 2 ) m NR 11 C(═O) (CH 2 ) m O(CH 2 ) m —**, —C(═O)(CH 2 ) m X 6 C(═O)X 1 X 2 C(═O)(CH 2 ) m —**, —C(═O)O((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 C(═O)(CH 2 ) m —**; —C(═O)O((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X C (═O)(CH 2 ) m NR 11 C(═O)(CH 2 ) m —**; —C(═O)O((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 C(═O)(CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)O((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X C (═O)((CH 2 ) m O) n (CH 2 ) m —**; —C(═O)O((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)(CH 2 ) m —**; C(═O)O((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)(CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)O((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O))X 5 C(═O)((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)O((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 C(═O)(CH 2 ) m NR 11 C(═O)((CH 2 ) m O) n (CH 2 ) m —**; C(═O)O((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 C(═O)(CH 2 ) m NR 11 C(═O)((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)O((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X(CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)O((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 ((CH 2 ) m O) n (CH 2 ) m —**; —C(═O)O((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 ((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)(CH 2 ) m —**; —C(═O)O((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 ((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)(CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)O((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 ((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)O((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 (CH 2 ) m NR 11 ((CH 2 ) m O) n (CH 2 ) m —**; —C(═O)O((CH 2 ) m O) n (CH 2 ) m NR 11 C(O)X 5 C(═O)(CH 2 ) m NR 11  ((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)O((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X(CH 2 ) m —**; —C(═O)O((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X C (═O)((CH 2 ) m O) n (CH 2 ) m —**; —C(═O)O((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X(CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)O(CH 2 ) m —**; C(═O)O((CH 2 ) m O) n (CH 2 ) m —**; —C(═O)O(CH 2 ) m NR 11  (CH 2 ) m —**; —C(═O)O(CH 2 ) m NR 11 (CH 2 ) m C(═O)X 2 X C (═O)—**; C(═O)O(CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)O(H 2 ) m X 6 C(═O)X 1 X 2 C(═O)((CH 2 ) m O) n (CH 2 ) m —**; —C(═O)O((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —**; C(═O)O((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)(CH 2 ) m —**; —C(═O)O(CH 2 ) m NR 11 C(═O(CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)O((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)(CH 2 ) m X(CH 2 ) m —**; —C(═O)O((CH 2 ) m O) n X 3 (CH 2 ) m —**; C(═O)O((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)O((CH 2 ) m O) n (CH 2 ) m C(═O)NR 11 (CH 2 ) m —**; C(═O)O(CH 2 ) m C(R 12 ) 2 —**; —C(═O)OCH 2 ) m C(R 12 ) 2 SS(CH 2 ) m NR 11 C(═O)(CH 2 ) m —**; —C(═O)O(CH 2 ) m C(═O)NR 11  (CH 2 ) m —**; —C(═O)(CH 2 ) m —**; C(═O)((CH 2 ) m O) n (CH 2 ) m —**; —C(═O)(CH 2 ) m NR 11 (CH 2 ) m —**; —C(═O)(CH 2 ) m NR 11  (CH 2 ) m C(═O)X 2 X 1 C(═O)—**; —C(═O)(CH 2 ) m X 3 (CH 2 ) m **; —C(═O)((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —**; C(═O)(CH) m NR 11 C(═O)(CH) m **; —C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)(CH 2 ) m —**; C(═O)(CH 2 ) m NR 11 C(O(CH 2 ) m X(CH 2 ) m —**; (CH 2 ) m NR 11 C(═O)X 1 X 2 C(═O)(CH 2 ) m —**. —(CH 2 ) m (CHOH)(CH 2 ) m NR 11 C(═O)X 1 X 2 C(═O)(CH 2 ) m **; —C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)(CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)((CH 2 ) m O) n X 3 (CH 2 ) m —**; C(═O)((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)((CH 2 ) m O) n (CH 2 ) m C(═O)NR 11  (CH 2 ) m —**; C(═O)(CH 2 ) m C(R 12 ) 2 —**; —C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 C(═O)(CH 2 ) m —**; —C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 C(═O)(CH 2 ) m NR 11 C(═O)(CH 2 ) m **; —C(═O) ((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 C(═O)(CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 C(═O)((CH 2 ) m O) n (CH 2 ) m —**; —C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)(CH 2 ) m —**; —C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)(CH 2 ) m X 3 (CH 2 ) m —**; —C(═O) ((CH 2 ) m O) n  (CH 2 ) m NR 11 C(═O))X 5 C(═O) ((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 C(═O)(CH 2 ) m NR 11 C(═O)((CH 2 ) m O) n (CH 2 ) m —** —C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 C(═O)(CH 2 ) m NR 11 C(═O)((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 (CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 ((CH 2 ) m O) n (CH 2 ) m —**; —C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 ((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)(CH 2 ) m —**; —C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 ((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)(CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 ((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 (CH 2 ) m NR 11  ((CH 2 ) m O) n (CH 2 ) m —**; —C(═O) ((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 C(═O)(CH 2 ) m NR 11  ((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 (CH 2 ) m —**; —C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 C(═O)((CH 2 ) m O) n (CH 2 ) m —**; —C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)X 5 (CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)(CH 2 ) m C(R 12 ) 2 SS(CH 2 ) m NR 11 C(═O)(CH 2 ) m —**; —C(═O)(CH 2 ) m C(═O)NR 11 (CH 2 ) m —**; C(═O)X 1 X 2 C(═O)(CH 2 ) m —**; —C(═O)X 1 X 2 C(═O)(CH 2 ) m NR 11 C(═O)(CH 2 ) m —**; C(═O)X 1 X 2 C(═O)(CH 2 ) m X 3 (CH 2 ) m *. —C(═O)X 1 X 2 C(═O)((CH 2 ) m O) n (CH 2 ) m —**; —C(═O)X 1 X 2 C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)(CH 2 ) m —**; —C(═O)X 1 X 2 C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)(CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)X 1 X 2 C(═O)((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)X 1 X 2 C(═O)(CH 2 ) m NR 11 C(═O)((CH 2 ) m O) n (CH 2 ) m —**; —C(═O)X 1 X 2 C(═O)(CH 2 ) m NR 11 C(═O) ((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)X 1 X 2 (CH 2 ) m X 3 (CH 2 ) m —**; C(═O)X 1 X 2 ((CH 2 ) m O) n (CH 2 ) m —**; —C(═O)X 1 X 2 ((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)(CH 2 ) m —**; —C(═O)X 1 X 2 ((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)(CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)X 1 X 2 ((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)X 1 X 2 (CH 2 ) m NR 11  ((CH 2 ) m O) n (CH 2 ) m —**; —C(═O)X 1 X 2 C(═O)(CH 2 ) m NR 11  ((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)NR 11 (CH 2 ) m —**; C(═O)NR 11 (CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)NR 11  (CH 2 ) m NR 11 C(═O)X 1 X 2 C(═O)(CH 2 ) m —**; —C(═O)NR 11 (CH 2 ) m NR 11 C(═O)O(CH 2 ) m —**; —C(═O)NR 11  (CH 2 ) m NR 11 C(═O)X 1 X 2 —**; C(═O)NR 11  (CH 2 ) m NR 11 C(═O)X 5 —; —C(═O)NR 11  (CH 2 ) m NR 11 C(═O)(CH 2 ) m X 5 (CH 2 ) m —**; —C(═O)X 1 C(═O)NR 11  (CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)NR 11  (CH 2 ) m NR 11 C(═O)(CH 2 ) m —**; —C(═O)NR 11 (CH 2 ) m NR 11 C(═O)(CH 2 ) m O(CH 2 ) m —**; —C(═O)NR 11  (CH 2 ) m NR 11 C(═O)X 1 X 2 C(═O)(CH 2 ) m O(CH 2 ) m —**; —C(═O)NR 11  (CH 2 ) m NR 11 C(═O)X 1 X 2 C(═O)(CH 2 ) m O(CH 2 ) m C(═O)—**; —C(═O)NR 11 (CH 2 ) m NR 11 C(═O)X 4 C(═O)NR 11 (CH 2 ) m NR 11 C(═O)(CH 2 ) m O(CH 2 ) m —**; —C(═O)NR 11 (CH 2 ) m NR 11 C(═O)X 1 X 2 C(═O) (CH 2 ) m —**; —C(═O)NR 11 (CH 2 ) m NR 11 C(═O)X 5 C(═O)(CH 2 ) m —**; —C(═O)NR 11 (CH 2 ) m NR 11 C(═O)X 5 C(═O)(CH 2 ) m NR 11 C(═O)(CH 2 ) m —**; —C(═O)NR(CH 2 ) m NR 11 C(═O)X 5 C(═O)(CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)NR 11 (CH 2 ) m NR 11 C(═O)X 5 C(═O)((CH 2 ) m O) n (CH 2 ) m —**; —C(═O)NR 11 (CH 2 ) m NR 11 C(═O)X 5 C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)(CH 2 ) m —**; —C(═O)NR 11 (CH 2 ) m NR 11 C(═O)X 5 C(═O)((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)(CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)NR 11 (CH 2 ) m NR 11 C(═O)X 5 C(═O) ((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)NR 11 (CH 2 ) m NR 11 C(═O)X 5 C(═O)(CH 2 ) m NR 11 C(═O)((CH 2 ) m O) n (CH 2 ) m —**; —C(═O)NR 11 (CH 2 ) m NR 11 C(═O)X 5 C(═O)(CH 2 ) m NR 11 C(═O)((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —**; —C(═O) NR 11 (CH 2 ) m NR 11 C(═O)X 5 (CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)NR 11 (CH 2 ) m NR 11 C(═O)X 5 ((CH 2 ) m O) n (CH 2 ) m —**; —C(═O)NR 11 (CH 2 ) m NR 11 C(═O)X 5 ((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)(CH 2 ) m —**; —C(═O)NR 11 (CH 2 ) m NR 11 C(═O)X 5 ((CH 2 ) m O) n (CH 2 ) m NR 11 C(═O)(CH 2 ) m X(CH 2 ) m —**; —C(═O) NR 11 (CH 2 ) m NR 11 C(═O)X 5 ((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)NR 11 (CH 2 ) m NR 11 C(═O)X 5 (CH 2 ) m NR 11 ((CH 2 ) m O) n (CH 2 ) m —**; —C(═O)NR 11 (CH 2 ) m NR 11 C(═O)X 5 C(═O)(CH 2 ) m NR 11 ((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —**; —C(═O) NR 11  (CH 2 ) m NR 11 C(═O)X 5 (CH 2 ) m —**; —C(═O)NR(CH 2 ) m NR 11 C(═O)X 5 C(═O)((CH 2 ) m O) n (CH 2 ) m —**; —C(═O) NR 11 (CH 2 ) m NR 11 C(═O)X 5 (CH 2 ) m X 3 (CH 2 ) m —**; —C(═O)X 1 C(═O)NR 11 (CH 2 ) m NR 11 C(═O)(CH 2 ) m —**; —C(═O)X 1 C(═O)NR 11 (CH 2 ) m X 3 (CH 2 ) m —**; C(═O)NR 11 (CH 2 ) m NR 11 C(═O)(CH 2 ) m —**. —C(═O)NR 11 (CH 2 ) m NR 11 C(═O)(CH 2 ) m X 3 (CH 2 ) m —**; C(═O)NR 11 (CH 2 ) m NR 11 C(═O)—**; —C(═O)X 1 X 2 (CH 2 ) m —**; C(═O)X 1 X 2 C(═O)((CH 2 ) m O) n (CH 2 ) m —**; —C(═O)X 1 X 2 (CH 2 ) m X 3 (CH 2 ) m —**; C(═O)NR 11  (CH 2 ) m X 3 (CH 2 ) m **; —C(═O)NR 11 ((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —**; C(═O)X 1 X 2 C(═O)((CH 2 ) m O) n (CH 2 ) m —**; —C(═O)X 1 X 2 C(═O)(CH 2 ) m —**; —C(═O)X 1 C(═O)(CH 2 ) m NR 11 C(═O)(CH 2 ) m —**; and —C(═O)X 1 C(═O)(CH 2 ) m NR 11 C(═O)((CH 2 ) m O) n (CH 2 ) m —**;
           where the ** of L 1  indicates the point of attachment to R 115 ;   
           R 115  is       

     
       
         
         
             
             
         
       
     
     —C(═O)—, —ON═***, —S—, —NHC(═O)CH 2 —, —S(═O) 2 CH 2 CH 2 —, —(CH 2 ) 2 S(═O) 2 CH 2 CH 2 —, —NHS(═O) 2 CH 2 CH 2 , —NHC(═O)CH 2 CH 2 —, —CH 2 NHCH 2 CH 2 —, —NHCH 2 CH 2 —, 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     where the *** of R 115  indicates the point of attachment to Ab;
         X 1  is       

     
       
         
         
             
             
         
       
     
     where the * of X 1  indicates the point of attachment to X 2 ;
         X 2  is selected from       

     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     where the * of X 2  indicates the point of attachment to X 1 ;
         X 3  is       

     
       
         
         
             
             
         
       
         
         
           
             X 4  is —O(CH 2 ) n SSC(R 12 ) 2 (CH 2 ) n — or —(CH 2 ) n C(R 12 ) 2 SS(CH 2 ) n O—; 
             X 5  is 
           
         
       
    
     
       
         
         
             
             
         
       
     
     where the ** of X 5  indicates orientation toward R 115 ;
         X 6  is       

     
       
         
         
             
             
         
       
     
     or, where the ** of X 6  indicates orientation toward R 115 ;
         each R 11  is independently selected from H and C 1 -C 6 alkyl;   each R 12  is independently selected from H and C 1 -C 6 alkyl;   R 13  is H or methyl;   R 14  is H, —CH 3  or phenyl;   each R 110  is independently selected from H, C 1 -C 6 alkyl, F, Cl, and —OH;   each R 111  is independently selected from H, C 1 -C 6 alkyl, F, Cl, —NH 2 , —OCH 3 , —OCH 2 CH 3 , —N(CH 3 ) 2 , —CN, —NO 2  and —OH;   each R 112  is independently selected from H, C 1-6 alkyl, fluoro, benzyloxy substituted with —C(═O)OH, benzyl substituted with —C(═O)OH, C 1-4 alkoxy substituted with —C(═O)OH and C 1-4 alkyl substituted with —C(═O)OH;   each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 and 18.   Ab is an anti-DC-SIGN antibody or fragment thereof, and   each y is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10,   and provided at least one of R 200  or R 210  is -L 1 R 115  or is substituted with —NHL 1 R 115 , or at least one of R 3 , R 4 , R 5 , R 7 , R 3a , R 4a , R 5a  or R 7a  is —OL 1 R 115          

     Embodiment 206 
     A DC-SIGN immunoconjugate selected from: 
     
       
         
         
             
             
         
       
     
     wherein: Ab, y, R 1 , R 1a , R 3 , R 3a , R 6 , R 6a , Y 3  and Y 4  are as defined in Embodiment 205. 
     Embodiment 207 
     A DC-SIGN immunoconjugate selected from: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     wherein: Ab, y, R 1 , R 1a , R 3 , R 3a , R 6  and R 6a  are as defined in Embodiment 205;
         Y 3  is OR 9 , N(R 10 ) 2 , SH or S − , and   Y 4  is OR 9 , N(R 10 ) 2 , SH or S − .       

     Embodiment 208 
     A DC-SIGN immunoconjugate selected from: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     wherein: Ab, y, R 1 , R 1a , R 3 , R 3a , R 6  and R 6a  are as defined in Embodiment 205;
         Y 3  is OR 9 , N(R 10 ) 2 , SH or S − , and   Y 4  is OR 9 , N(R 10 ) 2 , SH or S − .       

     Embodiment 209 
     An immunoconjugate selected from: 
     
       
         
         
             
             
         
       
     
     wherein: Ab, y, R 1 , R 1a , R 3 , R 3a , R 5 , R 6a , Y 3  and Y 4  are as defined in Embodiment 205. 
     Embodiment 210 
     A DC-SIGN immunoconjugate selected from: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     wherein: Ab, y, R 1 , R 1 , R 3a , R 5  and R 6a  are as defined in Embodiment 205;
         Y 3  is OR 9 , N(R 10 ) 2 , SH or S − , and   Y 4  is OR 9 , N(R 10 ) 2 , SH or S − .       

     Embodiment 211 
     A DC-SIGN immunoconjugate selected from: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     wherein: Ab, y, R 1 , R 1a  and R 5  are as defined in Embodiment 205;
         Y 3  is OR 9 , N(R 10 ) 2 , SH or S − , and   Y 4  is OR 9 , N(R 10 ) 2 , SH or S − .       

     Embodiment 212 
     A DC-SIGN immunoconjugate selected from: 
     
       
         
         
             
             
         
       
     
     wherein: Ab, y, R 1 , R 1a , R 3 , R 5a , R 6 , R 6a , Y 3  and Y 4  are as defined in Embodiment 205. 
     Embodiment 213 
     A DC-SIGN immunoconjugate selected from: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     wherein: Ab, y R 1 , R 1a , R 3 , R 5a , R 6  and R 6a  are as defined in Embodiment 205;
         Y 3  is OR 9 , N(R 10 ) 2 , SH or S − , and   Y 4  is OR 9 , N(R 10 ) 2 , SH or S − .       

     Embodiment 214 
     A DC-SIGN immunoconjugate selected from: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     wherein: Ab, y, R 1 , R 1 , R 5a  and R 6a  are as defined in Embodiment 205;
         Y 3  is OR 9 , N(R 10 ) 2 , SH or S − , and   Y 4  is OR 9 , N(R 10 ) 2 , SH or S − .       

     Embodiment 215 
     A DC-SIGN immunoconjugate selected from: 
     
       
         
         
             
             
         
       
     
     wherein: Ab, y R 1 , R 1a , R 5 , R 5a , Y 3  and Y 4  are as defined in Embodiment 205. 
     Embodiment 216 
     A DC-SIGN immunoconjugate selected from: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     wherein: Ab, y, R 1 , R 1a , R 5  and R 5a  are as defined in Embodiment 205;
         Y 3  is OR 9 , N(R 10 ) 2 , SH or S − , and   Y 4  is OR 9 , N(R 10 ) 2 , SH or S − .       

     Embodiment 217 
     A DC-SIGN immunoconjugate selected from: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     wherein: Ab, y, R 1 , R 1a , R 3 , R 3a , R 4 , R 4a , R 5 , R 7 , R and Y 3  are as defined in Embodiment 205. 
     Embodiment 218 
     A DC-SIGN immunoconjugate selected from: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     wherein: Ab, y, R 1 , R 1 , R 3 , R 3a , R 4 , R 4a , R 5 , R 7  and Y 3  are as defined in Embodiment 205;
         and Y 3  is OR 9 , N(R 10 ) 2 , SH or S − .       

     Embodiment 219 
     A DC-SIGN immunoconjugate selected from: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     wherein: Ab, y, R 1 , R 1a , R 1b , R 3 , R 3a , R 4 , R 4a , R 5 , R 7  and Y 3  are as defined in Embodiment 205, 
     Embodiment 220 
     A DC-SIGN immunoconjugate selected from: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     wherein: Ab, y, R 1 , R 1a , R 1b , R 3 , R 3a , R 4 , R 4a , R 5  and R 7  are as defined in Embodiment 205, and
 
each Y 3  is independently selected from OR 10 , N(R 10 ) 2 , SH and S − .
 
     Embodiment 221 
     A DC-SIGN immunoconjugate selected from: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     wherein: Ab, y, R 1 , R 1 , R 1b , R 3 , R 3a , R 4 , R 4a , R 5  and R 7  are as defined in Embodiment 205, and
 
each Y 3  is independently selected from OR 10 , N(R 10 ) 2 , SH and S − .
 
     Embodiment 222 
     A DC-SIGN immunoconjugate selected from: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     wherein: Ab, y, R 1 , R 1a , R 1b , R 3 , R 3a , R 4 , R 4a , R 5  and R 7  are as defined in Embodiment 205, and
 
each Y 3  is independently selected from OR 10 , N(R 10 ) 2 , SH and S − .
 
     Embodiment 223 
     A DC-SIGN immunoconjugate selected from: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     wherein: Ab, y, R 1 , R 1a , Rb, R 3 , R 3a , R 4 , R 4a , R 5  and R 7  are as defined in Embodiment 205, and
 
each Y 3  is independently selected from OR 0 , N(R 10 ) 2 , SH and S − .
 
     Embodiment 224 
     The DC-SIGN immunoconjugate of any one of Embodiments 188 to 223, wherein R 1  is 
     
       
         
         
             
             
         
       
     
     Embodiment 225 
     The DC-SIGN immunoconjugate of any one of Embodiments 188 to 223, wherein R 1a  is 
     
       
         
         
             
             
         
       
     
     Embodiment 226 
     The DC-SIGN immunoconjugate of any one of Embodiments 188 to 223, wherein R 1b  is 
     
       
         
         
             
             
         
       
     
     Embodiment 227 
     The DC-SIGN immunoconjugate of any one of Embodiments 188 to 223, wherein R 1a  is 
     
       
         
         
             
             
         
       
     
     Embodiment 228 
     The DC-SIGN immunoconjugate of any one of Embodiments 188 to 223, wherein R 1a  is 
     
       
         
         
             
             
         
       
     
     Embodiment 229 
     The DC-SIGN immunoconjugate of any one of Embodiments 188 to 223, wherein R 1b  is 
     
       
         
         
             
             
         
       
     
     Embodiment 230 
     The compound of any one of Embodiments 188 to 223, wherein R 1  is 
     
       
         
         
             
             
         
       
     
     wherein R 200  is -L 1 R 115 . 
     Embodiment 231 
     The compound of any one of Embodiments 188 to 223, wherein R 1a  is 
     
       
         
         
             
             
         
       
     
     wherein R 210  is -L 1 R 115 . 
     Embodiment 232 
     The compound of any one of Embodiments 188 to 223, wherein R 1b  is is 
     
       
         
         
             
             
         
       
     
     wherein R 210  is -L 1 R 115 . 
     Embodiment 233 
     The compound of any one of Embodiments 188 to 223, wherein R 1  is 
     
       
         
         
             
             
         
       
     
     wherein R 200  is -L 1 R 115 . 
     Embodiment 234 
     The compound of any one of Embodiments 188 to 223, wherein R 1a  is 
     
       
         
         
             
             
         
       
     
     wherein R 210  is -L 1 R 115 . 
     Embodiment 235 
     The compound of any one of Embodiments 188 to 223, wherein R 1b  is 
     
       
         
         
             
             
         
       
     
     wherein R 210  is -L 1 R 115 . 
     Embodiment 236 
     The DC-SIGN immunoconjugate of any one of Embodiments 188 to 223, wherein R 1  is 
     
       
         
         
             
             
         
       
     
     and R 1a  is 
     
       
         
         
             
             
         
       
     
     wherein R 200  is L 1 R 115  and R 210  is H. 
     Embodiment 237 
     The DC-SIGN immunoconjugate of any one of Embodiments 188 to 223, wherein R 1  is 
     
       
         
         
             
             
         
       
     
     and R 1a  is 
     
       
         
         
             
             
         
       
     
     wherein R 200  is H and R 210  is L 1 R 115 . 
     Embodiment 238 
     The DC-SIGN immunoconjugate of any one of Embodiments 188 to 223, wherein R 1  is 
     
       
         
         
             
             
         
       
     
     and R 1a  is 
     
       
         
         
             
             
         
       
     
     wherein R 200  is L 1 R 115  and R 210  is L 1 R 115    
     Embodiment 239 
     The DC-SIGN immunoconjugate of any one of Embodiments 188 to 223, wherein R 1  is 
     
       
         
         
             
             
         
       
     
     and R 1a  is 
     
       
         
         
             
             
         
       
     
     wherein R 200  is L 1 R 115  and R 210  is H. 
     Embodiment 240 
     The DC-SIGN immunoconjugate of any one of Embodiments 188 to 223, wherein R 1  is 
     
       
         
         
             
             
         
       
     
     and R 1a  is 
     
       
         
         
             
             
         
       
     
     wherein R 200  is H and R 210  is L 1 R 115 . 
     Embodiment 241 
     The DC-SIGN immunoconjugate of any one of Embodiments 188 to 223, wherein R 1  is 
     
       
         
         
             
             
         
       
     
     and R 1a  is 
     
       
         
         
             
             
         
       
     
     wherein R 200  is L 1 R 115  and R 210  is L 1 R 115 . 
     Embodiment 242 
     The DC-SIGN immunoconjugate of any one of Embodiments 188 to 223, wherein R 1  is 
     
       
         
         
             
             
         
       
     
     and R 1a  is 
     
       
         
         
             
             
         
       
     
     wherein R 200  is H and R 210  is L 1 R 115 . 
     Embodiment 243 
     The DC-SIGN immunoconjugate of any one of Embodiments 188 to 223, wherein R 1  is 
     
       
         
         
             
             
         
       
     
     and R 1a  is 
     
       
         
         
             
             
         
       
     
     wherein R 200  is L 1 R 15  and R 210  is H. 
     Embodiment 244 
     The DC-SIGN immunoconjugate of any one of Embodiments 188 to 223, wherein R 1  is 
     
       
         
         
             
             
         
       
     
     and R 1a  is 
     
       
         
         
             
             
         
       
     
     wherein R 200  is L 1 R 115  and R 210  is L 1 R 115 . 
     Embodiment 245 
     The DC-SIGN immunoconjugate of any one of Embodiments 188 to 223, wherein R 1  is 
     
       
         
         
             
             
         
       
     
     and R 1a  is 
     
       
         
         
             
             
         
       
     
     wherein R 200  is H and R 210  is L 1 R 115 . 
     Embodiment 246 
     The DC-SIGN immunoconjugate of any one of Embodiments 188 to 223, wherein R 1  is 
     
       
         
         
             
             
         
       
     
     and R 1a  is 
     
       
         
         
             
             
         
       
     
     wherein R 200  is L 1 R 115  and R 210  is H. 
     Embodiment 247 
     The DC-SIGN immunoconjugate of any one of Embodiments 188 to 223, wherein R 1  is 
     
       
         
         
             
             
         
       
     
     and R 1a  is 
     
       
         
         
             
             
         
       
     
     wherein R 200  is L 1 R 115  and R 210  is L 1 R 115 . 
     Embodiment 248 
     The DC-SIGN immunoconjugate of any one of Embodiments 188 to 223, wherein R 1  is 
     
       
         
         
             
             
         
       
     
     and R 1a  is 
     
       
         
         
             
             
         
       
     
     wherein R 200  is L 1 R 115  and R 210  is H. 
     Embodiment 249 
     The DC-SIGN immunoconjugate of any one of Embodiments 188 to 223, wherein R 1  is 
     
       
         
         
             
             
         
       
     
     and R 1a  is 
     
       
         
         
             
             
         
       
     
     wherein R 200  is H and R 210  is L 1 R 115 . 
     Embodiment 250 
     The DC-SIGN immunoconjugate of any one of Embodiments 188 to 223, wherein R 1  is 
     
       
         
         
             
             
         
       
     
     and R 1a  is 
     
       
         
         
             
             
         
       
     
     wherein R 200  is L 1 R 115  and R 210  is L 1 R 115 . 
     Embodiment 251 
     The DC-SIGN immunoconjugate of any one of Embodiments 188 to 223, wherein R 1  is 
     
       
         
         
             
             
         
       
     
     R 1b  is 
     
       
         
         
             
             
         
       
     
     and R 1a  is 
     
       
         
         
             
             
         
       
     
     wherein R 200  is L 1 R 115  and each R 210  is H. 
     Embodiment 252 
     The DC-SIGN immunoconjugate of any one of Embodiments 188 to 223, wherein R 1  is 
     
       
         
         
             
             
         
       
     
     R 1b  is 
     
       
         
         
             
             
         
       
     
     and R 1a  is 
     
       
         
         
             
             
         
       
     
     wherein R 200  is H, R 210  of R 1b  is L 1 R 115  and R 21  of R 1a  is H. 
     Embodiment 253 
     The DC-SIGN immunoconjugate of any one of Embodiments 188 to 223, wherein R 1  is 
     
       
         
         
             
             
         
       
     
     R 1b  is 
     
       
         
         
             
             
         
       
     
     and R 1a  is 
     
       
         
         
             
             
         
       
     
     wherein R 200  is H, R 210  of Rib is H and R 210  of R 1a  is L 1 R 115 . 
     Embodiment 254 
     The DC-SIGN immunoconjugate of any one of Embodiments 188 to 223, wherein R 1  is 
     
       
         
         
             
             
         
       
     
     wherein R 200  is H and one of R 3 , R 3a , R 5  or R 5a  is —OL 1 R 115 . 
     Embodiment 255 
     The DC-SIGN immunoconjugate of any one of Embodiments 188 to 223, wherein R 1a  is 
     
       
         
         
             
             
         
       
     
     wherein R 210  is H and one of R 3 , R 3a , R 5  or R 5a  is —OL 1 R 115 . 
     Embodiment 256 
     The DC-SIGN immunoconjugate of any one of Embodiments 188 to 223, wherein R 1b  is is 
     
       
         
         
             
             
         
       
     
     wherein R 210  is H and one of R 3 , R 3a , R 5  or R 5a  is —OL 1 R 115 . 
     Embodiment 257 
     The DC-SIGN immunoconjugate of any one of Embodiments 188 to 223, wherein R 1  is 
     
       
         
         
             
             
         
       
     
     wherein R 200  is H and one of R 3 , R 3a , R 5  or R 5a  is —OL 1 R 115 . 
     Embodiment 258 
     The DC-SIGN immunoconjugate of any one of Embodiments 188 to 223, wherein R 1a  is 
     
       
         
         
             
             
         
       
     
     wherein R 210  is is H and one of R 3 , R 3a , R 5  or R 5a  is —OL 1 R 115 . 
     Embodiment 259 
     The DC-SIGN immunoconjugate of any one of Embodiments 188 to 223, wherein R 1b  is 
     
       
         
         
             
             
         
       
     
     wherein R 210  is is H and one of R 3 , R 3a , R 5  or R 5a  is —OL 1 R 115 . 
     Embodiment 260 
     The DC-SIGN immunoconjugate of any one of Embodiments 188 to 223, wherein
         R 1  is       

     
       
         
         
             
             
         
       
     
     and R 1a  is 
     
       
         
         
             
             
         
       
     
     wherein R 200  is H, R 210  is H and one of R 3 , R 3a , R 5  or R 5a  is —OL 1 R 115    
     Embodiment 261 
     The DC-SIGN immunoconjugate of any one of Embodiments 188 to 223, wherein R 1  is 
     
       
         
         
             
             
         
       
     
     and R 1a  is 
     
       
         
         
             
             
         
       
     
     wherein R 200  is H, R 210  is H and one of R 3 , R 3a , R 5  or R 5a  is —OL 1 R 115 . 
     Embodiment 262 
     The DC-SIGN immunoconjugate of any one of Embodiments 188 to 223, wherein R 1  is 
     
       
         
         
             
             
         
       
     
     and R 1a  is 
     
       
         
         
             
             
         
       
     
     wherein R 200  is H, R 210  is H and one of R 3 , R 3a , R 5  or R 5a  is —OL 1 R 115 . 
     Embodiment 263 
     The DC-SIGN immunoconjugate of any one of Embodiments 188 to 223, wherein R 1  is 
     
       
         
         
             
             
         
       
     
     and R 1a  is 
     
       
         
         
             
             
         
       
     
     wherein R 200  is H, R 210  is H and one of R 3 , R 3a , R 5  or R 5a  is —OL 1 R 115 . 
     Embodiment 264 
     The DC-SIGN immunoconjugate of any one of Embodiments 188 to 223, wherein R 1  is 
     
       
         
         
             
             
         
       
     
     and R 1a  is 
     
       
         
         
             
             
         
       
     
     wherein R 200  is H, R 210  is H and one of R 3 , R 3a , R 5  or R 5a  is —OL 1 R 115 . 
     Embodiment 265 
     The DC-SIGN immunoconjugate of any one of Embodiments 188 to 223, wherein R 1  is 
     
       
         
         
             
             
         
       
     
     R 1b  is 
     
       
         
         
             
             
         
       
     
     and R 1a  is 
     
       
         
         
             
             
         
       
     
     wherein R 200  is H, R 210  is H and one of R 3 , R 3a , R 5  or R 5a  is —OL 1 R 115 . 
     Embodiment 266 
     The DC-SIGN immunoconjugate of any one of Embodiments 188 to 266, wherein:
         Y 3  is OH, O − , SH or S − , and   Y 4  is OH, O − , SH or S − .       

     Embodiment 267 
     The DC-SIGN immunoconjugate of any one of Embodiments 188 to 266, wherein:
         Y 3  is OH or O − , and   Y 4  is OH or O − .       

     Embodiment 268 
     The DC-SIGN immunoconjugate of any one of Embodiments 188 to 266, wherein:
         Y 3  is SH or S − , and   Y 4  is OH or O − .       

     Embodiment 269 
     The DC-SIGN immunoconjugate of any one of Embodiments 188 to 266, wherein:
         Y 3  is OH or O − , and   Y 4  is SH or S − .       

     Embodiment 270 
     The DC-SIGN immunoconjugate of any one of Embodiments 188 to 266, wherein:
         Y 3  is SH or S − , and   Y 4  is SH or S − .       

     Embodiment 271 
     The DC-SIGN immunoconjugate of any one of Embodiments 188 to 253 or Embodiments 267 to 271, wherein: R 2 , R 2a , R 4 , R 4a , R 6 , R 6a , R 7  and R 7a  are each H. 
     Embodiment 272 
     The DC-SIGN immunoconjugate of any one of Embodiments 188 to 253 or Embodiments 267 to 271, wherein: R 3  is —OH, F or —NH 2 . 
     Embodiment 273 
     The DC-SIGN immunoconjugate of any one of Embodiments 188 to 253 or Embodiments 267 to 271 wherein: R 3  is —OH or F. 
     Embodiment 274 
     The DC-SIGN immunoconjugate of any one of Embodiments 188 to 253 or Embodiments 267 to 271, wherein: R 3a  is —OH, F or —NH 2 . 
     Embodiment 275 
     The DC-SIGN immunoconjugate of any one of Embodiments 188 to 253 or Embodiments 267 to 271, wherein: R 3a  is —OH or F. 
     Embodiment 276 
     The DC-SIGN immunoconjugate of any one of Embodiments 188 to 253 or Embodiments 267 to 271, wherein: R 5  is —OH, F or —NH 2 . 
     Embodiment 277 
     The DC-SIGN immunoconjugate of any one of Embodiments 188 to 253 or Embodiments 267 to 271, wherein: R 5  is —OH or F. 
     Embodiment 278 
     The DC-SIGN immunoconjugate of any one of Embodiments 188 to 253 or Embodiments 267 to 271, wherein: R 5a  is —OH, F or —NH 2 . 
     Embodiment 279 
     The DC-SIGN immunoconjugate of any one of Embodiments 188 to 253 or Embodiments 267 to 271, wherein: R 5a  is —OH or F. 
     Embodiment 280 
     The DC-SIGN immunoconjugate of any one of Embodiments 188 to 253 or Embodiments 267 to 271, wherein when present:
         R 2 , R 2a , R 4 , R 4a , R 6 , R 6a , R 7  and R 7a  are each H;   R 3  is —OH, and   R 3a  is F.       

     Embodiment 281 
     The DC-SIGN immunoconjugate of any one of Embodiments 188 to 253 or Embodiments 267 to 271, wherein when present:
         R 2 , R 2a , R 4 , R 4a , R 6 , R 6a , R 7  and R 7a  are each H;   R 3  is F, and   R 3a  is —OH.       

     Embodiment 282 
     The DC-SIGN immunoconjugate of any one of Embodiments 188 to 253 or Embodiments 267 to 271, wherein when present:
         R 2 , R 2a , R 4 , R 4a , R 6 , R 6a , R 7  and R 7a  are each H;   R 3  is F, and   R 3a  is F.       

     Embodiment 283 
     The DC-SIGN immunoconjugate of any one of Embodiments 188 to 253 or Embodiments 267 to 271, wherein when present:
         R 2 , R 2a , R 4 , R 4a , R 6 , R 6a , R 7  and R 7a  are each H;   R 3  is —OH, and   R 3a  is —OH.       

     Embodiment 284 
     The DC-SIGN immunoconjugate of any one of Embodiments 188 to 253 or Embodiments 267 to 271, wherein when present:
         R 2 , R 2a , R 4 , R 4a , R 6 , R 6a , R 7  and R 7a  are each H;   R 3a  is —OH, and   R 5  is F.       

     Embodiment 285 
     The DC-SIGN immunoconjugate of any one of Embodiments 188 to 253 or Embodiments 267 to 271, wherein when present:
         R 2 , R 2a , R 4 , R 4a , R 6 , R 6a , R 7  and R 7a  are each H;   R 3a  is F, and   R 5  is —OH.       

     Embodiment 286 
     The DC-SIGN immunoconjugate of any one of Embodiments 188 to 253 or Embodiments 267 to 271, wherein when present:
         R 2 , R 2a , R 4 , R 4a , R 6 , R 6a , R 7  and R 7a  are each H;   R 3a  is F, and   R 5  is F.       

     Embodiment 287 
     The DC-SIGN immunoconjugate of any one of Embodiments 188 to 253 or Embodiments 267 to 271, wherein when present:
         R 2 , R 2a , R 4 , R 4a , R 6 , R 6a , R 7  and R 7a  are each H;   R 3a  is —OH, and   R 5  is —OH.       

     Embodiment 288 
     The DC-SIGN immunoconjugate of any one of Embodiments 188 to 253 or Embodiments 267 to 271, wherein when present:
         R 2 , R 2a , R 4 , R 4a , R 6 , R 6a , R 7  and R 7a  are each H;   R 3  is —OH, and   R 5a  is F.       

     Embodiment 289 
     The DC-SIGN immunoconjugate of any one of Embodiments 188 to 253 or Embodiments 267 to 271, wherein when present:
         R 2 , R 2a , R 4 , R 4a , R 6 , R 6a , R 7  and R 7a  are each H;   R 3  is F, and   R 5a  is —OH.       

     Embodiment 290 
     The DC-SIGN immunoconjugate of any one of Embodiments 188 to 253 or Embodiments 267 to 271, wherein when present:
         R 2 , R 2a , R 4 , R 4a , R 6 , R 6a , R 7  and R 7a  are each H;   R 3  is F, and   R 5a  is F.       

     Embodiment 291 
     The DC-SIGN immunoconjugate of any one of Embodiments 188 to 253 or Embodiments 267 to 271, wherein when present:
         R 2 , R 2a , R 4 , R 4a , R 6 , R 6a , R 7  and R 7a  are each H;   R 3  is —OH, and   R 5a  is —OH.       

     Embodiment 292 
     The DC-SIGN immunoconjugate of any one of Embodiments 188 to 253 or Embodiments 267 to 271, wherein when present:
         R 2 , R 2a , R 4 , R 4a , R 6 , R 6a , R 7  and R 7a  are each H;   R 5  is —OH, and   R 5a  is F.       

     Embodiment 293 
     The DC-SIGN immunoconjugate of any one of Embodiments 188 to 253 or Embodiments 267 to 271, wherein when present:
         R 2 , R 2a , R 4 , R 4a , R 6 , R 6a , R 7  and R 7a  are each H;   R 5  is F, and   R 5a  is —OH.       

     Embodiment 294 
     The DC-SIGN immunoconjugate of any one of Embodiments 188 to 253 or Embodiments 267 to 271, wherein when present:
         R 2 , R 2a , R 4 , R 4a , R 6 , R 6a , R 7  and R 7a  are each H;   R 5  is F, and   R 5a  is F.       

     Embodiment 295 
     The DC-SIGN immunoconjugate of any one of Embodiments 188 to 253 or Embodiments 267 to 271, wherein when present:
         R 2 , R 2a , R 4 , R 4a , R 6 , R 6a , R 7  and R 7a  are each H;   R 5  is —OH, and   R 5a  is —OH.       

     Embodiment 296 
     The DC-SIGN immunoconjugate of any one of Embodiments 188 to 253 or Embodiments 267 to 271, wherein:
         R 3  is —OH or F;   R 3a  is —OH or F;   R 5  is —OH or F;   R 5a  is —OH or F;   R 6  is H, and   R 6a  is H.       

     Embodiment 297 
     The DC-SIGN immunoconjugate of any one of Embodiments 188 to 253 or Embodiments 267 to 271, wherein:
         R 3  is H, —OH or F;   R 3a  is H, —OCH 3 , —OH or F;   R 5  is —OH or F;   R 4 , R 4a , R 6 , R 6a , R 7 , R 7a  are H, and   R 6a  is H.       

     Embodiment 298 
     The DC-SIGN immunoconjugate of any one of Embodiments 188 to 298, wherein:
         L 1  is —C(═O)O(CH 2 ) m NR 11 C(═O)(CH 2 ) m —**; —C(═O)O(CH 2 ) m NR 11 C(═O)(CH 2 ) m O(CH 2 ) m —**; —C(═O)O(CH 2 ) m NR 11 C(═O)X 1 X 2 C(═O)(CH 2 ) m —**; —C(═O)OC(R 12 ) 2 (CH 2 ) m NR 11 C(═O)X 1 X 2 C(═O)(CH 2 ) m —**; —C(═O)O(CH 2 ) m NR 8 C(═O)X 1 X 2 C(═O)(CH 2 ) m O(CH 2 ) m —**; —C(═O)O(CH 2 ) m NR 11 C(═O)X 1 X 2 C(═O)X 2 C(═CH 2 )O(CH 2 ) m C(═O)—**; —C(═O)O(CH 2 ) m NR 11 C(═O)X 4 C(═O)NR 11  (CH 2 ) m NR 11 C(═O)(CH 2 ) m O(CH 2 ) m —**; —C(═O)O(CH 2 ) m NR 11 C(═O)X 5 C(═O)(CH 2 ) m NR 11 C(═O)(CH 2 ) m —**; —C(═O)O(CH 2 ) m X 6 C(═O)X 1 X 2 C(═O)((CH 2 ) m O) n (CH 2 ) m **; —(CH 2 ) m NR 11 C(═O)X 1 X 2 C(═O)(CH 2 ) m —**; —(CH 2 ) m (CHOH)(CH 2 ) m NR 11 C(═O)X 1 X 2 C(═O)(CH 2 ) m **; —C(═O)X 6 C(═O)(CH 2 ) m NR 11 C(═O)X 1 X 2 C(═O)(CH 2 ) m —**; —C(═O)X 4 C(═O)NR(CH 2 ) m NR 11 C(═O)(CH 2 ) m O(CH 2 ) m —** C(═O)(CH 2 ) m NR 11 C(═O)X 1 X 2 C(═O)(CH 2 ) m —**, —C(═O)O(CH 2 ) m X 6 C(═O)X 1 X 2 C(═O)(CH 2 ) m —**, or —C(═O)(CH 2 ) m NR 11 C(═O)((CH 2 ) m O) n (CH 2 ) m —**;   where the ** of L, indicates the point of attachment to R 15  and   where R 11 , R 12 , X 1 , X 2 , m and n are s defined in Embodiment 205.       

     Embodiment 299 
     A DC-SIGN immunoconjugate selected from: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Embodiment 300 
     A DC-SIGN immunoconjugate selected from: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Provided are also protocols for some aspects of analytical methodology for evaluating DC-SIGN antibody conjugates of the invention. Such analytical methodology and results can demonstrate that the conjugates have favorable properties, for example properties that would make them easier to manufacture, easier to administer to patients, more efficacious, and/or potentially safer for patients. One example is the determination of molecular size by size exclusion chromatography (SEC) wherein the amount of desired antibody species in a sample is determined relative to the amount of high molecular weight contaminants (e.g., dimer, multimer, or aggregated antibody) or low molecular weight contaminants (e.g., antibody fragments, degradation products, or individual antibody chains) present in the sample. In general, it is desirable to have higher amounts of monomer and lower amounts of, for example, aggregated antibody due to the impact of, for example, aggregates on otherxample properties of the antibody sample such as but not limited to clearance rate, immunogenicity, and toxicity. A further example is the determination of the hydrophobicity by hydrophobic interaction chromatography (HIC) wherein the hydrophobicity of a sample is assessed relative to a set of standard antibodies of known properties. In general, it is desirable to have low hydrophobicity due to the impact of hydrophobicity on other properties of the antibody sample such as but not limited to aggregation, aggregation over time, adherence to surfaces, hepatotoxicity, clearance rates, and pharmacokinetic exposure. See Damle, N. K., Nat Biotechnol. 2008; 26(8):884-885; Singh, S. K., Pharm Res. 2015; 32(11):3541-71. When measured by hydrophobic interaction chromatography, higher hydrophobicity index scores (i.e. elution from HIC column faster) reflect lower hydrophobicity of the conjugates. As shown in Examples below, a majority of the tested antibody conjugates showed a hydrophobicity index of greater than 0.8. In some embodiments, provided are antibody conjugates having a hydrophobicity index of 0.8 or greater, as determined by hydrophobic interaction chromatography. 
     Anti-DC-SIGN Antibody 
     In some embodiments, antibody conjugates provided herein include an antibody or antibody fragment thereof (e.g., antigen binding fragment) that specifically binds to human DC-SIGN (anti-DC-SIGN antibody). DC-SIGN overexpression is observed in macrophages and dendritic cells in tumor microenvrionment as well as in lymphoid and peripheral tissues. Antibody conjugates comprising an anti-DC-SIGN antibody can be specifically targeted to macrophages and dendritic cells in tumors and/or lymphoid and peripheral tissues. 
     In some embodiments, DC-SIGN antibody conjugates provided herein include a monoclonal antibody or antibody fragment thereof that specifically binds to human DC-SIGN, e.g., a human or humanized anti-DC-SIGN monoclonal antibody. In some embodiments, the antibody or antibody fragment thereof that specifically binds to human DC-SIGN can be selected from the anti-DC-SIGN antibodies disclosed herein. 
     Suitable anti-DC-SIGN monoclonal antibodies include, but are not limited to, the anti-DC-SIGN antibodies described in U.S. Pat. Nos. 7,534,866; 7,786,267; 7,846,744; 8,409,577; 8,779,107; 8,883,160; 8,916,696; PCT Publication Nos: WO2004091543; WO2005027979; WO2006066229; WO2006081576; WO2007046893; WO2008011599; WO2010053561; WO2011031736; WO2012145209; WO2013009841; WO2013024059; WO2013049307; WO2013095966; WO2013142255; WO2013125891; WO2013163689; WO2014064187; WO2014083499; WO2014144960; WO2014176604; WO2014179601; WO2015004473; WO2015023355; WO2015048633; WO2015048641; WO2015054039; WO2015073307; WO2015112626; U.S. Patent Publication No: US2014045242; and Chinese Patent Publication No: CN103739714, the contents of which are herein incorporated by reference in their entireties. 
     In some embodiments, the anti-DC-SIGN antibody or antibody fragment (e.g., an antigen binding fragment) comprises a VH domain having an amino acid sequence of any VH domain described in Table 8. Other suitable anti-DC-SIGN antibodies or antibody fragments (e.g., antigen binding fragments) can include amino acids that have been mutated, yet have at least 80, 85, 90, 95, 96, 97, 98, or 99 percent identity in the VH domain with the VH regions depicted in the sequences described in Table 8. The present disclosure in certain embodiments also provides antibodies or antibody fragments (e.g., antigen binding fragments) that specifically bind to DC-SIGN, wherein the antibodies or antibody fragments (e.g., antigen binding fragments) comprise a VH CDR having an amino acid sequence of any one of the VH CDRs listed in Table 8. In particular embodiments, the invention provides antibodies or antibody fragments (e.g., antigen binding fragments) that specifically bind to DC-SIGN, comprising (or alternatively, consist of) one, two, three, four, five or more VH CDRs having an amino acid sequence of any of the VH CDRs listed in Table 8. 
     In some embodiments, the anti-DC-SIGN antibody or antibody fragment (e.g., antigen binding fragments) comprises a VL domain having an amino acid sequence of any VL domain described in Table 8. Other suitable anti-DC-SIGN antibodies or antibody fragments (e.g., antigen binding fragments can include amino acids that have been mutated, yet have at least 80, 85, 90, 95, 96, 97, 98, or 99 percent identity in the VL domain with the VL regions depicted in the sequences described in Table 8. The present disclosure also provides antibodies or antibody fragments (e.g., antigen binding fragments) that specifically bind to DC-SIGN, the antibodies or antibody fragments (e.g., antigen binding fragments) comprise a VL CDR having an amino acid sequence of any one of the VL CDRs listed in Table 8. In particular, the invention provides antibodies or antibody fragments (e.g., antigen binding fragments) that specifically bind to DC-SIGN, which comprise (or alternatively, consist of) one, two, three or more VL CDRs having an amino acid sequence of any of the VL CDRs listed in Table 8. 
     
       
         
           
               
             
               
                 TABLE 8 
               
               
                   
               
               
                 Sequences of exemplary anti-DC-SIGN monoclonal antibodies 
               
               
                   
               
             
            
               
                 &gt;2B2Hz 
               
            
           
           
               
               
               
            
               
                   
                 HCDR1 
                   
               
               
                 SEQ ID NO: 1 
                 (Combined) 
                 GYTFTNYGIN 
               
               
                   
                 HCDR2 
                   
               
               
                 SEQ ID NO: 2 
                 (Combined) 
                 YIYIGNDYTEYNERFKG 
               
               
                   
                 HCDR3 
                   
               
               
                 SEQ ID NO: 3 
                 (Combined) 
                 LYYGSSLYSYAMDY 
               
               
                   
                 HCDR1 
                   
               
               
                 SEQ ID NO: 4 
                 (Kabat) 
                 NYGIN 
               
               
                   
                 HCDR2 
                   
               
               
                 SEQ ID NO: 2 
                 (Kabat) 
                 YIYIGNDYTEYNERFKG 
               
               
                   
                 HCDR3 
                   
               
               
                 SEQ ID NO: 3 
                 (Kabat) 
                 LYYGSSLYSYAMDY 
               
               
                   
                 HCDR1 
                   
               
               
                 SEQ ID NO: 5 
                 (Chothia) 
                 GYTFTNY 
               
               
                   
                 HCDR2 
                   
               
               
                 SEQ ID NO: 6 
                 (Chothia) 
                 YIGNDY 
               
               
                   
                 HCDR3 
                   
               
               
                 SEQ ID NO: 3 
                 (Chothia) 
                 LYYGSSLYSYAMDY 
               
               
                   
                 HCDR1 
                   
               
               
                 SEQ ID NO: 7 
                 (IMGT) 
                 GYTFTNYG 
               
               
                   
                 HCDR2 
                   
               
               
                 SEQ ID NO: 8 
                 (IMGT) 
                 IYIGN 
               
               
                   
                 HCDR3 
                   
               
               
                 SEQ ID NO: 9 
                 (IMGT) 
                 ARLYYGSSLYSYAMDY 
               
               
                 SEQ ID NO: 
                 VH 
                 QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGINWVRQAPGQRLEWMGY 
               
               
                 10 
                   
                 IYIGNDYTEYNERFKGRVTITSDTSASTAYMELSSLRSEDTAVYYCARLYYGSSLY 
               
               
                   
                   
                 SYAMDYWGQGTTVTVSS 
               
               
                 SEQ ID NO: 
                 DNA VH 
                 CAAGTTCAGTTGGTTCAGTCTGGCGCCGAAGTGAAGAAACCTGGCGCCTC 
               
               
                 11 
                   
                 TGTGAAGGTGTCCTGCAAGGCTTCTGGCTACACCTTTACCAACTACGGCAT 
               
               
                   
                   
                 CAACTGGGTCCGACAGGCTCCTGGCCAGAGATTGGAGTGGATGGGCTAC 
               
               
                   
                   
                 ATCTACATCGGCAACGACTACACCGAGTACAACGAGCGGTTCAAGGGCAG 
               
               
                   
                   
                 AGTGACCATCACCTCTGACACCTCTGCCTCCACCGCCTACATGGAACTGTC 
               
               
                   
                   
                 CAGCCTGAGATCTGAGGACACCGCCGTGTACTACTGCGCCAGGCTGTACT 
               
               
                   
                   
                 ATGGCTCCTCCCTGTACAGCTATGCCATGGACTACTGGGGACAGGGCACA 
               
               
                   
                   
                 ACCGTGACAGTGAGCTCC 
               
               
                 SEQ ID NO: 
                 Heavy 
                 QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGNWVRQAPGQRLEWMGY 
               
               
                 12 
                 Chain 
                 IYIGNDYTEYNERFKGRVTITSDTSASTAYMELSSLRSEDTAVYYCARLYYGSSLY 
               
               
                   
                   
                 SYAMDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPC 
               
               
                   
                   
                 PVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHK 
               
               
                   
                   
                 PSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEV 
               
               
                   
                   
                 TCVVVAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH 
               
               
                   
                   
                 QDWLNGKEYKCKVSNKALAAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQ 
               
               
                   
                   
                 VSLTCLVKGFYPCDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSR 
               
               
                   
                   
                 WQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 
               
               
                 SEQ ID NO: 
                 DNA Heavy 
                 CAAGTTCAGTTGGTTCAGTCTGGCGCCGAAGTGAAGAAACCTGGCGCCTC 
               
               
                 13 
                 Chain 
                 TGTGAAGGTGTCCTGCAAGGCTTCTGGCTACACCTTTACCAACTACGGCAT 
               
               
                   
                   
                 CAACTGGGTCCGACAGGCTCCTGGCCAGAGATTGGAGTGGATGGGCTAC 
               
               
                   
                   
                 ATCTACATCGGCAACGACTACACCGAGTACAACGAGCGGTTCAAGGGCAG 
               
               
                   
                   
                 AGTGACCATCACCTCTGACACCTCTGCCTCCACCGCCTACATGGAACTGTC 
               
               
                   
                   
                 CAGCCTGAGATCTGAGGACACCGCCGTGTACTACTGCGCCAGGCTGTACT 
               
               
                   
                   
                 ATGGCTCCTCCCTGTACAGCTATGCCATGGACTACTGGGGACAGGGCACA 
               
               
                   
                   
                 ACCGTGACAGTGAGCTCCGCTAGCACCAAGGGCCCAAGTGTGTTTCCCCT 
               
               
                   
                   
                 GGCCCCCAGCAGCAAGTCTACTTCCGGCGGAACTGCTGCCCTGGGTTGCC 
               
               
                   
                   
                 TGGTGAAGGACTACTTCCCCTGTCCCGTGACAGTGTCCTGGAACTCTGGG 
               
               
                   
                   
                 GCTCTGACTTCCGGCGTGCACACCTTCCCCGCCGTGCTGCAGAGCAGCGG 
               
               
                   
                   
                 CCTGTACAGCCTGAGCAGCGTGGTGACAGTGCCCTCCAGCTCTCTGGGAA 
               
               
                   
                   
                 CCCAGACCTATATCTGCAACGTGAACCACAAGCCCAGCAACACCAAGGTG 
               
               
                   
                   
                 GACAAGAGAGTGGAGCCCAAGAGCTGCGACAAGACCCACACCTGCCCCC 
               
               
                   
                   
                 CCTGCCCAGCTCCAGAACTGCTGGGAGGGCCTTCCGTGTTCCTGTTCCCCC 
               
               
                   
                   
                 CCAAGCCCAAGGACACCCTGATGATCAGCAGGACCCCCGAGGTGACCTGC 
               
               
                   
                   
                 GTGGTGGTGGCCGTGTCCCACGAGGACCCAGAGGTGAAGTTCAACTGGT 
               
               
                   
                   
                 ACGTGGACGGCGTGGAGGTGCACAACGCCAAGACCAAGCCCAGAGAGGA 
               
               
                   
                   
                 GCAGTACAACAGCACCTACAGGGTGGTGTCCGTGCTGACCGTGCTGCACC 
               
               
                   
                   
                 AGGACTGGCTGAACGGCAAAGAATACAAGTGCAAAGTCTCCAACAAGGC 
               
               
                   
                   
                 CCTGGCTGCCCCAATCGAAAAGACAATCAGCAAGGCCAAGGGCCAGCCAC 
               
               
                   
                   
                 GGGAGCCCCAGGTGTACACCCTGCCCCCCAGCCGGGAGGAGATGACCAA 
               
               
                   
                   
                 GAACCAGGTGTCCCTGACCTGTCTGGTGAAGGGCTTCTACCCCTGTGATAT 
               
               
                   
                   
                 CGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAACTACAAGACC 
               
               
                   
                   
                 ACCCCCCCAGTGCTGGACAGCGACGGCAGCTTCTTCCTGTACAGCAAGCT 
               
               
                   
                   
                 GACCGTGGACAAGTCCAGGTGGCAGCAGGGCAACGTGTTCAGCTGCAGC 
               
               
                   
                   
                 GTGATGCACGAGGCCCTGCACAACCACTACACCCAGAAGTCCCTGAGCCT 
               
               
                   
                   
                 GAGCCCCGGCAAG 
               
               
                 SEQ ID NO: 
                 LCDR1 
                 RSSKSLLHSSGNTYLY 
               
               
                 14 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 LCDR2 
                 RMSNLAS 
               
               
                 15 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 LCDR3 
                 MQHLEYPYT 
               
               
                 16 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 LCDR1 
                 RSSKSLLHSSGNTYLY 
               
               
                 14 
                 (Ka bat) 
                   
               
               
                 SEQ ID NO: 
                 LCDR2 
                 RMSNLAS 
               
               
                 15 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 LCDR3 
                 MQHLEYPYT 
               
               
                 16 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 LCDR1 
                 SKSLLHSSGNTY 
               
               
                 17 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 LCDR2 
                 RMS 
               
               
                 18 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 LCDR3 
                 HLEYPY 
               
               
                 19 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 LCDR1 
                 KSLLHSSGNTY 
               
               
                 20 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 LCDR2 
                 RMS 
               
               
                 18 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 LCDR3 
                 MQHLEYPYT 
               
               
                 16 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 VL 
                 DIVMTQSPLSLPVTPGEPASISCRSSKSLLHSSGNTYLYWFLQKPGQSPQLLISR 
               
               
                 21 
                   
                 MSNLASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQHLEYPYTFGGGT 
               
               
                   
                   
                 KVEIK 
               
               
                 SEQ ID NO: 
                 DNA VL 
                 GACATTGTGATGACCCAGTCTCCACTGAGCCTGCCTGTGACACCTGGCGA 
               
               
                 22 
                   
                 GCCTGCTTCCATCTCCTGCCGGTCCTCTAAGTCCCTGCTGCACTCTTCCGGC 
               
               
                   
                   
                 AATACCTACCTGTACTGGTTCCTGCAGAAGCCCGGCCAGTCTCCTCAGCTG 
               
               
                   
                   
                 CTGATCTCCAGAATGTCCAACCTGGCCTCTGGCGTGCCCGACAGATTTTCT 
               
               
                   
                   
                 GGCTCTGGATCTGGCACCGACTTCACCCTGAAGATCTCTAGAGTGGAAGC 
               
               
                   
                   
                 CGAGGACGTGGGCGTGTACTACTGTATGCAGCACCTGGAATACCCCTACA 
               
               
                   
                   
                 CCTTCGGCGGAGGCACCAAGGTGGAAATCAAG 
               
               
                 SEQ ID NO: 
                 Light 
                 DIVMTQSPLSLPVTPGEPASISCRSSKSLLHSSGNTYLYWFLQKPGQSPQLLISR 
               
               
                 23 
                 Chain 
                 MSNLASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQHLEYPYTFGGGT 
               
               
                   
                   
                 KVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQ 
               
               
                   
                   
                 SGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSF 
               
               
                   
                   
                 NRGEC 
               
               
                   
                   
                 GACATTGTGATGACCCAGTCTCCACTGAGCCTGCCTGTGACACCTGGCGA 
               
               
                   
                   
                 GCCTGCTTCCATCTCCTGCCGGTCCTCTAAGTCCCTGCTGCACTCTTCCGGC 
               
               
                   
                   
                 AATACCTACCTGTACTGGTTCCTGCAGAAGCCCGGCCAGTCTCCTCAGCTG 
               
               
                   
                   
                 CTGATCTCCAGAATGTCCAACCTGGCCTCTGGCGTGCCCGACAGATTTTCT 
               
               
                   
                   
                 GGCTCTGGATCTGGCACCGACTTCACCCTGAAGATCTCTAGAGTGGAAGC 
               
               
                   
                   
                 CGAGGACGTGGGCGTGTACTACTGTATGCAGCACCTGGAATACCCCTACA 
               
               
                   
                   
                 CCTTCGGCGGAGGCACCAAGGTGGAAATCAAGCGTACGGTGGCCGCTCCC 
               
               
                   
                   
                 AGCGTGTTCATCTTCCCCCCCAGCGACGAGCAGCTGAAGAGTGGCACCGC 
               
               
                   
                   
                 CAGCGTGGTGTGCCTGCTGAACAACTTCTACCCCCGGGAGGCCAAGGTGC 
               
               
                   
                   
                 AGTGGAAGGTGGACAACGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGT 
               
               
                   
                   
                 CACCGAGCAGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGA 
               
               
                   
                   
                 CCCTGAGCAAGGCCGACTACGAGAAGCATAAGGTGTACGCCTGCGAGGT 
               
               
                 SEQ ID NO: 
                 DNA Light 
                 GACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACAGGGGCG 
               
               
                 24 
                 Chain 
                   
               
            
           
           
               
            
               
                 960K03 N925 
               
            
           
           
               
               
               
            
               
                 SEQ ID NO: 
                 HCDR1 
                 GFSLSTGGMSVS 
               
               
                 25 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 HCDR2 
                 LIDWDDDKYYSTSLKT 
               
               
                 26 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 HCDR3 
                 AHSGSYFDF 
               
               
                 27 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 HCDR1 
                 TGGMSVS 
               
               
                 28 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 HCDR2 
                 LIDWDDDKYYSTSLKT 
               
               
                 26 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 HCDR3 
                 AHSGSYFDF 
               
               
                 27 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 HCDR1 
                 GFSLSTGGM 
               
               
                 29 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 HCDR2 
                 DWDDD 
               
               
                 30 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 HCDR3 
                 AHSGSYFDF 
               
               
                 27 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 HCDR1 
                 GFSLSTGGMS 
               
               
                 31 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 HCDR2 
                 IDWDDDK 
               
               
                 32 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 HCDR3 
                 ARAHSGSYFDF 
               
               
                 33 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 VH 
                 QVTLRESGPALVKPTQTLTLTCTFSGFSLSTGGMSVSWIRQPPGKALEWLALI 
               
               
                 34 
                   
                 DWDDDKYYSTSLKTRLTISKDTSKNQLVLTMTNMDPVDTATYYCARAHSGSY 
               
               
                   
                   
                 FDFWGQGTLVTVSS 
               
               
                 SEQ ID NO: 
                 DNA VH 
                 CAGGTCACCTTGAGGGAGTCTGGTCCTGCGCTGGTGAAACCCACACAGAC 
               
               
                 35 
                   
                 CCTCACACTGACCTGCACCTTCTCTGGGTTCTCACTCAGCACTGGTGGAAT 
               
               
                   
                   
                 GAGTGTGAGCTGGATCCGTCAGCCCCCAGGGAAGGCCCTGGAGTGGCTT 
               
               
                   
                   
                 GCACTCATTGATTGGGATGATGATAAATACTACAGCACATCTCTGAAGACC 
               
               
                   
                   
                 AGGCTCACCATCTCCAAGGACACCTCCAAAAACCAGCTGGTCCTTACAATG 
               
               
                   
                   
                 ACCAACATGGACCCTGTGGACACAGCCACGTATTATTGTGCACGGGCTCAT 
               
               
                   
                   
                 AGTGGGAGCTACTTTGACTTCTGGGGCCAGGGAACCCTGGTCACCGTCTC 
               
               
                   
                   
                 CTCA 
               
               
                 SEQ ID NO: 
                 Heavy 
                 QVTLRESGPALVKPTQTLTLTCTFSGFSLSTGGMSVSWIRQPPGKALEWLALI 
               
               
                 36 
                 Chain 
                 DWDDDKYYSTSLKTRLTISKDTSKNQLVLTMTNMDPVDTATYYCARAHSGSY 
               
               
                   
                   
                 FDFWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPCPVTV 
               
               
                   
                   
                 SWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNT 
               
               
                   
                   
                 KVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVV 
               
               
                   
                   
                 VAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL 
               
               
                   
                   
                 NGKEYKCKVSNKALAAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCL 
               
               
                   
                   
                 VKGFYPCDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG 
               
               
                   
                   
                 NVFSCSVMHEALHNHYTQKSLSLSPGK 
               
               
                 SEQ ID NO: 
                 DNA Heavy 
                 CAGGTCACCTTGAGGGAGTCTGGTCCTGCGCTGGTGAAACCCACACAGAC 
               
               
                 37 
                 Chain 
                 CCTCACACTGACCTGCACCTTCTCTGGGTTCTCACTCAGCACTGGTGGAAT 
               
               
                   
                   
                 GAGTGTGAGCTGGATCCGTCAGCCCCCAGGGAAGGCCCTGGAGTGGCTT 
               
               
                   
                   
                 GCACTCATTGATTGGGATGATGATAAATACTACAGCACATCTCTGAAGACC 
               
               
                   
                   
                 AGGCTCACCATCTCCAAGGACACCTCCAAAAACCAGCTGGTCCTTACAATG 
               
               
                   
                   
                 ACCAACATGGACCCTGTGGACACAGCCACGTATTATTGTGCACGGGCTCAT 
               
               
                   
                   
                 AGTGGGAGCTACTTTGACTTCTGGGGCCAGGGAACCCTGGTCACCGTCTC 
               
               
                   
                   
                 CTCAGCCTCCACCAAGGGCCCATCGGTGTTTCCCCTGGCCCCCAGCAGCAA 
               
               
                   
                   
                 GTCTACTTCCGGCGGAACTGCTGCCCTGGGTTGCCTGGTGAAGGACTACTT 
               
               
                   
                   
                 CCCCTGTCCCGTGACAGTGTCCTGGAACTCTGGGGCTCTGACTTCCGGCGT 
               
               
                   
                   
                 GCACACCTTCCCCGCCGTGCTGCAGAGCAGCGGCCTGTACAGCCTGAGCA 
               
               
                   
                   
                 GCGTGGTGACAGTGCCCTCCAGCTCTCTGGGAACCCAGACCTATATCTGCA 
               
               
                   
                   
                 ACGTGAACCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTGGAGCC 
               
               
                   
                   
                 CAAGAGCTGCGACAAGACCCACACCTGCCCCCCCTGCCCAGCTCCAGAACT 
               
               
                   
                   
                 GCTGGGAGGGCCTTCCGTGTTCCTGTTCCCCCCCAAGCCCAAGGACACCCT 
               
               
                   
                   
                 GATGATCAGCAGGACCCCCGAGGTGACCTGCGTGGTGGTGGCCGTGTCCC 
               
               
                   
                   
                 ACGAGGACCCAGAGGTGAAGTTCAACTGGTACGTGGACGGCGTGGAGGT 
               
               
                   
                   
                 GCACAACGCCAAGACCAAGCCCAGAGAGGAGCAGTACAACAGCACCTAC 
               
               
                   
                   
                 AGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGACTGGCTGAACGGCA 
               
               
                   
                   
                 AAGAATACAAGTGCAAAGTCTCCAACAAGGCCCTGGCTGCCCCAATCGAA 
               
               
                   
                   
                 AAGACAATCAGCAAGGCCAAGGGCCAGCCACGGGAGCCCCAGGTGTACA 
               
               
                   
                   
                 CCCTGCCCCCCAGCCGGGAGGAGATGACCAAGAACCAGGTGTCCCTGACC 
               
               
                   
                   
                 TGTCTGGTGAAGGGCTTCTACCCCTGTGATATCGCCGTGGAGTGGGAGAG 
               
               
                   
                   
                 CAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCCAGTGCTGGACA 
               
               
                   
                   
                 GCGACGGCAGCTTCTTCCTGTACAGCAAGCTGACCGTGGACAAGTCCAGG 
               
               
                   
                   
                 TGGCAGCAGGGCAACGTGTTCAGCTGCAGCGTGATGCACGAGGCCCTGC 
               
               
                   
                   
                 ACAACCACTACACCCAGAAGTCCCTGAGCCTGAGCCCCGGCAAG 
               
               
                 SEQ ID NO: 
                 LCDR1 
                 RASQRISNWLA 
               
               
                 38 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 LCDR2 
                 KASSLES 
               
               
                 39 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 LCDR3 
                 QQFSSYWT 
               
               
                 40 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 LCDR1 
                 RASQRISNWLA 
               
               
                 38 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 LCDR2 
                 KASSLES 
               
               
                 39 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 LCDR3 
                 QQFSSYWT 
               
               
                 40 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 LCDR1 
                 SQRISNW 
               
               
                 41 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 LCDR2 
                 KAS 
               
               
                 42 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 LCDR3 
                 FSSYW 
               
               
                 43 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 LCDR1 
                 QRISNW 
               
               
                 44 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 LCDR2 
                 KAS 
               
               
                 42 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 LCDR3 
                 QQFSSYWT 
               
               
                 40 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 VL 
                 DIQMTQSPSTLSASVGDRVTITCRASQRISNWLAWYQQKPGKAPKLLIYKASS 
               
               
                 45 
                   
                 LESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQFSSYWTFGQGTKVEIK 
               
               
                 SEQ ID NO: 
                 DNA VL 
                 GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGAC 
               
               
                 46 
                   
                 AGAGTCACCATCACTTGCCGGGCCAGTCAGAGAATTAGTAACTGGTTGGC 
               
               
                   
                   
                 CTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAACTCCTGATCTATAAGG 
               
               
                   
                   
                 CGTCTAGTTTAGAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCT 
               
               
                   
                   
                 GGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCA 
               
               
                   
                   
                 ACTTATTACTGCCAACAGTTTAGTAGTTATTGGACGTTCGGCCAAGGGACC 
               
               
                   
                   
                 AAGGTGGAAATCAAA 
               
               
                 SEQ ID NO: 
                 Light 
                 DIQMTQSPSTLSASVGDRVTITCRASQRISNWLAWYQQKPGKAPKLLIYKASS 
               
               
                 47 
                  Chain 
                 LESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQFSSYWTFGQGTKVEIKR 
               
               
                   
                   
                 TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQ 
               
               
                   
                   
                 ESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 
               
               
                 SEQ ID NO: 
                 DNA Light 
                 GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGAC 
               
               
                 48 
                 Chain 
                 AGAGTCACCATCACTTGCCGGGCCAGTCAGAGAATTAGTAACTGGTTGGC 
               
               
                   
                   
                 CTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAACTCCTGATCTATAAGG 
               
               
                   
                   
                 CGTCTAGTTTAGAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCT 
               
               
                   
                   
                 GGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCA 
               
               
                   
                   
                 ACTTATTACTGCCAACAGTTTAGTAGTTATTGGACGTTCGGCCAAGGGACC 
               
               
                   
                   
                 AAGGTGGAAATCAAACGAACTGTGGCTGCACCAAGCGTGTTCATCTTCCC 
               
               
                   
                   
                 CCCCAGCGACGAGCAGCTGAAGAGTGGCACCGCCAGCGTGGTGTGCCTG 
               
               
                   
                   
                 CTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAGGTGGACA 
               
               
                   
                   
                 ACGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGTCACCGAGCAGGACAG 
               
               
                   
                   
                 CAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCG 
               
               
                   
                   
                 ACTACGAGAAGCATAAGGTGTACGCCTGCGAGGTGACCCACCAGGGCCT 
               
               
                   
                   
                 GTCCAGCCCCGTGACCAAGAGCTTCAACAGGGGCGAGTGC 
               
            
           
           
               
            
               
                 958N05 S93A 
               
            
           
           
               
               
               
            
               
                 SEQ ID NO: 
                 HCDR1 
                 GFSLSTSGISVS 
               
               
                 49 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 HCDR2 
                 LIDWDDDKYYSTSLKT 
               
               
                 26 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 HCDR3 
                 TPSGSYGRYFDL 
               
               
                 50 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 HCDR1 
                 TSGISVS 
               
               
                 51 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 HCDR2 
                 LIDWDDDKYYSTSLKT 
               
               
                 26 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 HCDR3 
                 TPSGSYGRYFDL 
               
               
                 50 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 HCDR1 
                 GFSLSTSGI 
               
               
                 52 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 HCDR2 
                 DWDDD 
               
               
                 30 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 HCDR3 
                 TPSGSYGRYFDL 
               
               
                 50 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 HCDR1 
                 GFSLSTSGIS 
               
               
                 53 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 HCDR2 
                 IDWDDDK 
               
               
                 32 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 HCDR3 
                 ARTPSGSYGRYFDL 
               
               
                 54 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 VH 
                 QVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGISVSWIRQPPGKALEWLALID 
               
               
                 55 
                   
                 WDDDKYYSTSLKTRLTISKDTSKNQVVLTMTNMDPVDTATYYCARTPSGSYG 
               
               
                   
                   
                 RYFDLWGRGTLVTVSS 
               
               
                 SEQ ID NO: 
                 DNA VH 
                 CAGGTCACCTTGAGGGAGTCTGGTCCTGCGCTGGTGAAACCCACACAGAC 
               
               
                 56 
                   
                 CCTCACACTGACCTGCACCTTCTCTGGGTTCTCACTCAGCACAAGTGGAAT 
               
               
                   
                   
                 ATCTGTGAGCTGGATCCGTCAGCCCCCAGGGAAGGCCCTGGAGTGGCTTG 
               
               
                   
                   
                 CACTCATTGATTGGGATGATGATAAATACTACAGCACATCTCTGAAGACCA 
               
               
                   
                   
                 GGCTCACCATCTCCAAGGACACCTCCAAAAACCAGGTGGTCCTTACAATGA 
               
               
                   
                   
                 CCAACATGGACCCTGTGGACACAGCCACGTATTATTGTGCACGGACCCCTA 
               
               
                   
                   
                 GTGGGAGCTATGGGCGATACTTCGATCTCTGGGGCCGTGGCACCCTGGTC 
               
               
                   
                   
                 ACTGTCTCCTCA 
               
               
                 SEQ ID NO: 
                 Heavy 
                 QVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGISVSWIRQPPGKALEWLALID 
               
               
                 57 
                 Chain 
                 WDDDKYYSTSLKTRLTISKDTSKNQVVLTMTNMDPVDTATYYCARTPSGSYG 
               
               
                   
                   
                 RYFDLWGRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPCPVT 
               
               
                   
                   
                 VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN 
               
               
                   
                   
                 TKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
               
               
                   
                   
                 VVAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD 
               
               
                   
                   
                 WLNGKEYKCKVSNKALAAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSL 
               
               
                   
                   
                 TCLVKGFYPCDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW 
               
               
                   
                   
                 QQGNVFSCSVMHEALHNHYTQKSLSLSPGK 
               
               
                 SEQ ID NO: 
                 DNA Heavy 
                 CAGGTCACCTTGAGGGAGTCTGGTCCTGCGCTGGTGAAACCCACACAGAC 
               
               
                 58 
                 Chain 
                 CCTCACACTGACCTGCACCTTCTCTGGGTTCTCACTCAGCACAAGTGGAAT 
               
               
                   
                   
                 ATCTGTGAGCTGGATCCGTCAGCCCCCAGGGAAGGCCCTGGAGTGGCTTG 
               
               
                   
                   
                 CACTCATTGATTGGGATGATGATAAATACTACAGCACATCTCTGAAGACCA 
               
               
                   
                   
                 GGCTCACCATCTCCAAGGACACCTCCAAAAACCAGGTGGTCCTTACAATGA 
               
               
                   
                   
                 CCAACATGGACCCTGTGGACACAGCCACGTATTATTGTGCACGGACCCCTA 
               
               
                   
                   
                 GTGGGAGCTATGGGCGATACTTCGATCTCTGGGGCCGTGGCACCCTGGTC 
               
               
                   
                   
                 ACTGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTGTTTCCCCTGGCCCCC 
               
               
                   
                   
                 AGCAGCAAGTCTACTTCCGGCGGAACTGCTGCCCTGGGTTGCCTGGTGAA 
               
               
                   
                   
                 GGACTACTTCCCCTGTCCCGTGACAGTGTCCTGGAACTCTGGGGCTCTGAC 
               
               
                   
                   
                 TTCCGGCGTGCACACCTTCCCCGCCGTGCTGCAGAGCAGCGGCCTGTACA 
               
               
                   
                   
                 GCCTGAGCAGCGTGGTGACAGTGCCCTCCAGCTCTCTGGGAACCCAGACC 
               
               
                   
                   
                 TATATCTGCAACGTGAACCACAAGCCCAGCAACACCAAGGTGGACAAGAG 
               
               
                   
                   
                 AGTGGAGCCCAAGAGCTGCGACAAGACCCACACCTGCCCCCCCTGCCCAG 
               
               
                   
                   
                 CTCCAGAACTGCTGGGAGGGCCTTCCGTGTTCCTGTTCCCCCCCAAGCCCA 
               
               
                   
                   
                 AGGACACCCTGATGATCAGCAGGACCCCCGAGGTGACCTGCGTGGTGGT 
               
               
                   
                   
                 GGCCGTGTCCCACGAGGACCCAGAGGTGAAGTTCAACTGGTACGTGGAC 
               
               
                   
                   
                 GGCGTGGAGGTGCACAACGCCAAGACCAAGCCCAGAGAGGAGCAGTACA 
               
               
                   
                   
                 ACAGCACCTACAGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGACTGG 
               
               
                   
                   
                 CTGAACGGCAAAGAATACAAGTGCAAAGTCTCCAACAAGGCCCTGGCTGC 
               
               
                   
                   
                 CCCAATCGAAAAGACAATCAGCAAGGCCAAGGGCCAGCCACGGGAGCCC 
               
               
                   
                   
                 CAGGTGTACACCCTGCCCCCCAGCCGGGAGGAGATGACCAAGAACCAGG 
               
               
                   
                   
                 TGTCCCTGACCTGTCTGGTGAAGGGCTTCTACCCCTGTGATATCGCCGTGG 
               
               
                   
                   
                 AGTGGGAGAGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCC 
               
               
                   
                   
                 AGTGCTGGACAGCGACGGCAGCTTCTTCCTGTACAGCAAGCTGACCGTGG 
               
               
                   
                   
                 ACAAGTCCAGGTGGCAGCAGGGCAACGTGTTCAGCTGCAGCGTGATGCA 
               
               
                   
                   
                 CGAGGCCCTGCACAACCACTACACCCAGAAGTCCCTGAGCCTGAGCCCCG 
               
               
                   
                   
                 GCAAG 
               
               
                 SEQ ID NO: 
                 LCDR1 
                 RASQSISNWLA 
               
               
                 59 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 LCDR2 
                 KASSLES 
               
               
                 39 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 LCDR3 
                 QQYNAYWT 
               
               
                 60 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 LCDR1 
                 RASQSISNWLA 
               
               
                 59 
                 (Ka bat) 
                   
               
               
                 SEQ ID NO: 
                 LCDR2 
                 KASSLES 
               
               
                 39 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 LCDR3 
                 QQYNAYWT 
               
               
                 60 
                 (Ka bat) 
                   
               
               
                 SEQ ID NO: 
                 LCDR1 
                 SQSISNW 
               
               
                 61 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 LCDR2 
                 KAS 
               
               
                 42 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 LCDR3 
                 YNAYW 
               
               
                 62 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 LCDR1 
                 QSISNW 
               
               
                 63 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 LCDR2 
                 KAS 
               
               
                 42 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 LCDR3 
                 QQYNAYWT 
               
               
                 60 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 VL 
                 DIQLTQSPSTLSASVGDRVTITCRASQSISNWLAWYQQKPGKAPKLLIYKASSL 
               
               
                 64 
                   
                 ESGVPSRFTGSGSGTEFTLTISSLQPDDFATYYCQQYNAYWTFGQGTKVEIK 
               
               
                 SEQ ID NO: 
                 DNA VL 
                 GACATCCAGTTGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGAC 
               
               
                 65 
                   
                 AGAGTCACCATCACTTGCCGGGCCAGTCAGAGTATTAGTAACTGGTTGGC 
               
               
                   
                   
                 CTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAACTCCTGATCTATAAGG 
               
               
                   
                   
                 CGTCTAGTTTAGAAAGTGGGGTCCCGTCAAGGTTCACCGGCAGTGGATCT 
               
               
                   
                   
                 GGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCA 
               
               
                   
                   
                 ACTTATTACTGCCAACAGTATAATGCCTATTGGACGTTCGGCCAAGGGACC 
               
               
                   
                   
                 AAGGTGGAAATCAAA 
               
               
                 SEQ ID NO: 
                 Light 
                 DIQLTQSPSTLSASVGDRVTITCRASQSISNWLAWYQQKPGKAPKLLIYKASSL 
               
               
                 66 
                 Chain 
                 ESGVPSRFTGSGSGTEFTLTISSLQPDDFATYYCQQYNAYWTFGQGTKVEIKR 
               
               
                   
                   
                 TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQ 
               
               
                   
                   
                 ESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 
               
               
                 SEQ ID NO: 
                 DNA Light 
                 GACATCCAGTTGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGAC 
               
               
                 67 
                 Chain 
                 AGAGTCACCATCACTTGCCGGGCCAGTCAGAGTATTAGTAACTGGTTGGC 
               
               
                   
                   
                 CTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAACTCCTGATCTATAAGG 
               
               
                   
                   
                 CGTCTAGTTTAGAAAGTGGGGTCCCGTCAAGGTTCACCGGCAGTGGATCT 
               
               
                   
                   
                 GGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCA 
               
               
                   
                   
                 vACTTATTACTGCCAACAGTATAATGCCTATTGGACGTTCGGCCAAGGGACC 
               
               
                   
                   
                 AAGGTGGAAATCAAACGAACTGTGGCTGCACCAAGCGTGTTCATCTTCCC 
               
               
                   
                   
                 CCCCAGCGACGAGCAGCTGAAGAGTGGCACCGCCAGCGTGGTGTGCCTG 
               
               
                   
                   
                 CTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAGGTGGACA 
               
               
                   
                   
                 ACGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGTCACCGAGCAGGACAG 
               
               
                   
                   
                 CAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCG 
               
               
                   
                   
                 ACTACGAGAAGCATAAGGTGTACGCCTGCGAGGTGACCCACCAGGGCCT 
               
               
                   
                   
                 GTCCAGCCCCGTGACCAAGAGCTTCAACAGGGGCGAGTGC 
               
            
           
           
               
            
               
                 960K03 N92Q 
               
            
           
           
               
               
               
            
               
                 SEQ ID NO: 
                 HCDR1 
                 GFSLSTGGMSVS 
               
               
                 25 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 HCDR2 
                 LIDWDDDKYYSTSLKT 
               
               
                 26 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 HCDR3 
                 AHSGSYFDF 
               
               
                 27 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 HCDR1 
                 TGGMSVS 
               
               
                 28 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 HCDR2 
                 LIDWDDDKYYSTSLKT 
               
               
                 26 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 HCDR3 
                 AHSGSYFDF 
               
               
                 27 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 HCDR1 
                 GFSLSTGGM 
               
               
                 29 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 HCDR2 
                 DWDDD 
               
               
                 30 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 HCDR3 
                 AHSGSYFDF 
               
               
                 27 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 HCDR1 
                 GFSLSTGGMS 
               
               
                 31 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 HCDR2 
                 IDWDDDK 
               
               
                 32 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 HCDR3 
                 ARAHSGSYFDF 
               
               
                 33 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 DWDD 
                 QVTLRESGPALVKPTQTLTLTCTFSGFSLSTGGMSVSWIRQPPGKALEWLALI 
               
               
                 34 
                 VH 
                 DKYYSTSLKTRLTISKDTSKNQLVLTMTNMDPVDTATYYCARAHSGSY 
               
               
                   
                   
                 FDFWGQGTLVTVSS 
               
               
                 SEQ ID NO: 
                 DNA VH 
                 CAGGTCACCTTGAGGGAGTCTGGTCCTGCGCTGGTGAAACCCACACAGAC 
               
               
                 35 
                   
                 CCTCACACTGACCTGCACCTTCTCTGGGTTCTCACTCAGCACTGGTGGAAT 
               
               
                   
                   
                 GAGTGTGAGCTGGATCCGTCAGCCCCCAGGGAAGGCCCTGGAGTGGCTT 
               
               
                   
                   
                 vGCACTCATTGATTGGGATGATGATAAATACTACAGCACATCTCTGAAGACC 
               
               
                   
                   
                 AGGCTCACCATCTCCAAGGACACCTCCAAAAACCAGCTGGTCCTTACAATG 
               
               
                   
                   
                 ACCAACATGGACCCTGTGGACACAGCCACGTATTATTGTGCACGGGCTCAT 
               
               
                   
                   
                 AGTGGGAGCTACTTTGACTTCTGGGGCCAGGGAACCCTGGTCACCGTCTC 
               
               
                   
                   
                 CTCA 
               
               
                 SEQ ID NO: 
                 Heavy 
                 QVTLRESGPALVKPTQTLTLTCTFSGFSLSTGGMSVSWIRQPPGKALEWLALI 
               
               
                 36 
                 Chain 
                 DWDDDKYYSTSLKTRLTISKDTSKNQLVLTMTNMDPVDTATYYCARAHSGSY 
               
               
                   
                   
                 FDFWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPCPVTV 
               
               
                   
                   
                 SWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNT 
               
               
                   
                   
                 KVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVV 
               
               
                   
                   
                 VAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL 
               
               
                   
                   
                 NGKEYKCKVSNKALAAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCL 
               
               
                   
                   
                 VKGFYPCDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG 
               
               
                   
                   
                 NVFSCSVMHEALHNHYTQKSLSLSPGK 
               
               
                 SEQ ID NO: 
                 DNA Heavy 
                 CAGGTCACCTTGAGGGAGTCTGGTCCTGCGCTGGTGAAACCCACACAGAC 
               
               
                 37 
                 Chain 
                 CCTCACACTGACCTGCACCTTCTCTGGGTTCTCACTCAGCACTGGTGGAAT 
               
               
                   
                   
                 vGAGTGTGAGCTGGATCCGTCAGCCCCCAGGGAAGGCCCTGGAGTGGCTT 
               
               
                   
                   
                 GCACTCATTGATTGGGATGATGATAAATACTACAGCACATCTCTGAAGACC 
               
               
                   
                   
                 AGGCTCACCATCTCCAAGGACACCTCCAAAAACCAGCTGGTCCTTACAATG 
               
               
                   
                   
                 ACCAACATGGACCCTGTGGACACAGCCACGTATTATTGTGCACGGGCTCAT 
               
               
                   
                   
                 AGTGGGAGCTACTTTGACTTCTGGGGCCAGGGAACCCTGGTCACCGTCTC 
               
               
                   
                   
                 CTCAGCCTCCACCAAGGGCCCATCGGTGTTTCCCCTGGCCCCCAGCAGCAA 
               
               
                   
                   
                 GTCTACTTCCGGCGGAACTGCTGCCCTGGGTTGCCTGGTGAAGGACTACTT 
               
               
                   
                   
                 CCCCTGTCCCGTGACAGTGTCCTGGAACTCTGGGGCTCTGACTTCCGGCGT 
               
               
                   
                   
                 GCACACCTTCCCCGCCGTGCTGCAGAGCAGCGGCCTGTACAGCCTGAGCA 
               
               
                   
                   
                 GCGTGGTGACAGTGCCCTCCAGCTCTCTGGGAACCCAGACCTATATCTGCA 
               
               
                   
                   
                 ACGTGAACCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTGGAGCC 
               
               
                   
                   
                 CAAGAGCTGCGACAAGACCCACACCTGCCCCCCCTGCCCAGCTCCAGAACT 
               
               
                   
                   
                 GCTGGGAGGGCCTTCCGTGTTCCTGTTCCCCCCCAAGCCCAAGGACACCCT 
               
               
                   
                   
                 GATGATCAGCAGGACCCCCGAGGTGACCTGCGTGGTGGTGGCCGTGTCCC 
               
               
                   
                   
                 ACGAGGACCCAGAGGTGAAGTTCAACTGGTACGTGGACGGCGTGGAGGT 
               
               
                   
                   
                 GCACAACGCCAAGACCAAGCCCAGAGAGGAGCAGTACAACAGCACCTAC 
               
               
                   
                   
                 AGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGACTGGCTGAACGGCA 
               
               
                   
                   
                 AAGAATACAAGTGCAAAGTCTCCAACAAGGCCCTGGCTGCCCCAATCGAA 
               
               
                   
                   
                 AAGACAATCAGCAAGGCCAAGGGCCAGCCACGGGAGCCCCAGGTGTACA 
               
               
                   
                   
                 CCCTGCCCCCCAGCCGGGAGGAGATGACCAAGAACCAGGTGTCCCTGACC 
               
               
                   
                   
                 TGTCTGGTGAAGGGCTTCTACCCCTGTGATATCGCCGTGGAGTGGGAGAG 
               
               
                   
                   
                 CAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCCAGTGCTGGACA 
               
               
                   
                   
                 GCGACGGCAGCTTCTTCCTGTACAGCAAGCTGACCGTGGACAAGTCCAGG 
               
               
                   
                   
                 TGGCAGCAGGGCAACGTGTTCAGCTGCAGCGTGATGCACGAGGCCCTGC 
               
               
                   
                   
                 ACAACCACTACACCCAGAAGTCCCTGAGCCTGAGCCCCGGCAAG 
               
               
                 SEQ ID NO: 
                 LCDR1 
                 RASQRISNWLA 
               
               
                 38 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 LCDR2 
                 KASSLES 
               
               
                 39 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 LCDR3 
                 QQFQSYWT 
               
               
                 68 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 LCDR1 
                 RASQRISNWLA 
               
               
                 38 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 LCDR2 
                 KASSLES 
               
               
                 39 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 LCDR3 
                 QQFQSYWT 
               
               
                 68 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 LCDR1 
                 SQRISNW 
               
               
                 41 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 LCDR2 
                 KAS 
               
               
                 42 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 LCDR3 
                 FQSYW 
               
               
                 69 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 LCDR1 
                 QRISNW 
               
               
                 44 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 LCDR2 
                 KAS 
               
               
                 42 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 LCDR3 
                 QQFQSYWT 
               
               
                 68 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 VL 
                 DIQMTQSPSTLSASVGDRVTITCRASQRISNWLAWYQQKPGKAPKLLIYKASS 
               
               
                 70 
                   
                 LESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQFQSYWTFGQGTKVEIK 
               
               
                 SEQ ID NO: 
                 DNA VL 
                 GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGAC 
               
               
                 71 
                   
                 AGAGTCACCATCACTTGCCGGGCCAGTCAGAGAATTAGTAACTGGTTGGC 
               
               
                   
                   
                 CTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAACTCCTGATCTATAAGG 
               
               
                   
                   
                 vCGTCTAGTTTAGAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCT 
               
               
                   
                   
                 GGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCA 
               
               
                   
                   
                 ACTTATTACTGCCAACAGTTTCAGAGTTATTGGACGTTCGGCCAAGGGACC 
               
               
                   
                   
                 AAGGTGGAAATCAAA 
               
               
                 SEQ ID NO: 
                 Light 
                 DIQMTQSPSTLSASVGDRVTITCRASQRISNWLAWYQQKPGKAPKLLIYKASS 
               
               
                 72 
                 Chain 
                 LESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQFQSYWTFGQGTKVEIKR 
               
               
                   
                   
                 TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQ 
               
               
                   
                   
                 ESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 
               
               
                 SEQ ID NO: 
                 DNA Light 
                 GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGAC 
               
               
                 73 
                 Chain 
                 AGAGTCACCATCACTTGCCGGGCCAGTCAGAGAATTAGTAACTGGTTGGC 
               
               
                   
                   
                 CTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAACTCCTGATCTATAAGG 
               
               
                   
                   
                 CGTCTAGTTTAGAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCT 
               
               
                   
                   
                 GGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCA 
               
               
                   
                   
                 ACTTATTACTGCCAACAGTTTCAGAGTTATTGGACGTTCGGCCAAGGGACC 
               
               
                   
                   
                 AAGGTGGAAATCAAACGAACTGTGGCTGCACCAAGCGTGTTCATCTTCCC 
               
               
                   
                   
                 CCCCAGCGACGAGCAGCTGAAGAGTGGCACCGCCAGCGTGGTGTGCCTG 
               
               
                   
                   
                 CTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAGGTGGACA 
               
               
                   
                   
                 ACGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGTCACCGAGCAGGACAG 
               
               
                   
                   
                 CAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCG 
               
               
                   
                   
                 ACTACGAGAAGCATAAGGTGTACGCCTGCGAGGTGACCCACCAGGGCCT 
               
               
                   
                   
                 GTCCAGCCCCGTGACCAAGAGCTTCAACAGGGGCGAGTGC 
               
            
           
           
               
            
               
                 952P16 N92Q 
               
            
           
           
               
               
               
            
               
                 SEQ ID NO: 
                 HCDR1 
                 GFSLSTSGVSVS 
               
               
                 74 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 HCDR2 
                 LIDWDDDKYYSTSLKT 
               
               
                 26 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 HCDR3 
                 TPSGSYGRYFDL 
               
               
                 50 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 HCDR1 
                 TSGVSVS 
               
               
                 75 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 HCDR2 
                 LIDWDDDKYYSTSLKT 
               
               
                 26 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 HCDR3 
                 TPSGSYGRYFDL 
               
               
                 50 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 HCDR1 
                 GFSLSTSGV 
               
               
                 76 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 HCDR2 
                 DWDDD 
               
               
                 30 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 HCDR3 
                 TPSGSYGRYFDL 
               
               
                 50 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 HCDR1 
                 GFSLSTSGVS 
               
               
                 77 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 HCDR2 
                 IDWDDDK 
               
               
                 32 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 HCDR3 
                 ARTPSGSYGRYFDL 
               
               
                 54 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 VH 
                 QVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGVSVSWIRQPPGKALEWLALID 
               
               
                 78 
                   
                 WDDDKYYSTSLKTRLTISKDTSKNQVVLTMTNMDPVDTATYYCARTPSGSYG 
               
               
                   
                   
                 RYFDLWGRGTLVTVSS 
               
               
                 SEQ ID NO: 
                 DNA VH 
                 CAGGTCACCTTGAGGGAGTCTGGTCCTGCGCTGGTGAAACCCACACAGAC 
               
               
                 79 
                   
                 CCTCACACTGACCTGCACCTTCTCTGGGTTCTCACTCAGCACTAGTGGAGT 
               
               
                   
                   
                 GTCTGTGAGTTGGATCCGTCAGCCCCCAGGGAAGGCCCTGGAGTGGCTTG 
               
               
                   
                   
                 CACTCATTGATTGGGATGATGATAAATACTACAGCACATCTCTGAAGACCA 
               
               
                   
                   
                 GGCTCACCATCTCCAAGGACACCTCCAAAAACCAGGTGGTCCTTACAATGA 
               
               
                   
                   
                 CCAACATGGACCCTGTGGACACAGCCACGTACTATTGTGCACGGACCCCTA 
               
               
                   
                   
                 GTGGGAGCTACGGGCGATACTTCGATCTCTGGGGCCGTGGCACCCTGGTC 
               
               
                   
                   
                 ACTGTCTCCTCA 
               
               
                 SEQ ID NO: 
                 Heavy 
                 QVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGVSVSWIRQPPGKALEWLALID 
               
               
                 80 
                 Chain 
                 WDDDKYYSTSLKTRLTISKDTSKNQVVLTMTNMDPVDTATYYCARTPSGSYG 
               
               
                   
                   
                 RYFDLWGRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPCPVT 
               
               
                   
                   
                 VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN 
               
               
                   
                   
                 TKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
               
               
                   
                   
                 VVAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD 
               
               
                   
                   
                 WLNGKEYKCKVSNKALAAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSL 
               
               
                   
                   
                 TCLVKGFYPCDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW 
               
               
                   
                   
                 QQGNVFSCSVMHEALHNHYTQKSLSLSPGK 
               
               
                 SEQ ID NO: 
                 DNA Heavy 
                 CAGGTCACCTTGAGGGAGTCTGGTCCTGCGCTGGTGAAACCCACACAGAC 
               
               
                 81 
                 Chain 
                 CCTCACACTGACCTGCACCTTCTCTGGGTTCTCACTCAGCACTAGTGGAGT 
               
               
                   
                   
                 GTCTGTGAGTTGGATCCGTCAGCCCCCAGGGAAGGCCCTGGAGTGGCTTG 
               
               
                   
                   
                 CACTCATTGATTGGGATGATGATAAATACTACAGCACATCTCTGAAGACCA 
               
               
                   
                   
                 GGCTCACCATCTCCAAGGACACCTCCAAAAACCAGGTGGTCCTTACAATGA 
               
               
                   
                   
                 CCAACATGGACCCTGTGGACACAGCCACGTACTATTGTGCACGGACCCCTA 
               
               
                   
                   
                 GTGGGAGCTACGGGCGATACTTCGATCTCTGGGGCCGTGGCACCCTGGTC 
               
               
                   
                   
                 ACTGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTGTTTCCCCTGGCCCCC 
               
               
                   
                   
                 AGCAGCAAGTCTACTTCCGGCGGAACTGCTGCCCTGGGTTGCCTGGTGAA 
               
               
                   
                   
                 GGACTACTTCCCCTGTCCCGTGACAGTGTCCTGGAACTCTGGGGCTCTGAC 
               
               
                   
                   
                 TTCCGGCGTGCACACCTTCCCCGCCGTGCTGCAGAGCAGCGGCCTGTACA 
               
               
                   
                   
                 GCCTGAGCAGCGTGGTGACAGTGCCCTCCAGCTCTCTGGGAACCCAGACC 
               
               
                   
                   
                 TATATCTGCAACGTGAACCACAAGCCCAGCAACACCAAGGTGGACAAGAG 
               
               
                   
                   
                 AGTGGAGCCCAAGAGCTGCGACAAGACCCACACCTGCCCCCCCTGCCCAG 
               
               
                   
                   
                 CTCCAGAACTGCTGGGAGGGCCTTCCGTGTTCCTGTTCCCCCCCAAGCCCA 
               
               
                   
                   
                 AGGACACCCTGATGATCAGCAGGACCCCCGAGGTGACCTGCGTGGTGGT 
               
               
                   
                   
                 GGCCGTGTCCCACGAGGACCCAGAGGTGAAGTTCAACTGGTACGTGGAC 
               
               
                   
                   
                 GGCGTGGAGGTGCACAACGCCAAGACCAAGCCCAGAGAGGAGCAGTACA 
               
               
                   
                   
                 ACAGCACCTACAGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGACTGG 
               
               
                   
                   
                 CTGAACGGCAAAGAATACAAGTGCAAAGTCTCCAACAAGGCCCTGGCTGC 
               
               
                   
                   
                 vCCCAATCGAAAAGACAATCAGCAAGGCCAAGGGCCAGCCACGGGAGCCC 
               
               
                   
                   
                 CAGGTGTACACCCTGCCCCCCAGCCGGGAGGAGATGACCAAGAACCAGG 
               
               
                   
                   
                 TGTCCCTGACCTGTCTGGTGAAGGGCTTCTACCCCTGTGATATCGCCGTGG 
               
               
                   
                   
                 AGTGGGAGAGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCC 
               
               
                   
                   
                 AGTGCTGGACAGCGACGGCAGCTTCTTCCTGTACAGCAAGCTGACCGTGG 
               
               
                   
                   
                 ACAAGTCCAGGTGGCAGCAGGGCAACGTGTTCAGCTGCAGCGTGATGCA 
               
               
                   
                   
                 CGAGGCCCTGCACAACCACTACACCCAGAAGTCCCTGAGCCTGAGCCCCG 
               
               
                   
                   
                 GCAAG 
               
               
                 SEQ ID NO: 
                 LCDR1 
                 RASQSISNWLA 
               
               
                 59 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 LCDR2 
                 KASSLES 
               
               
                 39 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 LCDR3 
                 QQYQSYWT 
               
               
                 82 
                 (Combined)  
                   
               
               
                 SEQ ID NO: 
                 LCDR1 
                 RASQSISNWLA 
               
               
                 59 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 LCDR2 
                 KASSLES 
               
               
                 39 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 LCDR3 
                 QQYQSYWT 
               
               
                 82 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 LCDR1 
                 SQSISNW 
               
               
                 61 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 LCDR2 
                 KAS 
               
               
                 42 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 LCDR3 
                 YQSYW 
               
               
                 83 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 LCDR1 
                 QSISNW 
               
               
                 63 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 LCDR2 
                 KAS 
               
               
                 42 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 LCDR3 
                 QQYQSYWT 
               
               
                 82 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 VL 
                 DIQMTQSPSTLSASVGDRVTITCRASQSISNWLAWYQQKPGKAPKLLIYKASS 
               
               
                 84 
                   
                 LESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQYQSYWTFGQGTKVEI 
               
               
                 SEQ ID NO: 
                 DNA VL 
                 GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGAC 
               
               
                 85 
                   
                 AGAGTCACCATCACTTGCCGGGCCAGTCAGAGTATTAGTAACTGGTTGGC 
               
               
                   
                   
                 CTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATAAGG 
               
               
                   
                   
                 CGTCTAGTTTAGAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCT 
               
               
                   
                   
                 GGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCA 
               
               
                   
                   
                 ACTTATTACTGCCAACAGTATCAGAGTTATTGGACGTTCGGCCAAGGGACC 
               
               
                   
                   
                 AAGGTGGAAATCAAA 
               
               
                 SEQ ID NO: 
                 Light 
                 DIQMTQSPSTLSASVGDRVTITCRASQSISNWLAWYQQKPGKAPKLLIYKASS 
               
               
                 86 
                 Chain 
                 LESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQYQSYWTFGQGTKVEIKR 
               
               
                   
                   
                 TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQ 
               
               
                   
                   
                 ESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 
               
               
                   
                   
                 GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGAC 
               
               
                   
                   
                 AGAGTCACCATCACTTGCCGGGCCAGTCAGAGTATTAGTAACTGGTTGGC 
               
               
                   
                   
                 CTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATAAGG 
               
               
                   
                   
                 CGTCTAGTTTAGAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCT 
               
               
                   
                   
                 GGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCA 
               
               
                   
                   
                 ACTTATTACTGCCAACAGTATCAGAGTTATTGGACGTTCGGCCAAGGGACC 
               
               
                   
                   
                 AAGGTGGAAATCAAACGAACTGTGGCTGCACCAAGCGTGTTCATCTTCCC 
               
               
                   
                   
                 CCCCAGCGACGAGCAGCTGAAGAGTGGCACCGCCAGCGTGGTGTGCCTG 
               
               
                   
                   
                 CTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAGGTGGACA 
               
               
                   
                   
                 ACGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGTCACCGAGCAGGACAG 
               
               
                   
                   
                 CAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCG 
               
               
                 SEQ ID NO: 
                 DNA Light 
                 ACTACGAGAAGCATAAGGTGTACGCCTGCGAGGTGACCCACCAGGGCCT 
               
               
                 87 
                 Chain 
                 GTCCAGCCCCGTGACCAAGAGCTTCAACAGGGGCGAGTGC 
               
            
           
           
               
            
               
                 952G04 N92Q 
               
            
           
           
               
               
               
            
               
                 SEQ ID NO: 
                 HCDR1 
                 GFSLSTSGVSVT 
               
               
                 88 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 HCDR2 
                 LIDWDDDKYYSTSLKT 
               
               
                 26 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 HCDR3 
                 TPSGSYGRYFDL 
               
               
                 50 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 HCDR1 
                 TSGVSVT 
               
               
                 89 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 HCDR2 
                 LIDWDDDKYYSTSLKT 
               
               
                 26 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 HCDR3 
                 TPSGSYGRYFDL 
               
               
                 50 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 HCDR1 
                 GFSLSTSGV 
               
               
                 76 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 HCDR2 
                 DWDDD 
               
               
                 30 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 HCDR3 
                 TPSGSYGRYFDL 
               
               
                 50 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 HCDR1 
                 GFSLSTSGVS 
               
               
                 77 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 HCDR2 
                 IDWDDDK 
               
               
                 32 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 HCDR3 
                 ARTPSGSYGRYFDL 
               
               
                 54 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 VH 
                 QVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGVSVTWIRQPPGKALEWLALID 
               
               
                 90 
                   
                 WDDDKYYSTSLKTRLAISKDTSKNQVVLTMTNMDPVDTATYYCARTPSGSYG 
               
               
                   
                   
                 RYFDLWGRGTLVTVSS 
               
               
                 SEQ ID NO: 
                 DNA VH 
                 CAGGTCACCTTGAGGGAGTCTGGTCCTGCGCTGGTGAAACCCACACAGAC 
               
               
                 91 
                   
                 CCTCACACTGACCTGCACCTTCTCTGGGTTCTCACTCAGCACTAGTGGAGT 
               
               
                   
                   
                 GTCTGTGACCTGGATCCGTCAGCCCCCAGGGAAGGCCCTGGAGTGGCTTG 
               
               
                   
                   
                 CACTCATTGATTGGGATGATGATAAATACTACAGCACATCTCTGAAGACCA 
               
               
                   
                   
                 GGCTCGCCATCTCCAAGGACACCTCCAAAAACCAGGTGGTCCTTACAATGA 
               
               
                   
                   
                 CCAACATGGACCCTGTGGACACAGCCACGTATTATTGTGCACGGACCCCTA 
               
               
                   
                   
                 GTGGGAGCTACGGGCGATACTTCGATCTCTGGGGCCGTGGCACCCTGGTC 
               
               
                   
                   
                 ACTGTCTCCTCA 
               
               
                 SEQ ID NO: 
                 Heavy 
                 QVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGVSVTWIRQPPGKALEWLALID 
               
               
                 92 
                 Chain 
                 WDDDKYYSTSLKTRLAISKDTSKNQVVLTMTNMDPVDTATYYCARTPSGSYG 
               
               
                   
                   
                 RYFDLWGRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPCPVT 
               
               
                   
                   
                 VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN 
               
               
                   
                   
                 TKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
               
               
                   
                   
                 VVAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD 
               
               
                   
                   
                 WLNGKEYKCKVSNKALAAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSL 
               
               
                   
                   
                 TCLVKGFYPCDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW 
               
               
                   
                   
                 QQGNVFSCSVMHEALHNHYTQKSLSLSPGK 
               
               
                 SEQ ID NO: 
                 DNA Heavy 
                 CAGGTCACCTTGAGGGAGTCTGGTCCTGCGCTGGTGAAACCCACACAGAC 
               
               
                 93 
                 Chain 
                 CCTCACACTGACCTGCACCTTCTCTGGGTTCTCACTCAGCACTAGTGGAGT 
               
               
                   
                   
                 GTCTGTGACCTGGATCCGTCAGCCCCCAGGGAAGGCCCTGGAGTGGCTTG 
               
               
                   
                   
                 CACTCATTGATTGGGATGATGATAAATACTACAGCACATCTCTGAAGACCA 
               
               
                   
                   
                 GGCTCGCCATCTCCAAGGACACCTCCAAAAACCAGGTGGTCCTTACAATGA 
               
               
                   
                   
                 CCAACATGGACCCTGTGGACACAGCCACGTATTATTGTGCACGGACCCCTA 
               
               
                   
                   
                 GTGGGAGCTACGGGCGATACTTCGATCTCTGGGGCCGTGGCACCCTGGTC 
               
               
                   
                   
                 ACTGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTGTTTCCCCTGGCCCCC 
               
               
                   
                   
                 AGCAGCAAGTCTACTTCCGGCGGAACTGCTGCCCTGGGTTGCCTGGTGAA 
               
               
                   
                   
                 GGACTACTTCCCCTGTCCCGTGACAGTGTCCTGGAACTCTGGGGCTCTGAC 
               
               
                   
                   
                 TTCCGGCGTGCACACCTTCCCCGCCGTGCTGCAGAGCAGCGGCCTGTACA 
               
               
                   
                   
                 GCCTGAGCAGCGTGGTGACAGTGCCCTCCAGCTCTCTGGGAACCCAGACC 
               
               
                   
                   
                 TATATCTGCAACGTGAACCACAAGCCCAGCAACACCAAGGTGGACAAGAG 
               
               
                   
                   
                 AGTGGAGCCCAAGAGCTGCGACAAGACCCACACCTGCCCCCCCTGCCCAG 
               
               
                   
                   
                 CTCCAGAACTGCTGGGAGGGCCTTCCGTGTTCCTGTTCCCCCCCAAGCCCA 
               
               
                   
                   
                 AGGACACCCTGATGATCAGCAGGACCCCCGAGGTGACCTGCGTGGTGGT 
               
               
                   
                   
                 GGCCGTGTCCCACGAGGACCCAGAGGTGAAGTTCAACTGGTACGTGGAC 
               
               
                   
                   
                 GGCGTGGAGGTGCACAACGCCAAGACCAAGCCCAGAGAGGAGCAGTACA 
               
               
                   
                   
                 ACAGCACCTACAGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGACTGG 
               
               
                   
                   
                 CTGAACGGCAAAGAATACAAGTGCAAAGTCTCCAACAAGGCCCTGGCTGC 
               
               
                   
                   
                 CCCAATCGAAAAGACAATCAGCAAGGCCAAGGGCCAGCCACGGGAGCCC 
               
               
                   
                   
                 CAGGTGTACACCCTGCCCCCCAGCCGGGAGGAGATGACCAAGAACCAGG 
               
               
                   
                   
                 TGTCCCTGACCTGTCTGGTGAAGGGCTTCTACCCCTGTGATATCGCCGTGG 
               
               
                   
                   
                 AGTGGGAGAGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCC 
               
               
                   
                   
                 AGTGCTGGACAGCGACGGCAGCTTCTTCCTGTACAGCAAGCTGACCGTGG 
               
               
                   
                   
                 ACAAGTCCAGGTGGCAGCAGGGCAACGTGTTCAGCTGCAGCGTGATGCA 
               
               
                   
                   
                 CGAGGCCCTGCACAACCACTACACCCAGAAGTCCCTGAGCCTGAGCCCCG 
               
               
                   
                   
                 GCAAG 
               
               
                 SEQ ID NO: 
                 LCDR1 
                 RASQSISTWLA 
               
               
                 94 
                 (Combined)  
                   
               
               
                 SEQ ID NO: 
                 LCDR2 
                 EASSLES 
               
               
                 95 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 LCDR3 
                 QQYQSYWT 
               
               
                 82 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 LCDR1 
                 RASQSISTWLA 
               
               
                 94 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 LCDR2 
                 EASSLES 
               
               
                 95 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 LCDR3 
                 QQYQSYWT 
               
               
                 82 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 LCDR1 
                 SQSISTW 
               
               
                 96 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 LCDR2 
                 EAS 
               
               
                 97 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 LCDR3 
                 YQSYW 
               
               
                 83 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 LCDR1 
                 QSISTW 
               
               
                 98 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 LCDR2 
                 EAS 
               
               
                 97 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 LCDR3 
                 QQYQSYWT 
               
               
                 82 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 VL 
                 DIQMTQSPSTLSASVGDRVTITCRASQSISTWLAWYQQKPGKAPKLLIYEASSL 
               
               
                 99 
                   
                 ESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQYQSYWTFGQGTKVEIK 
               
               
                 SEQ ID NO: 
                 DNA VL 
                 GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGAC 
               
               
                 100 
                   
                 AGAGTCACCATCACTTGCCGGGCCAGTCAGAGTATTAGTACCTGGTTGGC 
               
               
                   
                   
                 CTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGAGG 
               
               
                   
                   
                 CGTCTAGTTTAGAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCT 
               
               
                   
                   
                 GGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCA 
               
               
                   
                   
                 ACTTATTACTGCCAACAGTATCAGAGTTATTGGACGTTCGGCCAAGGGACC 
               
               
                   
                   
                 AAGGTGGAAATCAAA 
               
               
                 SEQ ID NO: 
                 Light 
                 DIQMTQSPSTLSASVGDRVTITCRASQSISTWLAWYQQKPGKAPKLLIYEASSL 
               
               
                 101 
                 Chain 
                 ESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQYQSYWTFGQGTKVEIKRT 
               
               
                   
                   
                 VAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQE 
               
               
                   
                   
                 SVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 
               
               
                   
                   
                 GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGAC 
               
               
                   
                   
                 AGAGTCACCATCACTTGCCGGGCCAGTCAGAGTATTAGTACCTGGTTGGC 
               
               
                   
                   
                 CTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGAGG 
               
               
                   
                   
                 CGTCTAGTTTAGAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCT 
               
               
                   
                   
                 GGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCA 
               
               
                   
                   
                 ACTTATTACTGCCAACAGTATCAGAGTTATTGGACGTTCGGCCAAGGGACC 
               
               
                   
                   
                 AAGGTGGAAATCAAACGAACTGTGGCTGCACCAAGCGTGTTCATCTTCCC 
               
               
                   
                   
                 CCCCAGCGACGAGCAGCTGAAGAGTGGCACCGCCAGCGTGGTGTGCCTG 
               
               
                   
                   
                 CTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAGGTGGACA 
               
               
                   
                   
                 ACGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGTCACCGAGCAGGACAG 
               
               
                   
                   
                 CAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCG 
               
               
                 SEQ ID NO: 
                 DNA Light 
                 ACTACGAGAAGCATAAGGTGTACGCCTGCGAGGTGACCCACCAGGG 
               
               
                 102 
                 Chain 
                 GTCCAGCCCCGTGACCAAGAGCTTCAACAGGGGCGAGTGCCCT 
               
            
           
           
               
            
               
                 232 Chimeric 
               
            
           
           
               
               
               
            
               
                 SEQ ID NO: 1 
                 HCDR1 
                 GYTFTNYGIN 
               
               
                   
                 (Combined) 
                   
               
               
                 SEQ ID NO: 2 
                 HCDR2 
                 YIYIGNDYTEYNERFKG 
               
               
                   
                 (Combined) 
                   
               
               
                 SEQ ID NO: 3 
                 HCDR3 
                 LYYGSSLYSYAMDY 
               
               
                   
                 (Combined) 
                   
               
               
                 SEQ ID NO: 4 
                 HCDR1 
                 NYGIN 
               
               
                   
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 2 
                 HCDR2 
                 YIYIGNDYTEYNERFKG 
               
               
                   
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 3 
                 HCDR3 
                 LYYGSSLYSYAMDY 
               
               
                   
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 5 
                 HCDR1 
                 GYTFTNY 
               
               
                   
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 6 
                 HCDR2 
                 YIGNDY 
               
               
                   
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 3 
                 HCDR3 
                 LYYGSSLYSYAMDY 
               
               
                   
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 7 
                 HCDR1 
                 GYTFTNYG 
               
               
                   
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 8 
                 HCDR2 
                 IYIGN 
               
               
                   
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 9 
                 HCDR3 
                 ARLYYGSSLYSYAMDY 
               
               
                   
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 VH 
                 EVQLQQSGAELVRPGSSVKMSCKTSGYTFTNYGINWVKQRPGQGLEWIGYIY 
               
               
                 103 
                   
                 IGNDYTEYNERFKGKATLTSDTSSSTAHIQLNSLTSEDSAIYFCARLYYGSSLYSY 
               
               
                   
                   
                 AMDYWGQGTSVTVSS 
               
               
                 SEQ ID NO: 
                 DNA VH 
                 GAGGTTCAGCTGCAGCAGTCTGGAGCTGAGTTGGTGAGGCCTGGGTCCTC 
               
               
                 104 
                   
                 AGTGAAGATGTCCTGCAAGACTTCTGGATATACATTCACAAACTACGGTAT 
               
               
                   
                   
                 AAACTGGGTGAAGCAGAGGCCTGGACAGGGCCTGGAATGGATTGGATAT 
               
               
                   
                   
                 ATTTATATTGGAAATGATTATACTGAGTACAATGAGAGGTTCAAGGGCAA 
               
               
                   
                   
                 GGCCACACTGACTTCAGACACATCCTCCAGCACAGCCCACATACAACTCAA 
               
               
                   
                   
                 CAGCCTGACATCTGAGGACTCTGCAATCTATTTCTGTGCAAGACTTTACTAC 
               
               
                   
                   
                 GGTAGTAGCCTCTATTCTTATGCTATGGACTACTGGGGTCAAGGAACCTCT 
               
               
                   
                   
                 GTCACAGTCTCCTCT 
               
               
                 SEQ ID NO: 
                 Heavy 
                 EVQLQQSGAELVRPGSSVKMSCKTSGYTFTNYGINWVKQRPGQGLEWIGYIY 
               
               
                 105 
                 Chain 
                 IGNDYTEYNERFKGKATLTSDTSSSTAHIQLNSLTSEDSAIYFCARLYYGSSLYSY 
               
               
                   
                   
                 AMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPCPV 
               
               
                   
                   
                 TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPS 
               
               
                   
                   
                 NTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC 
               
               
                   
                   
                 VVVAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLIVLHQD 
               
               
                   
                   
                 WLNGKEYKCKVSNKALAAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSL 
               
               
                   
                   
                 TCLVKGFYPCDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW 
               
               
                   
                   
                 QQGNVFSCSVMHEALHNHYTQKSLSLSPGK 
               
               
                 SEQ ID NO: 
                 DNA Heavy 
                 GAGGTTCAGCTGCAGCAGTCTGGAGCTGAGTTGGTGAGGCCTGGGTCCTC 
               
               
                 106 
                 Chain 
                 AGTGAAGATGTCCTGCAAGACTTCTGGATATACATTCACAAACTACGGTAT 
               
               
                   
                   
                 AAACTGGGTGAAGCAGAGGCCTGGACAGGGCCTGGAATGGATTGGATAT 
               
               
                   
                   
                 ATTTATATTGGAAATGATTATACTGAGTACAATGAGAGGTTCAAGGGCAA 
               
               
                   
                   
                 GGCCACACTGACTTCAGACACATCCTCCAGCACAGCCCACATACAACTCAA 
               
               
                   
                   
                 CAGCCTGACATCTGAGGACTCTGCAATCTATTTCTGTGCAAGACTTTACTAC 
               
               
                   
                   
                 GGTAGTAGCCTCTATTCTTATGCTATGGACTACTGGGGTCAAGGAACCTCT 
               
               
                   
                   
                 GTCACAGTCTCCTCTGCTAGCACCAAGGGCCCAAGTGTGTTTCCCCTGGCC 
               
               
                   
                   
                 CCCAGCAGCAAGTCTACTTCCGGCGGAACTGCTGCCCTGGGTTGCCTGGT 
               
               
                   
                   
                 GAAGGACTACTTCCCCTGTCCCGTGACAGTGTCCTGGAACTCTGGGGCTCT 
               
               
                   
                   
                 GACTTCCGGCGTGCACACCTTCCCCGCCGTGCTGCAGAGCAGCGGCCTGT 
               
               
                   
                   
                 ACAGCCTGAGCAGCGTGGTGACAGTGCCCTCCAGCTCTCTGGGAACCCAG 
               
               
                   
                   
                 ACCTATATCTGCAACGTGAACCACAAGCCCAGCAACACCAAGGTGGACAA 
               
               
                   
                   
                 GAGAGTGGAGCCCAAGAGCTGCGACAAGACCCACACCTGCCCCCCCTGCC 
               
               
                   
                   
                 CAGCTCCAGAACTGCTGGGAGGGCCTTCCGTGTTCCTGTTCCCCCCCAAGC 
               
               
                   
                   
                 CCAAGGACACCCTGATGATCAGCAGGACCCCCGAGGTGACCTGCGTGGTG 
               
               
                   
                   
                 GTGGCCGTGTCCCACGAGGACCCAGAGGTGAAGTTCAACTGGTACGTGG 
               
               
                   
                   
                 ACGGCGTGGAGGTGCACAACGCCAAGACCAAGCCCAGAGAGGAGCAGTA 
               
               
                   
                   
                 CAACAGCACCTACAGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGACT 
               
               
                   
                   
                 GGCTGAACGGCAAAGAATACAAGTGCAAAGTCTCCAACAAGGCCCTGGCT 
               
               
                   
                   
                 GCCCCAATCGAAAAGACAATCAGCAAGGCCAAGGGCCAGCCACGGGAGC 
               
               
                   
                   
                 CCCAGGTGTACACCCTGCCCCCCAGCCGGGAGGAGATGACCAAGAACCAG 
               
               
                   
                   
                 GTGTCCCTGACCTGTCTGGTGAAGGGCTTCTACCCCTGTGATATCGCCGTG 
               
               
                   
                   
                 GAGTGGGAGAGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCC 
               
               
                   
                   
                 CAGTGCTGGACAGCGACGGCAGCTTCTTCCTGTACAGCAAGCTGACCGTG 
               
               
                   
                   
                 GACAAGTCCAGGTGGCAGCAGGGCAACGTGTTCAGCTGCAGCGTGATGC 
               
               
                   
                   
                 ACGAGGCCCTGCACAACCACTACACCCAGAAGTCCCTGAGCCTGAGCCCC 
               
               
                   
                   
                 GGCAAG 
               
               
                 SEQ ID NO: 
                 LCDR1 
                 RSSKSLLHSSGNTYLY 
               
               
                 14 
                 (Combined)  
                   
               
               
                 SEQ ID NO: 
                 LCDR2 
                 RMSNLAS 
               
               
                 15 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 LCDR3 
                 MQHLEYPYT 
               
               
                 16 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 LCDR1 
                 RSSKSLLHSSGNTYLY 
               
               
                 14 
                 (Ka bat) 
                   
               
               
                 SEQ ID NO: 
                 LCDR2 
                 RMSNLAS 
               
               
                 15 
                 (Ka bat) 
                   
               
               
                 SEQ ID NO: 
                 LCDR3 
                 MQHLEYPYT 
               
               
                 16 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 LCDR1 
                 SKSLLHSSGNTY 
               
               
                 17 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 LCDR2 
                 RMS 
               
               
                 18 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 LCDR3 
                 HLEYPY 
               
               
                 19 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 LCDR1 
                 KSLLHSSGNTY 
               
               
                 20 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 LCDR2 
                 RMS 
               
               
                 18 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 LCDR3 
                 MQHLEYPYT 
               
               
                 16 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 VL 
                 DIVMTQAAPSVSVTPGESVSISCRSSKSLLHSSGNTYLYWFLQRPGQSPQLLIS 
               
               
                 107 
                   
                 RMSNLASGVPDRFSGSGSGTAFTLRISRVEAEDVGVYYCMQHLEYPYTFGGG 
               
               
                   
                   
                 TKLELK 
               
               
                 SEQ ID NO: 
                 DNA VL 
                 GATATTGTGATGACTCAGGCTGCACCCTCTGTATCTGTCACTCCTGGAGAG 
               
               
                 108 
                   
                 TCAGTATCCATCTCCTGCAGGTCTAGTAAGAGTCTCCTCCATAGTAGTGGC 
               
               
                   
                   
                 AACACTTACTTGTATTGGTTCCTGCAGAGGCCAGGCCAGTCTCCTCAGCTC 
               
               
                   
                   
                 CTGATATCTCGGATGTCCAACCTTGCCTCAGGAGTCCCAGACAGGTTCAGT 
               
               
                   
                   
                 GGCAGTGGGTCAGGAACTGCTTTCACACTGAGAATCAGTAGAGTGGAGG 
               
               
                   
                   
                 CTGAGGATGTGGGTGTTTATTATTGTATGCAACATCTAGAATATCCGTACA 
               
               
                   
                   
                 CGTTCGGAGGGGGGACCAAGCTGGAGCTAAAA 
               
               
                 SEQ ID NO: 
                 Light 
                 DIVMTQAAPSVSVTPGESVSISCRSSKSLLHSSGNTYLYWFLQRPGQSPQLLIS 
               
               
                 109 
                 Chain 
                 RMSNLASGVPDRFSGSGSGTAFTLRISRVEAEDVGVYYCMQHLEYPYTFGGG 
               
               
                   
                   
                 TKLELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNAL 
               
               
                   
                   
                 QSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKS 
               
               
                   
                   
                 FNRGEC 
               
               
                 SEQ ID NO: 
                 DNA Light 
                 GATATTGTGATGACTCAGGCTGCACCCTCTGTATCTGTCACTCCTGGAGAG 
               
               
                 110 
                 Chain 
                 TCAGTATCCATCTCCTGCAGGTCTAGTAAGAGTCTCCTCCATAGTAGTGGC 
               
               
                   
                   
                 AACACTTACTTGTATTGGTTCCTGCAGAGGCCAGGCCAGTCTCCTCAGCTC 
               
               
                   
                   
                 CTGATATCTCGGATGTCCAACCTTGCCTCAGGAGTCCCAGACAGGTTCAGT 
               
               
                   
                   
                 GGCAGTGGGTCAGGAACTGCTTTCACACTGAGAATCAGTAGAGTGGAGG 
               
               
                   
                   
                 CTGAGGATGTGGGTGTTTATTATTGTATGCAACATCTAGAATATCCGTACA 
               
               
                   
                   
                 CGTTCGGAGGGGGGACCAAGCTGGAGCTAAAACGTACGGTGGCCGCTCC 
               
               
                   
                   
                 CAGCGTGTTCATCTTCCCCCCCAGCGACGAGCAGCTGAAGAGTGGCACCG 
               
               
                   
                   
                 CCAGCGTGGTGTGCCTGCTGAACAACTTCTACCCCCGGGAGGCCAAGGTG 
               
               
                   
                   
                 CAGTGGAAGGTGGACAACGCCCTGCAGAGCGGCAACAGCCAGGAGAGC 
               
               
                   
                   
                 GTCACCGAGCAGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCT 
               
               
                   
                   
                 GACCCTGAGCAAGGCCGACTACGAGAAGCATAAGGTGTACGCCTGCGAG 
               
               
                   
                   
                 GTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACAGGGG 
               
               
                   
                   
                 CGAGTGC 
               
            
           
           
               
            
               
                 960K03 Parental 
               
            
           
           
               
               
               
            
               
                 SEQ ID NO: 
                 HCDR1 
                 GFSLSTGGMCVS 
               
               
                 111 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 HCDR2 
                 LIDWDDDKYYSTSLKT 
               
               
                 26 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 HCDR3 
                 AHSGSYFDF 
               
               
                 27 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 HCDR1 
                 TGGMCVS 
               
               
                 112 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 HCDR2 
                 LIDWDDDKYYSTSLKT 
               
               
                 26 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 HCDR3 
                 AHSGSYFDF 
               
               
                 27 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 HCDR1 
                 GFSLSTGGM 
               
               
                 29 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 HCDR2 
                 DWDDD 
               
               
                 30 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 HCDR3 
                 AHSGSYFDF 
               
               
                 27 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 HCDR1 
                 GFSLSTGGMC 
               
               
                 113 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 HCDR2 
                 IDWDDDK 
               
               
                 32 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 HCDR3 
                 ARAHSGSYFDF 
               
               
                 33 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 VH 
                 QVTLRESGPALVKPTQTLTLTCTFSGFSLSTGGMCVSWIRQPPGKALEWLALI 
               
               
                 114 
                   
                 DWDDDKYYSTSLKTRLTISKDTSKNQLVLTMTNMDPVDTATYYCARAHSGSY 
               
               
                   
                   
                 FDFWGQGTLVTVSS 
               
               
                 SEQ ID NO: 
                 DNA VH 
                 CAGGTCACCTTGAGGGAGTCTGGTCCTGCGCTGGTGAAACCCACACAGAC 
               
               
                 115 
                   
                 CCTCACACTGACCTGCACCTTCTCTGGGTTCTCACTCAGCACTGGTGGAAT 
               
               
                   
                   
                 GTGTGTGAGCTGGATCCGTCAGCCCCCAGGGAAGGCCCTGGAGTGGCTTG 
               
               
                   
                   
                 CACTCATTGATTGGGATGATGATAAATACTACAGCACATCTCTGAAGACCA 
               
               
                   
                   
                 GGCTCACCATCTCCAAGGACACCTCCAAAAACCAGCTGGTCCTTACAATGA 
               
               
                   
                   
                 CCAACATGGACCCTGTGGACACAGCCACGTATTATTGTGCACGGGCTCATA 
               
               
                   
                   
                 GTGGGAGCTACTTTGACTTCTGGGGCCAGGGAACCCTGGTCACCGTCTCC 
               
               
                   
                   
                 TCA 
               
               
                 SEQ ID NO: 
                 Heavy 
                 QVTLRESGPALVKPTQTLTLTCTFSGFSLSTGGMCVSWIRQPPGKALEWLALI 
               
               
                 116 
                 Chain 
                 DWDDDKYYSTSLKTRLTISKDTSKNQLVLTMTNMDPVDTATYYCARAHSGSY 
               
               
                   
                   
                 FDFWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPCPVTV 
               
               
                   
                   
                 SWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNT 
               
               
                   
                   
                 KVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVV 
               
               
                   
                   
                 VAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL 
               
               
                   
                   
                 NGKEYKCKVSNKALAAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCL 
               
               
                   
                   
                 VKGFYPCDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG 
               
               
                   
                   
                 NVFSCSVMHEALHNHYTQKSLSLSPGK 
               
               
                 SEQ ID NO: 
                 DNA Heavy 
                 CAGGTCACCTTGAGGGAGTCTGGTCCTGCGCTGGTGAAACCCACACAGAC 
               
               
                 117 
                 Chain 
                 CCTCACACTGACCTGCACCTTCTCTGGGTTCTCACTCAGCACTGGTGGAAT 
               
               
                   
                   
                 GTGTGTGAGCTGGATCCGTCAGCCCCCAGGGAAGGCCCTGGAGTGGCTTG 
               
               
                   
                   
                 CACTCATTGATTGGGATGATGATAAATACTACAGCACATCTCTGAAGACCA 
               
               
                   
                   
                 GGCTCACCATCTCCAAGGACACCTCCAAAAACCAGCTGGTCCTTACAATGA 
               
               
                   
                   
                 CCAACATGGACCCTGTGGACACAGCCACGTATTATTGTGCACGGGCTCATA 
               
               
                   
                   
                 GTGGGAGCTACTTTGACTTCTGGGGCCAGGGAACCCTGGTCACCGTCTCC 
               
               
                   
                   
                 TCAGCCTCCACCAAGGGCCCATCGGTGTTTCCCCTGGCCCCCAGCAGCAAG 
               
               
                   
                   
                 TCTACTTCCGGCGGAACTGCTGCCCTGGGTTGCCTGGTGAAGGACTACTTC 
               
               
                   
                   
                 CCCTGTCCCGTGACAGTGTCCTGGAACTCTGGGGCTCTGACTTCCGGCGTG 
               
               
                   
                   
                 CACACCTTCCCCGCCGTGCTGCAGAGCAGCGGCCTGTACAGCCTGAGCAG 
               
               
                   
                   
                 CGTGGTGACAGTGCCCTCCAGCTCTCTGGGAACCCAGACCTATATCTGCAA 
               
               
                   
                   
                 CGTGAACCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTGGAGCCC 
               
               
                   
                   
                 AAGAGCTGCGACAAGACCCACACCTGCCCCCCCTGCCCAGCTCCAGAACT 
               
               
                   
                   
                 GCTGGGAGGGCCTTCCGTGTTCCTGTTCCCCCCCAAGCCCAAGGACACCCT 
               
               
                   
                   
                 GATGATCAGCAGGACCCCCGAGGTGACCTGCGTGGTGGTGGCCGTGTCCC 
               
               
                   
                   
                 ACGAGGACCCAGAGGTGAAGTTCAACTGGTACGTGGACGGCGTGGAGGT 
               
               
                   
                   
                 GCACAACGCCAAGACCAAGCCCAGAGAGGAGCAGTACAACAGCACCTAC 
               
               
                   
                   
                 AGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGACTGGCTGAACGGCA 
               
               
                   
                   
                 AAGAATACAAGTGCAAAGTCTCCAACAAGGCCCTGGCTGCCCCAATCGAA 
               
               
                   
                   
                 AAGACAATCAGCAAGGCCAAGGGCCAGCCACGGGAGCCCCAGGTGTACA 
               
               
                   
                   
                 CCCTGCCCCCCAGCCGGGAGGAGATGACCAAGAACCAGGTGTCCCTGACC 
               
               
                   
                   
                 TGTCTGGTGAAGGGCTTCTACCCCTGTGATATCGCCGTGGAGTGGGAGAG 
               
               
                   
                   
                 CAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCCAGTGCTGGACA 
               
               
                   
                   
                 GCGACGGCAGCTTCTTCCTGTACAGCAAGCTGACCGTGGACAAGTCCAGG 
               
               
                   
                   
                 TGGCAGCAGGGCAACGTGTTCAGCTGCAGCGTGATGCACGAGGCCCTGC 
               
               
                   
                   
                 ACAACCACTACACCCAGAAGTCCCTGAGCCTGAGCCCCGGCAAG 
               
               
                 SEQ ID NO: 
                 LCDR1 
                 RASQRISNWLA 
               
               
                 38 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 LCDR2 
                 KASSLES 
               
               
                 39 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 LCDR3 
                 QQFNSYWT 
               
               
                 118 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 LCDR1 
                 RASQRISNWLA 
               
               
                 38 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 LCDR2 
                 KASSLES 
               
               
                 39 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 LCDR3 
                 QQFNSYWT 
               
               
                 118 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 LCDR1 
                 SQRISNW 
               
               
                 41 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 LCDR2 
                 KAS 
               
               
                 42 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 LCDR3 
                 FNSYW 
               
               
                 119 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 LCDR1 
                 QRISNW 
               
               
                 44 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 LCDR2 
                 KAS 
               
               
                 42 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 LCDR3 
                 QQFNSYWT 
               
               
                 118 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 VL 
                 DIQMTQSPSTLSASVGDRVTITCRASQRISNWLAWYQQKPGKAPKLLIYKASS 
               
               
                 120 
                   
                 LESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQFNSYWTFGQGTKVEIK 
               
               
                 SEQ ID NO: 
                 DNA VL 
                 GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGAC 
               
               
                 121 
                   
                 AGAGTCACCATCACTTGCCGGGCCAGTCAGAGAATTAGTAACTGGTTGGC 
               
               
                   
                   
                 CTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAACTCCTGATCTATAAGG 
               
               
                   
                   
                 CGTCTAGTTTAGAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCT 
               
               
                   
                   
                 GGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCA 
               
               
                   
                   
                 ACTTATTACTGCCAACAGTTTAATAGTTATTGGACGTTCGGCCAAGGGACC 
               
               
                   
                   
                 AAGGTGGAAATCAAA 
               
               
                 SEQ ID NO: 
                 Light 
                 DIQMTQSPSTLSASVGDRVTITCRASQRISNWLAWYQQKPGKAPKLLIYKASS 
               
               
                 122 
                 Chain 
                 LESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQFNSYWTFGQGTKVEIKR 
               
               
                   
                   
                 TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQ 
               
               
                   
                   
                 ESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 
               
               
                 SEQ ID NO: 
                 DNA Light 
                 GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGAC 
               
               
                 123 
                 Chain 
                 AGAGTCACCATCACTTGCCGGGCCAGTCAGAGAATTAGTAACTGGTTGGC 
               
               
                   
                   
                 CTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAACTCCTGATCTATAAGG 
               
               
                   
                   
                 CGTCTAGTTTAGAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCT 
               
               
                   
                   
                 GGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCA 
               
               
                   
                   
                 ACTTATTACTGCCAACAGTTTAATAGTTATTGGACGTTCGGCCAAGGGACC 
               
               
                   
                   
                 AAGGTGGAAATCAAACGAACTGTGGCTGCACCAAGCGTGTTCATCTTCCC 
               
               
                   
                   
                 CCCCAGCGACGAGCAGCTGAAGAGTGGCACCGCCAGCGTGGTGTGCCTG 
               
               
                   
                   
                 CTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAGGTGGACA 
               
               
                   
                   
                 ACGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGTCACCGAGCAGGACAG 
               
               
                   
                   
                 CAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCG 
               
               
                   
                   
                 ACTACGAGAAGCATAAGGTGTACGCCTGCGAGGTGACCCACCAGGGCCT 
               
               
                   
                   
                 GTCCAGCCCCGTGACCAAGAGCTTCAACAGGGGCGAGTGC 
               
            
           
           
               
            
               
                 958N05 Parental 
               
            
           
           
               
               
               
            
               
                 SEQ ID NO: 
                 HCDR1 
                 GFSLSTSGISVS 
               
               
                 49 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 HCDR2 
                 LIDWDDDKYYSTSLKT 
               
               
                 26 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 HCDR3 
                 TPSGSYGRYFDL 
               
               
                 50 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 HCDR1 
                 TSGISVS 
               
               
                 51 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 HCDR2 
                 LIDWDDDKYYSTSLKT 
               
               
                 26 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 HCDR3 
                 TPSGSYGRYFDL 
               
               
                 50 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 HCDR1 
                 GFSLSTSGI 
               
               
                 52 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 HCDR2 
                 DWDDD 
               
               
                 30 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 HCDR3 
                 TPSGSYGRYFDL 
               
               
                 50 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 HCDR1 
                 GFSLSTSGIS 
               
               
                 53 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 HCDR2 
                 IDWDDDK 
               
               
                 32 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 HCDR3 
                 ARTPSGSYGRYFDL 
               
               
                 54 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 VH 
                 QVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGISVSWIRQPPGKALEWLALID 
               
               
                 55 
                   
                 WDDDKYYSTSLKTRLTISKDTSKNQVVLTMTNMDPVDTATYYCARTPSGSYG 
               
               
                   
                   
                 RYFDLWGRGTLVTVSS 
               
               
                 SEQ ID NO: 
                 DNA VH 
                 CAGGTCACCTTGAGGGAGTCTGGTCCTGCGCTGGTGAAACCCACACAGAC 
               
               
                 56 
                   
                 CCTCACACTGACCTGCACCTTCTCTGGGTTCTCACTCAGCACAAGTGGAAT 
               
               
                   
                   
                 ATCTGTGAGCTGGATCCGTCAGCCCCCAGGGAAGGCCCTGGAGTGGCTTG 
               
               
                   
                   
                 CACTCATTGATTGGGATGATGATAAATACTACAGCACATCTCTGAAGACCA 
               
               
                   
                   
                 GGCTCACCATCTCCAAGGACACCTCCAAAAACCAGGTGGTCCTTACAATGA 
               
               
                   
                   
                 CCAACATGGACCCTGTGGACACAGCCACGTATTATTGTGCACGGACCCCTA 
               
               
                   
                   
                 GTGGGAGCTATGGGCGATACTTCGATCTCTGGGGCCGTGGCACCCTGGTC 
               
               
                   
                   
                 ACTGTCTCCTCA 
               
               
                 SEQ ID NO: 
                 Heavy 
                 QVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGISVSWIRQPPGKALEWLALID 
               
               
                 57 
                 Chain 
                 WDDDKYYSTSLKTRLTISKDTSKNQVVLTMTNMDPVDTATYYCARTPSGSYG 
               
               
                   
                   
                 RYFDLWGRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPCPVT 
               
               
                   
                   
                 VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN 
               
               
                   
                   
                 TKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
               
               
                   
                   
                 VVAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD 
               
               
                   
                   
                 WLNGKEYKCKVSNKALAAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSL 
               
               
                   
                   
                 TCLVKGFYPCDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW 
               
               
                   
                   
                 QQGNVFSCSVMHEALHNHYTQKSLSLSPGK 
               
               
                 SEQ ID NO: 
                 DNA Heavy 
                 CAGGTCACCTTGAGGGAGTCTGGTCCTGCGCTGGTGAAACCCACACAGAC 
               
               
                 58 
                 Chain 
                 CCTCACACTGACCTGCACCTTCTCTGGGTTCTCACTCAGCACAAGTGGAAT 
               
               
                   
                   
                 ATCTGTGAGCTGGATCCGTCAGCCCCCAGGGAAGGCCCTGGAGTGGCTTG 
               
               
                   
                   
                 CACTCATTGATTGGGATGATGATAAATACTACAGCACATCTCTGAAGACCA 
               
               
                   
                   
                 GGCTCACCATCTCCAAGGACACCTCCAAAAACCAGGTGGTCCTTACAATGA 
               
               
                   
                   
                 CCAACATGGACCCTGTGGACACAGCCACGTATTATTGTGCACGGACCCCTA 
               
               
                   
                   
                 GTGGGAGCTATGGGCGATACTTCGATCTCTGGGGCCGTGGCACCCTGGTC 
               
               
                   
                   
                 ACTGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTGTTTCCCCTGGCCCCC 
               
               
                   
                   
                 AGCAGCAAGTCTACTTCCGGCGGAACTGCTGCCCTGGGTTGCCTGGTGAA 
               
               
                   
                   
                 GGACTACTTCCCCTGTCCCGTGACAGTGTCCTGGAACTCTGGGGCTCTGAC 
               
               
                   
                   
                 TTCCGGCGTGCACACCTTCCCCGCCGTGCTGCAGAGCAGCGGCCTGTACA 
               
               
                   
                   
                 GCCTGAGCAGCGTGGTGACAGTGCCCTCCAGCTCTCTGGGAACCCAGACC 
               
               
                   
                   
                 TATATCTGCAACGTGAACCACAAGCCCAGCAACACCAAGGTGGACAAGAG 
               
               
                   
                   
                 AGTGGAGCCCAAGAGCTGCGACAAGACCCACACCTGCCCCCCCTGCCCAG 
               
               
                   
                   
                 CTCCAGAACTGCTGGGAGGGCCTTCCGTGTTCCTGTTCCCCCCCAAGCCCA 
               
               
                   
                   
                 AGGACACCCTGATGATCAGCAGGACCCCCGAGGTGACCTGCGTGGTGGT 
               
               
                   
                   
                 GGCCGTGTCCCACGAGGACCCAGAGGTGAAGTTCAACTGGTACGTGGAC 
               
               
                   
                   
                 GGCGTGGAGGTGCACAACGCCAAGACCAAGCCCAGAGAGGAGCAGTACA 
               
               
                   
                   
                 ACAGCACCTACAGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGACTGG 
               
               
                   
                   
                 CTGAACGGCAAAGAATACAAGTGCAAAGTCTCCAACAAGGCCCTGGCTGC 
               
               
                   
                   
                 CCCAATCGAAAAGACAATCAGCAAGGCCAAGGGCCAGCCACGGGAGCCC 
               
               
                   
                   
                 CAGGTGTACACCCTGCCCCCCAGCCGGGAGGAGATGACCAAGAACCAGG 
               
               
                   
                   
                 TGTCCCTGACCTGTCTGGTGAAGGGCTTCTACCCCTGTGATATCGCCGTGG 
               
               
                   
                   
                 AGTGGGAGAGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCC 
               
               
                   
                   
                 AGTGCTGGACAGCGACGGCAGCTTCTTCCTGTACAGCAAGCTGACCGTGG 
               
               
                   
                   
                 ACAAGTCCAGGTGGCAGCAGGGCAACGTGTTCAGCTGCAGCGTGATGCA 
               
               
                   
                   
                 CGAGGCCCTGCACAACCACTACACCCAGAAGTCCCTGAGCCTGAGCCCCG 
               
               
                   
                   
                 GCAAG 
               
               
                 SEQ ID NO: 
                 LCDR1 
                 RASQSISNWLA 
               
               
                 59 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 LCDR2 
                 KASSLES 
               
               
                 39 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 LCDR3 
                 QQYNSYWT 
               
               
                 124 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 LCDR1 
                 RASQSISNWLA 
               
               
                 59 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 LCDR2 
                 KASSLES 
               
               
                 39 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 LCDR3 
                 QQYNSYWT 
               
               
                 124 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 LCDR1 
                 SQSISNW 
               
               
                 61 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 LCDR2 
                 KAS 
               
               
                 42 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 LCDR3 
                 YNSYW 
               
               
                 125 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 LCDR1 
                 QSISNW 
               
               
                 63 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 LCDR2 
                 KAS 
               
               
                 42 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 LCDR3 
                 QQYNSYWT 
               
               
                 124 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 VL 
                 DIQLTQSPSTLSASVGDRVTITCRASQSISNWLAWYQQKPGKAPKLLIYKASSL 
               
               
                 126 
                   
                 ESGVPSRFTGSGSGTEFTLTISSLQPDDFATYYCQQYNSYWTFGQGTKVEIK 
               
               
                 SEQ ID NO: 
                 DNA VL 
                 GACATCCAGTTGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGAC 
               
               
                 127 
                   
                 AGAGTCACCATCACTTGCCGGGCCAGTCAGAGTATTAGTAACTGGTTGGC 
               
               
                   
                   
                 CTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAACTCCTGATCTATAAGG 
               
               
                   
                   
                 CGTCTAGTTTAGAAAGTGGGGTCCCGTCAAGGTTCACCGGCAGTGGATCT 
               
               
                   
                   
                 GGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCA 
               
               
                   
                   
                 ACTTATTACTGCCAACAGTATAATAGTTATTGGACGTTCGGCCAAGGGACC 
               
               
                   
                   
                 AAGGTGGAAATCAAA 
               
               
                 SEQ ID NO: 
                 Light 
                 DIQLTQSPSTLSASVGDRVTITCRASQSISNWLAWYQQKPGKAPKLLIYKASSL 
               
               
                 128 
                 Chain 
                 ESGVPSRFTGSGSGTEFTLTISSLQPDDFATYYCQQYNSYWTFGQGTKVEIKRT 
               
               
                   
                   
                 VAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQE 
               
               
                   
                   
                 SVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 
               
               
                 SEQ ID NO: 
                 DNA Light 
                 GACATCCAGTTGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGAC 
               
               
                 129 
                 Chain 
                 AGAGTCACCATCACTTGCCGGGCCAGTCAGAGTATTAGTAACTGGTTGGC 
               
               
                   
                   
                 CTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAACTCCTGATCTATAAGG 
               
               
                   
                   
                 CGTCTAGTTTAGAAAGTGGGGTCCCGTCAAGGTTCACCGGCAGTGGATCT 
               
               
                   
                   
                 GGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCA 
               
               
                   
                   
                 ACTTATTACTGCCAACAGTATAATAGTTATTGGACGTTCGGCCAAGGGACC 
               
               
                   
                   
                 AAGGTGGAAATCAAACGAACTGTGGCTGCACCAAGCGTGTTCATCTTCCC 
               
               
                   
                   
                 CCCCAGCGACGAGCAGCTGAAGAGTGGCACCGCCAGCGTGGTGTGCCTG 
               
               
                   
                   
                 CTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAGGTGGACA 
               
               
                   
                   
                 ACGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGTCACCGAGCAGGACAG 
               
               
                   
                   
                 CAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCG 
               
               
                   
                   
                 ACTACGAGAAGCATAAGGTGTACGCCTGCGAGGTGACCCACCAGGGCCT 
               
               
                   
                   
                 GTCCAGCCCCGTGACCAAGAGCTTCAACAGGGGCGAGTGC 
               
            
           
           
               
            
               
                 952P16 Parental 
               
            
           
           
               
               
               
            
               
                 SEQ ID NO: 
                 HCDR1 
                 GFSLSTSGVSVS 
               
               
                 74 
                 (Combined)  
                   
               
               
                 SEQ ID NO: 
                 HCDR2 
                 LIDWDDDKYYSTSLKT 
               
               
                 26 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 HCDR3 
                 TPSGSYGRYFDL 
               
               
                 50 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 HCDR1 
                 TSGVSVS 
               
               
                 75 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 HCDR2 
                 LIDWDDDKYYSTSLKT 
               
               
                 26 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 HCDR3 
                 TPSGSYGRYFDL 
               
               
                 50 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 HCDR1 
                 GFSLSTSGV 
               
               
                 76 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 HCDR2 
                 DWDDD 
               
               
                 30 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 HCDR3 
                 TPSGSYGRYFDL 
               
               
                 50 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 HCDR1 
                 GFSLSTSGVS 
               
               
                 77 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 HCDR2 
                 IDWDDDK 
               
               
                 32 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 HCDR3 
                 ARTPSGSYGRYFDL 
               
               
                 54 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 VH 
                 QVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGVSVSWIRQPPGKALEWLALID 
               
               
                 78 
                   
                 WDDDKYYSTSLKTRLTISKDTSKNQVVLTMTNMDPVDTATYYCARTPSGSYG 
               
               
                   
                   
                 RYFDLWGRGTLVTVSS 
               
               
                 SEQ ID NO: 
                 DNA VH 
                 CAGGTCACCTTGAGGGAGTCTGGTCCTGCGCTGGTGAAACCCACACAGAC 
               
               
                 79 
                   
                 CCTCACACTGACCTGCACCTTCTCTGGGTTCTCACTCAGCACTAGTGGAGT 
               
               
                   
                   
                 GTCTGTGAGTTGGATCCGTCAGCCCCCAGGGAAGGCCCTGGAGTGGCTTG 
               
               
                   
                   
                 CACTCATTGATTGGGATGATGATAAATACTACAGCACATCTCTGAAGACCA 
               
               
                   
                   
                 GGCTCACCATCTCCAAGGACACCTCCAAAAACCAGGTGGTCCTTACAATGA 
               
               
                   
                   
                 CCAACATGGACCCTGTGGACACAGCCACGTACTATTGTGCACGGACCCCTA 
               
               
                   
                   
                 GTGGGAGCTACGGGCGATACTTCGATCTCTGGGGCCGTGGCACCCTGGTC 
               
               
                   
                   
                 ACTGTCTCCTCA 
               
               
                 SEQ ID NO: 
                 Heavy 
                 QVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGVSVSWIRQPPGKALEWLALID 
               
               
                 80 
                 Chain 
                 WDDDKYYSTSLKTRLTISKDTSKNQVVLTMTNMDPVDTATYYCARTPSGSYG 
               
               
                   
                   
                 RYFDLWGRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPCPVT 
               
               
                   
                   
                 VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN 
               
               
                   
                   
                 TKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
               
               
                   
                   
                 VVAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD 
               
               
                   
                   
                 WLNGKEYKCKVSNKALAAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSL 
               
               
                   
                   
                 TCLVKGFYPCDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSW 
               
               
                   
                   
                 QQGNVFSCSVMHEALHNHYTQKSLSLSPGK 
               
               
                 SEQ ID NO: 
                 DNA Heavy 
                 CAGGTCACCTTGAGGGAGTCTGGTCCTGCGCTGGTGAAACCCACACAGAC 
               
               
                 81 
                 Chain 
                 CCTCACACTGACCTGCACCTTCTCTGGGTTCTCACTCAGCACTAGTGGAGT 
               
               
                   
                   
                 GTCTGTGAGTTGGATCCGTCAGCCCCCAGGGAAGGCCCTGGAGTGGCTTG 
               
               
                   
                   
                 CACTCATTGATTGGGATGATGATAAATACTACAGCACATCTCTGAAGACCA 
               
               
                   
                   
                 GGCTCACCATCTCCAAGGACACCTCCAAAAACCAGGTGGTCCTTACAATGA 
               
               
                   
                   
                 CCAACATGGACCCTGTGGACACAGCCACGTACTATTGTGCACGGACCCCTA 
               
               
                   
                   
                 GTGGGAGCTACGGGCGATACTTCGATCTCTGGGGCCGTGGCACCCTGGTC 
               
               
                   
                   
                 ACTGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTGTTTCCCCTGGCCCCC 
               
               
                   
                   
                 AGCAGCAAGTCTACTTCCGGCGGAACTGCTGCCCTGGGTTGCCTGGTGAA 
               
               
                   
                   
                 GGACTACTTCCCCTGTCCCGTGACAGTGTCCTGGAACTCTGGGGCTCTGAC 
               
               
                   
                   
                 TTCCGGCGTGCACACCTTCCCCGCCGTGCTGCAGAGCAGCGGCCTGTACA 
               
               
                   
                   
                 GCCTGAGCAGCGTGGTGACAGTGCCCTCCAGCTCTCTGGGAACCCAGACC 
               
               
                   
                   
                 TATATCTGCAACGTGAACCACAAGCCCAGCAACACCAAGGTGGACAAGAG 
               
               
                   
                   
                 AGTGGAGCCCAAGAGCTGCGACAAGACCCACACCTGCCCCCCCTGCCCAG 
               
               
                   
                   
                 CTCCAGAACTGCTGGGAGGGCCTTCCGTGTTCCTGTTCCCCCCCAAGCCCA 
               
               
                   
                   
                 AGGACACCCTGATGATCAGCAGGACCCCCGAGGTGACCTGCGTGGTGGT 
               
               
                   
                   
                 GGCCGTGTCCCACGAGGACCCAGAGGTGAAGTTCAACTGGTACGTGGAC 
               
               
                   
                   
                 GGCGTGGAGGTGCACAACGCCAAGACCAAGCCCAGAGAGGAGCAGTACA 
               
               
                   
                   
                 ACAGCACCTACAGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGACTGG 
               
               
                   
                   
                 CTGAACGGCAAAGAATACAAGTGCAAAGTCTCCAACAAGGCCCTGGCTGC 
               
               
                   
                   
                 CCCAATCGAAAAGACAATCAGCAAGGCCAAGGGCCAGCCACGGGAGCCC 
               
               
                   
                   
                 CAGGTGTACACCCTGCCCCCCAGCCGGGAGGAGATGACCAAGAACCAGG 
               
               
                   
                   
                 TGTCCCTGACCTGTCTGGTGAAGGGCTTCTACCCCTGTGATATCGCCGTGG 
               
               
                   
                   
                 AGTGGGAGAGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCC 
               
               
                   
                   
                 AGTGCTGGACAGCGACGGCAGCTTCTTCCTGTACAGCAAGCTGACCGTGG 
               
               
                   
                   
                 ACAAGTCCAGGTGGCAGCAGGGCAACGTGTTCAGCTGCAGCGTGATGCA 
               
               
                   
                   
                 CGAGGCCCTGCACAACCACTACACCCAGAAGTCCCTGAGCCTGAGCCCCG 
               
               
                   
                   
                 GCAAG 
               
               
                 SEQ ID NO: 
                 LCDR1 
                 RASQSISNWLA 
               
               
                 59 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 LCDR2 
                 KASSLES 
               
               
                 39 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 LCDR3 
                 QQYNSYWT 
               
               
                 124 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 LCDR1 
                 RASQSISNWLA 
               
               
                 59 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 LCDR2 
                 KASSLES 
               
               
                 39 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 LCDR3 
                 QQYNSYWT 
               
               
                 124 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 LCDR1 
                 SQSISNW 
               
               
                 61 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 LCDR2 
                 KAS 
               
               
                 42 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 LCDR3 
                 YNSYW 
               
               
                 125 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 LCDR1 
                 QSISNW 
               
               
                 63 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 LCDR2 
                 KAS 
               
               
                 42 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 LCDR3 
                 QQYNSYWT 
               
               
                 124 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 VL 
                 DIQMTQSPSTLSASVGDRVTITCRASQSISNWLAWYQQKPGKAPKLLIYKASS 
               
               
                 130 
                   
                 LESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQYNSYWTFGQGTKVEIK 
               
               
                 SEQ ID NO: 
                 DNA VL 
                 GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGAC 
               
               
                 131 
                   
                 AGAGTCACCATCACTTGCCGGGCCAGTCAGAGTATTAGTAACTGGTTGGC 
               
               
                   
                   
                 CTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATAAGG 
               
               
                   
                   
                 CGTCTAGTTTAGAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCT 
               
               
                   
                   
                 GGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCA 
               
               
                   
                   
                 ACTTATTACTGCCAACAGTATAATAGTTATTGGACGTTCGGCCAAGGGACC 
               
               
                   
                   
                 AAGGTGGAAATCAAA 
               
               
                 SEQ ID NO: 
                 Light 
                 DIQMTQSPSTLSASVGDRVTITCRASQSISNWLAWYQQKPGKAPKLLIYKASS 
               
               
                 132 
                 Chain 
                 LESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQYNSYWTFGQGTKVEIKR 
               
               
                   
                   
                 TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQ 
               
               
                   
                   
                 ESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 
               
               
                 SEQ ID NO: 
                 DNA Light 
                 GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGAC 
               
               
                 133 
                 Chain 
                 AGAGTCACCATCACTTGCCGGGCCAGTCAGAGTATTAGTAACTGGTTGGC 
               
               
                   
                   
                 CTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATAAGG 
               
               
                   
                   
                 CGTCTAGTTTAGAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCT 
               
               
                   
                   
                 vGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCA 
               
               
                   
                   
                 ACTTATTACTGCCAACAGTATAATAGTTATTGGACGTTCGGCCAAGGGACC 
               
               
                   
                   
                 AAGGTGGAAATCAAACGAACTGTGGCTGCACCAAGCGTGTTCATCTTCCC 
               
               
                   
                   
                 CCCCAGCGACGAGCAGCTGAAGAGTGGCACCGCCAGCGTGGTGTGCCTG 
               
               
                   
                   
                 CTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAGGTGGACA 
               
               
                   
                   
                 ACGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGTCACCGAGCAGGACAG 
               
               
                   
                   
                 CAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCG 
               
               
                   
                   
                 ACTACGAGAAGCATAAGGTGTACGCCTGCGAGGTGACCCACCAGGGCCT 
               
               
                   
                   
                 GTCCAGCCCCGTGACCAAGAGCTTCAACAGGGGCGAGTGC 
               
            
           
           
               
            
               
                 952G04 Parental 
               
            
           
           
               
               
               
            
               
                 SEQ ID NO: 
                 HCDR1 
                 GFSLSTSGVSVT 
               
               
                 88 
                 (Combined)  
                   
               
               
                 SEQ ID NO: 
                 HCDR2 
                 LIDWDDDKYYSTSLKT 
               
               
                 26 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 HCDR3 
                 TPSGSYGRYFDL 
               
               
                 50 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 HCDR1 
                 TSGVSVT 
               
               
                 89 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 HCDR2 
                 LIDWDDDKYYSTSLKT 
               
               
                 26 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 HCDR3 
                 TPSGSYGRYFDL 
               
               
                 50 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 HCDR1 
                 GFSLSTSGV 
               
               
                 76 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 HCDR2 
                 DWDDD 
               
               
                 30 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 HCDR3 
                 TPSGSYGRYFDL 
               
               
                 50 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 HCDR1 
                 GFSLSTSGVS 
               
               
                 77 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 HCDR2 
                 IDWDDDK 
               
               
                 32 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 HCDR3 
                 ARTPSGSYGRYFDL 
               
               
                 54 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 VH 
                 QVTLRESG PALVKPTQTLTLTCTFSGFSLSTSGVSVTWIRQPPGKALEWLALID 
               
               
                 90 
                   
                 WDDDKYYSTSLKTRLAISKDTSKNQVVLTMTNMDPVDTATYYCARTPSGSYG 
               
               
                   
                   
                 RYFDLWGRGTLVTVSS 
               
               
                 SEQ ID NO: 
                 DNA VH 
                 CAGGTCACCTTGAGGGAGTCTGGTCCTGCGCTGGTGAAACCCACACAGAC 
               
               
                 91 
                   
                 CCTCACACTGACCTGCACCTTCTCTGGGTTCTCACTCAGCACTAGTGGAGT 
               
               
                   
                   
                 GTCTGTGACCTGGATCCGTCAGCCCCCAGGGAAGGCCCTGGAGTGGCTTG 
               
               
                   
                   
                 CACTCATTGATTGGGATGATGATAAATACTACAGCACATCTCTGAAGACCA 
               
               
                   
                   
                 GGCTCGCCATCTCCAAGGACACCTCCAAAAACCAGGTGGTCCTTACAATGA 
               
               
                   
                   
                 CCAACATGGACCCTGTGGACACAGCCACGTATTATTGTGCACGGACCCCTA 
               
               
                   
                   
                 GTGGGAGCTACGGGCGATACTTCGATCTCTGGGGCCGTGGCACCCTGGTC 
               
               
                   
                   
                 ACTGTCTCCTCA 
               
               
                 SEQ ID NO: 
                 Heavy 
                 QVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGVSVTWIRQPPGKALEWLALID 
               
               
                 92 
                 Chain 
                 WDDDKYYSTSLKTRLAISKDTSKNQVVLTMTNMDPVDTATYYCARTPSGSYG 
               
               
                   
                   
                 RYFDLWGRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPCPVT 
               
               
                   
                   
                 VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN 
               
               
                   
                   
                 TKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
               
               
                   
                   
                 VVAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD 
               
               
                   
                   
                 WLNGKEYKCKVSNKALAAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSL 
               
               
                   
                   
                 TCLVKGFYPCDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW 
               
               
                   
                   
                 QQGNVFSCSVMHEALHNHYTQKSLSLSPGK 
               
               
                 SEQ ID NO: 
                 DNA Heavy 
                 CAGGTCACCTTGAGGGAGTCTGGTCCTGCGCTGGTGAAACCCACACAGAC 
               
               
                 93 
                 Chain 
                 CCTCACACTGACCTGCACCTTCTCTGGGTTCTCACTCAGCACTAGTGGAGT 
               
               
                   
                   
                 GTCTGTGACCTGGATCCGTCAGCCCCCAGGGAAGGCCCTGGAGTGGCTTG 
               
               
                   
                   
                 CACTCATTGATTGGGATGATGATAAATACTACAGCACATCTCTGAAGACCA 
               
               
                   
                   
                 GGCTCGCCATCTCCAAGGACACCTCCAAAAACCAGGTGGTCCTTACAATGA 
               
               
                   
                   
                 CCAACATGGACCCTGTGGACACAGCCACGTATTATTGTGCACGGACCCCTA 
               
               
                   
                   
                 GTGGGAGCTACGGGCGATACTTCGATCTCTGGGGCCGTGGCACCCTGGTC 
               
               
                   
                   
                 ACTGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTGTTTCCCCTGGCCCCC 
               
               
                   
                   
                 AGCAGCAAGTCTACTTCCGGCGGAACTGCTGCCCTGGGTTGCCTGGTGAA 
               
               
                   
                   
                 GGACTACTTCCCCTGTCCCGTGACAGTGTCCTGGAACTCTGGGGCTCTGAC 
               
               
                   
                   
                 TTCCGGCGTGCACACCTTCCCCGCCGTGCTGCAGAGCAGCGGCCTGTACA 
               
               
                   
                   
                 GCCTGAGCAGCGTGGTGACAGTGCCCTCCAGCTCTCTGGGAACCCAGACC 
               
               
                   
                   
                 TATATCTGCAACGTGAACCACAAGCCCAGCAACACCAAGGTGGACAAGAG 
               
               
                   
                   
                 AGTGGAGCCCAAGAGCTGCGACAAGACCCACACCTGCCCCCCCTGCCCAG 
               
               
                   
                   
                 CTCCAGAACTGCTGGGAGGGCCTTCCGTGTTCCTGTTCCCCCCCAAGCCCA 
               
               
                   
                   
                 AGGACACCCTGATGATCAGCAGGACCCCCGAGGTGACCTGCGTGGTGGT 
               
               
                   
                   
                 GGCCGTGTCCCACGAGGACCCAGAGGTGAAGTTCAACTGGTACGTGGAC 
               
               
                   
                   
                 GGCGTGGAGGTGCACAACGCCAAGACCAAGCCCAGAGAGGAGCAGTACA 
               
               
                   
                   
                 ACAGCACCTACAGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGACTGG 
               
               
                   
                   
                 CTGAACGGCAAAGAATACAAGTGCAAAGTCTCCAACAAGGCCCTGGCTGC 
               
               
                   
                   
                 CCCAATCGAAAAGACAATCAGCAAGGCCAAGGGCCAGCCACGGGAGCCC 
               
               
                   
                   
                 CAGGTGTACACCCTGCCCCCCAGCCGGGAGGAGATGACCAAGAACCAGG 
               
               
                   
                   
                 TGTCCCTGACCTGTCTGGTGAAGGGCTTCTACCCCTGTGATATCGCCGTGG 
               
               
                   
                   
                 AGTGGGAGAGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCC 
               
               
                   
                   
                 AGTGCTGGACAGCGACGGCAGCTTCTTCCTGTACAGCAAGCTGACCGTGG 
               
               
                   
                   
                 ACAAGTCCAGGTGGCAGCAGGGCAACGTGTTCAGCTGCAGCGTGATGCA 
               
               
                   
                   
                 CGAGGCCCTGCACAACCACTACACCCAGAAGTCCCTGAGCCTGAGCCCCG 
               
               
                   
                   
                 GCAAG 
               
               
                 SEQ ID NO: 
                 LCDR1 
                 RASQSISTWLA 
               
               
                 94 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 LCDR2 
                 EASSLES 
               
               
                 95 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 LCDR3 
                 QQYNSYWT 
               
               
                 124 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 LCDR1 
                 RASQSISTWLA 
               
               
                 94 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 LCDR2 
                 EASSLES 
               
               
                 95 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 LCDR3 
                 QQYNSYWT 
               
               
                 124 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 LCDR1 
                 SQSISTW 
               
               
                 96 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 LCDR2 
                 EAS 
               
               
                 97 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 LCDR3 
                 YNSYW 
               
               
                 125 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 LCDR1 
                 QSISTW 
               
               
                 98 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 LCDR2 
                 EAS 
               
               
                 97 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 LCDR3 
                 QQYNSYWT 
               
               
                 124 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 VL 
                 DIQMTQSPSTLSASVGDRVTITCRASQSISTWLAWYQQKPGKAPKLLIYEASSL 
               
               
                 134 
                   
                 ESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQYNSYWTFGQGTKVEIK 
               
               
                 SEQ ID NO: 
                 DNA VL 
                 GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGAC 
               
               
                 135 
                   
                 AGAGTCACCATCACTTGCCGGGCCAGTCAGAGTATTAGTACCTGGTTGGC 
               
               
                   
                   
                 CTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGAGG 
               
               
                   
                   
                 CGTCTAGTTTAGAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCT 
               
               
                   
                   
                 GGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCA 
               
               
                   
                   
                 ACTTATTACTGCCAACAGTATAATAGTTATTGGACGTTCGGCCAAGGGACC 
               
               
                   
                   
                 AAGGTGGAAATCAAA 
               
               
                 SEQ ID NO: 
                 Light 
                 DIQMTQSPSTLSASVGDRVTITCRASQSISTWLAWYQQKPGKAPKLLIYEASSL 
               
               
                 136 
                 Chain 
                 ESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQYNSYWTFGQGTKVEIKRT 
               
               
                   
                   
                 VAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQE 
               
               
                   
                   
                 SVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 
               
               
                 SEQ ID NO: 
                 DNA Light 
                 GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGAC 
               
               
                 137 
                 Chain 
                 AGAGTCACCATCACTTGCCGGGCCAGTCAGAGTATTAGTACCTGGTTGGC 
               
               
                   
                   
                 CTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGAGG 
               
               
                   
                   
                 CGTCTAGTTTAGAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCT 
               
               
                   
                   
                 GGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCA 
               
               
                   
                   
                 ACTTATTACTGCCAACAGTATAATAGTTATTGGACGTTCGGCCAAGGGACC 
               
               
                   
                   
                 AAGGTGGAAATCAAACGAACTGTGGCTGCACCAAGCGTGTTCATCTTCCC 
               
               
                   
                   
                 CCCCAGCGACGAGCAGCTGAAGAGTGGCACCGCCAGCGTGGTGTGCCTG 
               
               
                   
                   
                 CTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAGGTGGACA 
               
               
                   
                   
                 ACGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGTCACCGAGCAGGACAG 
               
               
                   
                   
                 CAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCG 
               
               
                   
                   
                 ACTACGAGAAGCATAAGGTGTACGCCTGCGAGGTGACCCACCAGGGCCT 
               
               
                   
                   
                 GTCCAGCCCCGTGACCAAGAGCTTCAACAGGGGCGAGTGC 
               
            
           
           
               
            
               
                 892D15 Parental  
               
            
           
           
               
               
               
            
               
                 SEQ ID NO: 
                 HCDR1 
                 GFSPSTSGMSVS 
               
               
                 138 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 HCDR2 
                 LIDWDDDKYFSTSLKT 
               
               
                 139 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 HCDR3 
                 AHSGSYFDY 
               
               
                 140 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 HCDR1 
                 TSGMSVS 
               
               
                 141 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 HCDR2 
                 LIDWDDDKYFSTSLKT 
               
               
                 139 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 HCDR3 
                 AHSGSYFDY 
               
               
                 140 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 HCDR1 
                 GFSPSTSGM 
               
               
                 142 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 HCDR2 
                 DWDDD 
               
               
                 30 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 HCDR3 
                 AHSGSYFDY 
               
               
                 140 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 HCDR1 
                 GFSPSTSGMS 
               
               
                 143 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 HCDR2 
                 IDWDDDK 
               
               
                 32 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 HCDR3 
                 ARAHSGSYFDY 
               
               
                 144 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 VH 
                 QVTLRESGPALVKPTQTLTLTCTFSGFSPSTSGMSVSWIRQPPGKALEWLALID 
               
               
                 145 
                   
                 WDDDKYFSTSLKTRLTISKDTSKNQVVLTMTNMDPVDTATYYCARAHSGSYF 
               
               
                   
                   
                 DYWGQGTLVTVSS 
               
               
                 SEQ ID NO: 
                 DNA VH 
                 CAGGTCACCTTGAGGGAGTCTGGTCCTGCGCTGGTGAAACCCACACAGAC 
               
               
                 146 
                   
                 CCTCACACTGACCTGCACCTTCTCTGGGTTCTCACCCAGCACTAGTGGAAT 
               
               
                   
                   
                 GTCTGTGAGCTGGATCCGTCAGCCCCCAGGGAAGGCCCTGGAGTGGCTTG 
               
               
                   
                   
                 CACTTATTGATTGGGATGATGATAAATACTTTAGCACATCTCTGAAGACCA 
               
               
                   
                   
                 GGCTCACCATCTCCAAGGACACCTCCAAAAACCAGGTGGTCCTTACAATGA 
               
               
                   
                   
                 CCAACATGGACCCTGTAGACACAGCCACGTATTATTGTGCACGGGCCCATA 
               
               
                   
                   
                 GTGGGAGCTACTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCC 
               
               
                   
                   
                 TCA 
               
               
                 SEQ ID NO: 
                 Heavy 
                 QVTLRESGPALVKPTQTLTLTCTFSGFSPSTSGMSVSWIRQPPGKALEWLALID 
               
               
                 147 
                 Chain 
                 WDDDKYFSTSLKTRLTISKDTSKNQVVLTMTNMDPVDTATYYCARAHSGSYF 
               
               
                   
                   
                 DYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPCPVTVS 
               
               
                   
                   
                 WNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTK 
               
               
                   
                   
                 VDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVV 
               
               
                   
                   
                 AVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLN 
               
               
                   
                   
                 GKEYKCKVSNKALAAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV 
               
               
                   
                   
                 KGFYPCDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN 
               
               
                   
                   
                 VFSCSVMHEALHNHYTQKSLSLSPGK 
               
               
                 SEQ ID NO: 
                 DNA Heavy 
                 CAGGTCACCTTGAGGGAGTCTGGTCCTGCGCTGGTGAAACCCACACAGAC 
               
               
                 148 
                 Chain 
                 CCTCACACTGACCTGCACCTTCTCTGGGTTCTCACCCAGCACTAGTGGAAT 
               
               
                   
                   
                 GTCTGTGAGCTGGATCCGTCAGCCCCCAGGGAAGGCCCTGGAGTGGCTTG 
               
               
                   
                   
                 CACTTATTGATTGGGATGATGATAAATACTTTAGCACATCTCTGAAGACCA 
               
               
                   
                   
                 GGCTCACCATCTCCAAGGACACCTCCAAAAACCAGGTGGTCCTTACAATGA 
               
               
                   
                   
                 CCAACATGGACCCTGTAGACACAGCCACGTATTATTGTGCACGGGCCCATA 
               
               
                   
                   
                 GTGGGAGCTACTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCC 
               
               
                   
                   
                 TCAGCCTCCACCAAGGGCCCATCGGTGTTTCCCCTGGCCCCCAGCAGCAAG 
               
               
                   
                   
                 TCTACTTCCGGCGGAACTGCTGCCCTGGGTTGCCTGGTGAAGGACTACTTC 
               
               
                   
                   
                 CCCTGTCCCGTGACAGTGTCCTGGAACTCTGGGGCTCTGACTTCCGGCGTG 
               
               
                   
                   
                 CACACCTTCCCCGCCGTGCTGCAGAGCAGCGGCCTGTACAGCCTGAGCAG 
               
               
                   
                   
                 CGTGGTGACAGTGCCCTCCAGCTCTCTGGGAACCCAGACCTATATCTGCAA 
               
               
                   
                   
                 CGTGAACCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTGGAGCCC 
               
               
                   
                   
                 AAGAGCTGCGACAAGACCCACACCTGCCCCCCCTGCCCAGCTCCAGAACT 
               
               
                   
                   
                 GCTGGGAGGGCCTTCCGTGTTCCTGTTCCCCCCCAAGCCCAAGGACACCCT 
               
               
                   
                   
                 GATGATCAGCAGGACCCCCGAGGTGACCTGCGTGGTGGTGGCCGTGTCCC 
               
               
                   
                   
                 ACGAGGACCCAGAGGTGAAGTTCAACTGGTACGTGGACGGCGTGGAGGT 
               
               
                   
                   
                 GCACAACGCCAAGACCAAGCCCAGAGAGGAGCAGTACAACAGCACCTAC 
               
               
                   
                   
                 AGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGACTGGCTGAACGGCA 
               
               
                   
                   
                 AAGAATACAAGTGCAAAGTCTCCAACAAGGCCCTGGCTGCCCCAATCGAA 
               
               
                   
                   
                 AAGACAATCAGCAAGGCCAAGGGCCAGCCACGGGAGCCCCAGGTGTACA 
               
               
                   
                   
                 CCCTGCCCCCCAGCCGGGAGGAGATGACCAAGAACCAGGTGTCCCTGACC 
               
               
                   
                   
                 TGTCTGGTGAAGGGCTTCTACCCCTGTGATATCGCCGTGGAGTGGGAGAG 
               
               
                   
                   
                 CAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCCAGTGCTGGACA 
               
               
                   
                   
                 GCGACGGCAGCTTCTTCCTGTACAGCAAGCTGACCGTGGACAAGTCCAGG 
               
               
                   
                   
                 TGGCAGCAGGGCAACGTGTTCAGCTGCAGCGTGATGCACGAGGCCCTGC 
               
               
                   
                   
                 ACAACCACTACACCCAGAAGTCCCTGAGCCTGAGCCCCGGCAAG 
               
               
                 SEQ ID NO: 
                 LCDR1 
                 RASQSISNWLA 
               
               
                 59 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 LCDR2 
                 KASSLES 
               
               
                 39 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 LCDR3 
                 QQFNSYWT 
               
               
                 118 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 LCDR1 
                 RASQSISNWLA 
               
               
                 59 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 LCDR2 
                 KASSLES 
               
               
                 39 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 LCDR3 
                 QQFNSYWT 
               
               
                 118 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 LCDR1 
                 SQSISNW 
               
               
                 61 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 LCDR2 
                 KAS 
               
               
                 42 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 LCDR3 
                 FNSYW 
               
               
                 119 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 LCDR1 
                 QSISNW 
               
               
                 63 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 LCDR2 
                 KAS 
               
               
                 42 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 LCDR3 
                 QQFNSYWT 
               
               
                 118 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 VL 
                 DIQMTQSPSTLSASVGDRVTITCRASQSISNWLAWYQQKPGKAPKLLIYKASS 
               
               
                 149 
                   
                 LESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQFNSYWTFGQGTKVEIK 
               
               
                 SEQ ID NO: 
                 DNA VL 
                 GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGAC 
               
               
                 150 
                   
                 AGAGTCACCATCACTTGCCGGGCCAGTCAGAGTATTAGTAACTGGTTGGC 
               
               
                   
                   
                 CTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAACTCCTGATCTATAAGG 
               
               
                   
                   
                 CGTCTAGTTTAGAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCT 
               
               
                   
                   
                 GGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCA 
               
               
                   
                   
                 ACTTATTACTGCCAACAGTTTAATAGTTATTGGACGTTCGGCCAAGGGACC 
               
               
                   
                   
                 AAGGTGGAAATCAAA 
               
               
                 SEQ ID NO: 
                 Light 
                 DIQMTQSPSTLSASVGDRVTITCRASQSISNWLAWYQQKPGKAPKLLIYKASS 
               
               
                 151 
                 Chain 
                 LESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQFNSYWTFGQGTKVEIKR 
               
               
                   
                   
                 TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQ 
               
               
                   
                   
                 ESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 
               
               
                 SEQ ID NO: 
                 DNA Light 
                 GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGAC 
               
               
                 152 
                 Chain 
                 AGAGTCACCATCACTTGCCGGGCCAGTCAGAGTATTAGTAACTGGTTGGC 
               
               
                   
                   
                 CTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAACTCCTGATCTATAAGG 
               
               
                   
                   
                 CGTCTAGTTTAGAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCT 
               
               
                   
                   
                 GGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCA 
               
               
                   
                   
                 ACTTATTACTGCCAACAGTTTAATAGTTATTGGACGTTCGGCCAAGGGACC 
               
               
                   
                   
                 AAGGTGGAAATCAAACGAACTGTGGCTGCACCAAGCGTGTTCATCTTCCC 
               
               
                   
                   
                 CCCCAGCGACGAGCAGCTGAAGAGTGGCACCGCCAGCGTGGTGTGCCTG 
               
               
                   
                   
                 CTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAGGTGGACA 
               
               
                   
                   
                 ACGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGTCACCGAGCAGGACAG 
               
               
                   
                   
                 CAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCG 
               
               
                   
                   
                 ACTACGAGAAGCATAAGGTGTACGCCTGCGAGGTGACCCACCAGGGCCT 
               
               
                   
                   
                 GTCCAGCCCCGTGACCAAGAGCTTCAACAGGGGCGAGTGC 
               
            
           
           
               
            
               
                 914M09 Parental 
               
            
           
           
               
               
               
            
               
                 SEQ ID NO: 
                 HCDR1 
                 GGSISSYYWN 
               
               
                 153 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 HCDR2 
                 RIYTSGSTNYNPSLKS 
               
               
                 154 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 HCDR3 
                 DSGGFYYYYGMDV 
               
               
                 155 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 HCDR1 
                 SYYWN 
               
               
                 156 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 HCDR2 
                 RIYTSGSTNYNPSLKS 
               
               
                 154 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 HCDR3 
                 DSGGFYYYYGMDV 
               
               
                 155 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 HCDR1 
                 GGSISSY 
               
               
                 157 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 HCDR2 
                 YTSGS 
               
               
                 158 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 HCDR3 
                 DSGGFYYYYGMDV 
               
               
                 155 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 HCDR1 
                 GGSISSYY 
               
               
                 159 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 HCDR2 
                 IYTSGST 
               
               
                 160 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 HCDR3 
                 ARDSGGFYYYYGMDV 
               
               
                 161 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 VH 
                 QVQLQESGPGLVKPSETLSLTCAVSGGSISSYYWNLIRQPAGKGLEWIGRIYTS 
               
               
                 162 
                   
                 GSTNYNPSLKSRVTMSVDTSKNQFSLKLSSVTAADTAVYYCARDSGGFYYYYG 
               
               
                   
                   
                 MDVWGQGTTVTVSS 
               
               
                 SEQ ID NO: 
                 DNA VH 
                 CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGA 
               
               
                 163 
                   
                 CCCTGTCCCTCACCTGCGCTGTCTCTGGTGGCTCCATCAGTAGTTACTACTG 
               
               
                   
                   
                 GAACTTAATCCGGCAGCCCGCCGGGAAGGGACTGGAGTGGATTGGGCGT 
               
               
                   
                   
                 ATCTATACCAGTGGGAGCACCAACTACAACCCCTCCCTCAAGAGTCGAGTC 
               
               
                   
                   
                 ACCATGTCAGTAGACACGTCCAAGAACCAGTTCTCCCTGAAGCTGAGCTCT 
               
               
                   
                   
                 GTGACCGCCGCGGACACGGCCGTGTATTACTGTGCGAGAGACTCCGGGG 
               
               
                   
                   
                 GGTTCTACTACTACTACGGTATGGACGTCTGGGGCCAAGGGACCACGGTC 
               
               
                   
                   
                 ACCGTCTCCTCA 
               
               
                 SEQ ID NO: 
                 Heavy 
                 QVQLQESGPGLVKPSETLSLTCAVSGGSISSYYWNLIRQPAGKGLEWIGRIYTS 
               
               
                 164 
                 Chain 
                 GSTNYNPSLKSRVTMSVDTSKNQFSLKLSSVTAADTAVYYCARDSGGFYYYYG 
               
               
                   
                   
                 MDVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPCPVT 
               
               
                   
                   
                 VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN 
               
               
                   
                   
                 TKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
               
               
                   
                   
                 VVAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD 
               
               
                   
                   
                 WLNGKEYKCKVSNKALAAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSL 
               
               
                   
                   
                 TCLVKGFYPCDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW 
               
               
                   
                   
                 QQGNVFSCSVMHEALHNHYTQKSLSLSPGK 
               
               
                 SEQ ID NO: 
                 DNA Heavy 
                 CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGA 
               
               
                 165 
                 Chain 
                 CCCTGTCCCTCACCTGCGCTGTCTCTGGTGGCTCCATCAGTAGTTACTACTG 
               
               
                   
                   
                 GAACTTAATCCGGCAGCCCGCCGGGAAGGGACTGGAGTGGATTGGGCGT 
               
               
                   
                   
                 ATCTATACCAGTGGGAGCACCAACTACAACCCCTCCCTCAAGAGTCGAGTC 
               
               
                   
                   
                 ACCATGTCAGTAGACACGTCCAAGAACCAGTTCTCCCTGAAGCTGAGCTCT 
               
               
                   
                   
                 GTGACCGCCGCGGACACGGCCGTGTATTACTGTGCGAGAGACTCCGGGG 
               
               
                   
                   
                 GGTTCTACTACTACTACGGTATGGACGTCTGGGGCCAAGGGACCACGGTC 
               
               
                   
                   
                 ACCGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTGTTTCCCCTGGCCCCC 
               
               
                   
                   
                 AGCAGCAAGTCTACTTCCGGCGGAACTGCTGCCCTGGGTTGCCTGGTGAA 
               
               
                   
                   
                 GGACTACTTCCCCTGTCCCGTGACAGTGTCCTGGAACTCTGGGGCTCTGAC 
               
               
                   
                   
                 TTCCGGCGTGCACACCTTCCCCGCCGTGCTGCAGAGCAGCGGCCTGTACA 
               
               
                   
                   
                 GCCTGAGCAGCGTGGTGACAGTGCCCTCCAGCTCTCTGGGAACCCAGACC 
               
               
                   
                   
                 TATATCTGCAACGTGAACCACAAGCCCAGCAACACCAAGGTGGACAAGAG 
               
               
                   
                   
                 AGTGGAGCCCAAGAGCTGCGACAAGACCCACACCTGCCCCCCCTGCCCAG 
               
               
                   
                   
                 CTCCAGAACTGCTGGGAGGGCCTTCCGTGTTCCTGTTCCCCCCCAAGCCCA 
               
               
                   
                   
                 AGGACACCCTGATGATCAGCAGGACCCCCGAGGTGACCTGCGTGGTGGT 
               
               
                   
                   
                 GGCCGTGTCCCACGAGGACCCAGAGGTGAAGTTCAACTGGTACGTGGAC 
               
               
                   
                   
                 GGCGTGGAGGTGCACAACGCCAAGACCAAGCCCAGAGAGGAGCAGTACA 
               
               
                   
                   
                 ACAGCACCTACAGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGACTGG 
               
               
                   
                   
                 CTGAACGGCAAAGAATACAAGTGCAAAGTCTCCAACAAGGCCCTGGCTGC 
               
               
                   
                   
                 CCCAATCGAAAAGACAATCAGCAAGGCCAAGGGCCAGCCACGGGAGCCC 
               
               
                   
                   
                 CAGGTGTACACCCTGCCCCCCAGCCGGGAGGAGATGACCAAGAACCAGG 
               
               
                   
                   
                 TGTCCCTGACCTGTCTGGTGAAGGGCTTCTACCCCTGTGATATCGCCGTGG 
               
               
                   
                   
                 AGTGGGAGAGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCC 
               
               
                   
                   
                 AGTGCTGGACAGCGACGGCAGCTTCTTCCTGTACAGCAAGCTGACCGTGG 
               
               
                   
                   
                 ACAAGTCCAGGTGGCAGCAGGGCAACGTGTTCAGCTGCAGCGTGATGCA 
               
               
                   
                   
                 CGAGGCCCTGCACAACCACTACACCCAGAAGTCCCTGAGCCTGAGCCCCG 
               
               
                   
                   
                 GCAAG 
               
               
                 SEQ ID NO: 
                 LCDR1 
                 RASQGISSYLA 
               
               
                 166 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 LCDR2 
                 AASTLQG 
               
               
                 167 
                 (Combined)  
                   
               
               
                 SEQ ID NO: 
                 LCDR3 
                 QQLNSYPWT 
               
               
                 168 
                 (Combined)  
                   
               
               
                 SEQ ID NO: 
                 LCDR1 
                 RASQGISSYLA 
               
               
                 166 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 LCDR2 
                 AASTLQG 
               
               
                 167 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 LCDR3 
                 QQLNSYPWT 
               
               
                 168 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 LCDR1 
                 SQGISSY 
               
               
                 169 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 LCDR2 
                 AAS 
               
               
                 170 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 LCDR3 
                 LNSYPW 
               
               
                 171 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 LCDR1 
                 QGISSY 
               
               
                 172 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 LCDR2 
                 AASTLQGGVP 
               
               
                 173 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 LCDR3 
                 QQLNSYPWT 
               
               
                 168 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 VL 
                 DIQLTQSPSFLSASVGDRVTITCRASQGISSYLAWYQQKPGKAPKLLIYAASTLQ 
               
               
                 174 
                   
                 GGVPSRFSGSGSGTEFTLTISSLQPEDFATYHCQQLNSYPWTFGQGTKVEIK 
               
               
                   
                   
                 GACATCCAGTTGACCCAGTCTCCATCCTTCCTGTCTGCATCTGTAGGAGAC 
               
               
                   
                   
                 AGAGTCACCATCACTTGCCGGGCCAGTCAGGGCATTAGCAGTTATTTAGCC 
               
               
                   
                   
                 TGGTATCAGCAAAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGC 
               
               
                   
                   
                 ATCCACCTTGCAAGGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTG 
               
               
                   
                   
                 GGACAGAATTCACTCTCACAATCAGCAGCCTGCAGCCTGAAGATTTTGCAA 
               
               
                 SEQ ID NO: 
                 DNA VL 
                 CTTATCACTGTCAACAGCTTAATAGTTACCCGTGGACGTTCGGCCAAGGGA 
               
               
                 175 
                   
                 CCAAGGTGGAAATCAAA 
               
               
                 SEQ ID NO: 
                 Light 
                 DIQLTQSPSFLSASVGDRVTITCRASQGISSYLAWYQQKPGKAPKLLIYAASTLQ 
               
               
                 176 
                 Chain 
                 GGVPSRFSGSGSGTEFTLTISSLQPEDFATYHCQQLNSYPWTFGQGTKVEIKRT 
               
               
                   
                   
                 VAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQE 
               
               
                   
                   
                 SVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 
               
               
                   
                   
                 GACATCCAGTTGACCCAGTCTCCATCCTTCCTGTCTGCATCTGTAGGAGAC 
               
               
                   
                   
                 AGAGTCACCATCACTTGCCGGGCCAGTCAGGGCATTAGCAGTTATTTAGCC 
               
               
                   
                   
                 TGGTATCAGCAAAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGC 
               
               
                   
                   
                 ATCCACCTTGCAAGGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTG 
               
               
                   
                   
                 GGACAGAATTCACTCTCACAATCAGCAGCCTGCAGCCTGAAGATTTTGCAA 
               
               
                   
                   
                 CTTATCACTGTCAACAGCTTAATAGTTACCCGTGGACGTTCGGCCAAGGGA 
               
               
                   
                   
                 CCAAGGTGGAAATCAAACGAACTGTGGCTGCACCAAGCGTGTTCATCTTC 
               
               
                   
                   
                 CCCCCCAGCGACGAGCAGCTGAAGAGTGGCACCGCCAGCGTGGTGTGCCT 
               
               
                   
                   
                 GCTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAGGTGGAC 
               
               
                   
                   
                 AACGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGTCACCGAGCAGGACA 
               
               
                   
                   
                 GCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCC 
               
               
                 SEQ ID NO: 
                 DNA Light 
                 GACTACGAGAAGCATAAGGTGTACGCCTGCGAGGTGACCCACCAGGGCC 
               
               
                 177 
                 Chain 
                 TGTCCAGCCCCGTGACCAAGAGCTTCAACAGGGGCGAGTGC 
               
            
           
           
               
            
               
                 906C18 Parental 
               
            
           
           
               
               
               
            
               
                 SEQ ID NO: 
                 HCDR1 
                 GFTFNNYWMN 
               
               
                 178 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 HCDR2 
                 NIRQDGSEKYYVDSVKG 
               
               
                 179 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 HCDR3 
                 ERAYCSTTSCPDYSNDY 
               
               
                 180 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 HCDR1 
                 NYWMN 
               
               
                 181 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 HCDR2 
                 NIRQDGSEKYYVDSVKG 
               
               
                 179 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 HCDR3 
                 ERAYCSTTSCPDYSNDY 
               
               
                 180 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 HCDR1 
                 GFTFNNY 
               
               
                 182 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 HCDR2 
                 RQDGSE 
               
               
                 183 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 HCDR3 
                 ERAYCSTTSCPDYSNDY 
               
               
                 180 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 HCDR1 
                 GFTFNNYW 
               
               
                 184 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 HCDR2 
                 IRQDGSEK 
               
               
                 185 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 HCDR3 
                 ARERAYCSTTSCPDYSNDY 
               
               
                 186 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 VH 
                 EVQLVESGGGLVQPGGSLRLSCAASGFTFNNYWMNWVRQAPGKGLEWVA 
               
               
                 187 
                   
                 NIRQDGSEKYYVDSVKGRFTISRDNAKNSLFLQMNSLRAEDTAVYYCARERAY 
               
               
                   
                   
                 CSTTSCPDYSNDYWGQGTLVTVSS 
               
               
                 SEQ ID NO: 
                 DNA VH 
                 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGT 
               
               
                 188 
                   
                 CCCTGAGGCTCTCCTGTGCAGCCTCTGGATTCACCTTTAATAACTATTGGAT 
               
               
                   
                   
                 GAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTGGCCAAC 
               
               
                   
                   
                 ATAAGACAAGATGGAAGTGAAAAATACTATGTGGACTCTGTGAAGGGCC 
               
               
                   
                   
                 GATTCACCATCTCCAGAGACAACGCCAAGAACTCACTGTTTCTACAAATGA 
               
               
                   
                   
                 ACAGCCTGAGAGCCGAGGACACGGCTGTATATTACTGTGCGAGAGAGAG 
               
               
                   
                   
                 GGCCTATTGTAGTACTACCAGCTGCCCTGACTACAGTAATGACTACTGGGG 
               
               
                   
                   
                 CCAGGGAACCCTGGTCACCGTCTCCTCA 
               
               
                 SEQ ID NO: 
                 Heavy 
                 EVQLVESGGGLVQPGGSLRLSCAASGFTFNNYWMNWVRQAPGKGLEWVA 
               
               
                 189 
                 Chain 
                 NIRQDGSEKYYVDSVKGRFTISRDNAKNSLFLQMNSLRAEDTAVYYCARERAY 
               
               
                   
                   
                 CSTTSCPDYSNDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV 
               
               
                   
                   
                 KDYFPCPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC 
               
               
                   
                   
                 NVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMI 
               
               
                   
                   
                 SRTPEVTCVVVAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVS 
               
               
                   
                   
                 VLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQPREPQVYTLPPSREE 
               
               
                   
                   
                 MTKNQVSLTCLVKGFYPCDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKL 
               
               
                   
                   
                 TVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 
               
               
                 SEQ ID NO: 
                 DNA Heavy 
                 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGT 
               
               
                 190 
                 Chain 
                 CCCTGAGGCTCTCCTGTGCAGCCTCTGGATTCACCTTTAATAACTATTGGAT 
               
               
                   
                   
                 GAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTGGCCAAC 
               
               
                   
                   
                 ATAAGACAAGATGGAAGTGAAAAATACTATGTGGACTCTGTGAAGGGCC 
               
               
                   
                   
                 GATTCACCATCTCCAGAGACAACGCCAAGAACTCACTGTTTCTACAAATGA 
               
               
                   
                   
                 ACAGCCTGAGAGCCGAGGACACGGCTGTATATTACTGTGCGAGAGAGAG 
               
               
                   
                   
                 GGCCTATTGTAGTACTACCAGCTGCCCTGACTACAGTAATGACTACTGGGG 
               
               
                   
                   
                 CCAGGGAACCCTGGTCACCGTCTCCTCAGCCTCCACCAAGGGCCCATCGGT 
               
               
                   
                   
                 GTTTCCCCTGGCCCCCAGCAGCAAGTCTACTTCCGGCGGAACTGCTGCCCT 
               
               
                   
                   
                 GGGTTGCCTGGTGAAGGACTACTTCCCCTGTCCCGTGACAGTGTCCTGGA 
               
               
                   
                   
                 ACTCTGGGGCTCTGACTTCCGGCGTGCACACCTTCCCCGCCGTGCTGCAGA 
               
               
                   
                   
                 GCAGCGGCCTGTACAGCCTGAGCAGCGTGGTGACAGTGCCCTCCAGCTCT 
               
               
                   
                   
                 CTGGGAACCCAGACCTATATCTGCAACGTGAACCACAAGCCCAGCAACAC 
               
               
                   
                   
                 CAAGGTGGACAAGAGAGTGGAGCCCAAGAGCTGCGACAAGACCCACACC 
               
               
                   
                   
                 TGCCCCCCCTGCCCAGCTCCAGAACTGCTGGGAGGGCCTTCCGTGTTCCTG 
               
               
                   
                   
                 TTCCCCCCCAAGCCCAAGGACACCCTGATGATCAGCAGGACCCCCGAGGT 
               
               
                   
                   
                 GACCTGCGTGGTGGTGGCCGTGTCCCACGAGGACCCAGAGGTGAAGTTC 
               
               
                   
                   
                 AACTGGTACGTGGACGGCGTGGAGGTGCACAACGCCAAGACCAAGCCCA 
               
               
                   
                   
                 GAGAGGAGCAGTACAACAGCACCTACAGGGTGGTGTCCGTGCTGACCGT 
               
               
                   
                   
                 GCTGCACCAGGACTGGCTGAACGGCAAAGAATACAAGTGCAAAGTCTCCA 
               
               
                   
                   
                 ACAAGGCCCTGGCTGCCCCAATCGAAAAGACAATCAGCAAGGCCAAGGG 
               
               
                   
                   
                 CCAGCCACGGGAGCCCCAGGTGTACACCCTGCCCCCCAGCCGGGAGGAG 
               
               
                   
                   
                 ATGACCAAGAACCAGGTGTCCCTGACCTGTCTGGTGAAGGGCTTCTACCCC 
               
               
                   
                   
                 TGTGATATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAACT 
               
               
                   
                   
                 ACAAGACCACCCCCCCAGTGCTGGACAGCGACGGCAGCTTCTTCCTGTACA 
               
               
                   
                   
                 GCAAGCTGACCGTGGACAAGTCCAGGTGGCAGCAGGGCAACGTGTTCAG 
               
               
                   
                   
                 CTGCAGCGTGATGCACGAGGCCCTGCACAACCACTACACCCAGAAGTCCC 
               
               
                   
                   
                 TGAGCCTGAGCCCCGGCAAG 
               
               
                 SEQ ID NO: 
                 LCDR1 
                 RASQTINNNLA 
               
               
                 191 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 LCDR2 
                 GASTGAT 
               
               
                 192 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 LCDR3 
                 QQYNNWPRGLT 
               
               
                 193 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 LCDR1 
                 RASQTINNNLA 
               
               
                 191 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 LCDR2 
                 GASTGAT 
               
               
                 192 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 LCDR3 
                 QQYNNWPRGLT 
               
               
                 193 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 LCDR1 
                 SQTINNN 
               
               
                 194 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 LCDR2 
                 GAS 
               
               
                 195 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 LCDR3 
                 YNNWPRGL 
               
               
                 196 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 LCDR1 
                 QTINNN 
               
               
                 197 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 LCDR2 
                 GASTGATGIP 
               
               
                 198 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 LCDR3 
                 QQYNNWPRGLT 
               
               
                 193 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 VL 
                 EIVMTQSPATLSVSPGERATLSCRASQTINNNLAWFQQKPGQTPRLLIYGAST 
               
               
                 199 
                   
                 GATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYNNWPRGLTFGGGTKV 
               
               
                   
                   
                 EIK 
               
               
                 SEQ ID NO: 
                 DNA VL 
                 GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCTGTGTCTCCAGGGGA 
               
               
                 200 
                   
                 AAGAGCCACCCTCTCCTGCAGGGCCAGTCAGACTATTAACAACAACTTAGC 
               
               
                   
                   
                 CTGGTTCCAGCAGAAACCTGGCCAGACTCCCAGGCTCCTCATCTATGGTGC 
               
               
                   
                   
                 ATCCACCGGGGCCACTGGTATCCCAGCCAGGTTCAGTGGCAGTGGGTCTG 
               
               
                   
                   
                 GGACAGAGTTCACTCTCACCATCAGCAGCCTGCAGTCTGAAGATTTTGCAG 
               
               
                   
                   
                 TTTATTACTGTCAGCAGTATAATAACTGGCCTCGAGGACTCACTTTCGGCG 
               
               
                   
                   
                 GAGGGACCAAGGTGGAGATCAAA 
               
               
                 SEQ ID NO: 
                 Light 
                 EIVMTQSPATLSVSPGERATLSCRASQTINNNLAWFQQKPGQTPRLLIYGAST 
               
               
                 201 
                 Chain 
                 GATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYNNWPRGLTFGGGTKV 
               
               
                   
                   
                 EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSG 
               
               
                   
                   
                 NSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNR 
               
               
                   
                   
                 GEC 
               
               
                 SEQ ID NO: 
                 DNA Light 
                 GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCTGTGTCTCCAGGGGA 
               
               
                 202 
                 Chain 
                 AAGAGCCACCCTCTCCTGCAGGGCCAGTCAGACTATTAACAACAACTTAGC 
               
               
                   
                   
                 CTGGTTCCAGCAGAAACCTGGCCAGACTCCCAGGCTCCTCATCTATGGTGC 
               
               
                   
                   
                 ATCCACCGGGGCCACTGGTATCCCAGCCAGGTTCAGTGGCAGTGGGTCTG 
               
               
                   
                   
                 GGACAGAGTTCACTCTCACCATCAGCAGCCTGCAGTCTGAAGATTTTGCAG 
               
               
                   
                   
                 TTTATTACTGTCAGCAGTATAATAACTGGCCTCGAGGACTCACTTTCGGCG 
               
               
                   
                   
                 GAGGGACCAAGGTGGAGATCAAACGAACTGTGGCTGCACCAAGCGTGTT 
               
               
                   
                   
                 CATCTTCCCCCCCAGCGACGAGCAGCTGAAGAGTGGCACCGCCAGCGTGG 
               
               
                   
                   
                 TGTGCCTGCTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAG 
               
               
                   
                   
                 GTGGACAACGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGTCACCGAGC 
               
               
                   
                   
                 AGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGC 
               
               
                   
                   
                 AAGGCCGACTACGAGAAGCATAAGGTGTACGCCTGCGAGGTGACCCACC 
               
               
                   
                   
                 AGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACAGGGGCGAGTGC 
               
            
           
           
               
            
               
                 956E02 Parental 
               
            
           
           
               
               
               
            
               
                 SEQ ID NO: 
                 HCDR1 
                 GYTFTGYYIN 
               
               
                 203 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 HCDR2 
                 WINPNSGDTNYAQKFQG 
               
               
                 204 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 HCDR3 
                 ENSGYGKLFDY 
               
               
                 205 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 HCDR1 
                 GYYIN 
               
               
                 206 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 HCDR2 
                 WINPNSGDTNYAQKFQG 
               
               
                 204 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 HCDR3 
                 ENSGYGKLFDY 
               
               
                 205 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 HCDR1 
                 GYTFTGY 
               
               
                 207 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 HCDR2 
                 NPNSGD 
               
               
                 208 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 HCDR3 
                 ENSGYGKLFDY 
               
               
                 205 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 HCDR1 
                 GYTFTGYY 
               
               
                 209 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 HCDR2 
                 INPNSGDT 
               
               
                 210 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 HCDR3 
                 ARENSGYGKLFDY 
               
               
                 211 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 VH 
                 QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYINWVRQAPGQGLEWMG 
               
               
                 212 
                   
                 WINPNSGDTNYAQKFQGRVTMTRDPSISTAYMELSRLRSDDTAVYYCARENS 
               
               
                   
                   
                 GYGKLFDYWGQGTLVTVSS 
               
               
                 SEQ ID NO: 
                 DNA VH 
                 CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGCCT 
               
               
                 213 
                   
                 CAGTGAAGGTCTCCTGCAAGGCTTCTGGATACACCTTCACCGGCTACTATA 
               
               
                   
                   
                 TAAATTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGATG 
               
               
                   
                   
                 GATCAACCCTAACAGTGGTGACACAAACTATGCACAGAAGTTTCAGGGCA 
               
               
                   
                   
                 GGGTCACCATGACCAGGGACCCGTCCATCAGCACAGCCTACATGGAGCTG 
               
               
                   
                   
                 AGCAGGCTGAGATCTGACGACACGGCCGTGTATTACTGTGCGAGAGAGA 
               
               
                   
                   
                 ATAGTGGCTACGGGAAGCTTTTTGACTACTGGGGCCAGGGAACCCTGGTC 
               
               
                   
                   
                 ACCGTCTCCTCA 
               
               
                 SEQ ID NO: 
                 Heavy 
                 QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYINWVRQAPGQGLEWMG 
               
               
                 214 
                 Chain 
                 WINPNSGDTNYAQKFQGRVTMTRDPSISTAYMELSRLRSDDTAVYYCARENS 
               
               
                   
                   
                 GYGKLFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFP 
               
               
                   
                   
                 CPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH 
               
               
                   
                   
                 KPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPE 
               
               
                   
                   
                 VTCVVVAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVL 
               
               
                   
                   
                 HQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQPREPQVYTLPPSREEMTKN 
               
               
                   
                   
                 QVSLTCLVKGFYPCDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDK 
               
               
                   
                   
                 SRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 
               
               
                 SEQ ID NO: 
                 DNA Heavy 
                 CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGCCT 
               
               
                 215 
                 Chain 
                 CAGTGAAGGTCTCCTGCAAGGCTTCTGGATACACCTTCACCGGCTACTATA 
               
               
                   
                   
                 TAAATTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGATG 
               
               
                   
                   
                 GATCAACCCTAACAGTGGTGACACAAACTATGCACAGAAGTTTCAGGGCA 
               
               
                   
                   
                 GGGTCACCATGACCAGGGACCCGTCCATCAGCACAGCCTACATGGAGCTG 
               
               
                   
                   
                 AGCAGGCTGAGATCTGACGACACGGCCGTGTATTACTGTGCGAGAGAGA 
               
               
                   
                   
                 ATAGTGGCTACGGGAAGCTTTTTGACTACTGGGGCCAGGGAACCCTGGTC 
               
               
                   
                   
                 ACCGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTGTTTCCCCTGGCCCCC 
               
               
                   
                   
                 AGCAGCAAGTCTACTTCCGGCGGAACTGCTGCCCTGGGTTGCCTGGTGAA 
               
               
                   
                   
                 GGACTACTTCCCCTGTCCCGTGACAGTGTCCTGGAACTCTGGGGCTCTGAC 
               
               
                   
                   
                 TTCCGGCGTGCACACCTTCCCCGCCGTGCTGCAGAGCAGCGGCCTGTACA 
               
               
                   
                   
                 GCCTGAGCAGCGTGGTGACAGTGCCCTCCAGCTCTCTGGGAACCCAGACC 
               
               
                   
                   
                 TATATCTGCAACGTGAACCACAAGCCCAGCAACACCAAGGTGGACAAGAG 
               
               
                   
                   
                 AGTGGAGCCCAAGAGCTGCGACAAGACCCACACCTGCCCCCCCTGCCCAG 
               
               
                   
                   
                 CTCCAGAACTGCTGGGAGGGCCTTCCGTGTTCCTGTTCCCCCCCAAGCCCA 
               
               
                   
                   
                 AGGACACCCTGATGATCAGCAGGACCCCCGAGGTGACCTGCGTGGTGGT 
               
               
                   
                   
                 GGCCGTGTCCCACGAGGACCCAGAGGTGAAGTTCAACTGGTACGTGGAC 
               
               
                   
                   
                 GGCGTGGAGGTGCACAACGCCAAGACCAAGCCCAGAGAGGAGCAGTACA 
               
               
                   
                   
                 ACAGCACCTACAGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGACTGG 
               
               
                   
                   
                 CTGAACGGCAAAGAATACAAGTGCAAAGTCTCCAACAAGGCCCTGGCTGC 
               
               
                   
                   
                 CCCAATCGAAAAGACAATCAGCAAGGCCAAGGGCCAGCCACGGGAGCCC 
               
               
                   
                   
                 CAGGTGTACACCCTGCCCCCCAGCCGGGAGGAGATGACCAAGAACCAGG 
               
               
                   
                   
                 TGTCCCTGACCTGTCTGGTGAAGGGCTTCTACCCCTGTGATATCGCCGTGG 
               
               
                   
                   
                 AGTGGGAGAGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCC 
               
               
                   
                   
                 AGTGCTGGACAGCGACGGCAGCTTCTTCCTGTACAGCAAGCTGACCGTGG 
               
               
                   
                   
                 ACAAGTCCAGGTGGCAGCAGGGCAACGTGTTCAGCTGCAGCGTGATGCA 
               
               
                   
                   
                 CGAGGCCCTGCACAACCACTACACCCAGAAGTCCCTGAGCCTGAGCCCCG 
               
               
                   
                   
                 GCAAG 
               
               
                 SEQ ID NO: 
                 LCDR1 
                 RSSQSLLHSNGYNYLD 
               
               
                 216 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 LCDR2 
                 LGSNRAS 
               
               
                 217 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 LCDR3 
                 MQALQTPYT 
               
               
                 218 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 LCDR1 
                 RSSQSLLHSNGYNYLD 
               
               
                 216 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 LCDR2 
                 LGSNRAS 
               
               
                 217 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 LCDR3 
                 MQALQTPYT 
               
               
                 218 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 LCDR1 
                 SQSLLHSNGYNY 
               
               
                 219 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 LCDR2 
                 LGS 
               
               
                 220 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 LCDR3 
                 ALQTPY 
               
               
                 221 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 LCDR1 
                 QSLLHSNGYNY 
               
               
                 222 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 LCDR2 
                 LGS 
               
               
                 220 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 LCDR3 
                 MQALQTPYT 
               
               
                 218 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 VL 
                 DIVMTQSPLSLPGTPGEPASISCRSSQSLLHSNGYNYLDWYLQKPGQSPQFLIY 
               
               
                 223 
                   
                 LGSNRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQALQTPYTFGQG 
               
               
                   
                   
                 TKLEIK 
               
               
                 SEQ ID NO: 
                 DNA VL 
                 GATATTGTGATGACTCAGTCTCCACTCTCCCTGCCCGGCACCCCTGGAGAG 
               
               
                 224 
                   
                 CCGGCCTCCATCTCCTGCAGGTCTAGTCAGAGCCTCCTGCATAGTAATGGA 
               
               
                   
                   
                 TACAACTATTTGGATTGGTACCTGCAGAAGCCAGGGCAGTCTCCACAGTTC 
               
               
                   
                   
                 CTGATCTATTTGGGTTCTAATCGGGCCTCCGGGGTCCCTGACAGGTTCAGT 
               
               
                   
                   
                 GGCAGTGGATCAGGCACAGATTTTACACTGAAAATCAGCAGAGTGGAGG 
               
               
                   
                   
                 CTGAGGATGTTGGGGTTTATTACTGCATGCAAGCTCTACAAACTCCGTACA 
               
               
                   
                   
                 CTTTTGGCCAGGGGACCAAGCTGGAGATCAAA 
               
               
                 SEQ ID NO: 
                 Light 
                 DIVMTQSPLSLPGTPGEPASISCRSSQSLLHSNGYNYLDWYLQKPGQSPQFLIY 
               
               
                 225 
                 Chain 
                 LGSNRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQALQTPYTFGQG 
               
               
                   
                   
                 TKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNAL 
               
               
                   
                   
                 QSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKS 
               
               
                   
                   
                 FNRGEC 
               
               
                 SEQ ID NO: 
                 DNA Light 
                 GATATTGTGATGACTCAGTCTCCACTCTCCCTGCCCGGCACCCCTGGAGAG 
               
               
                 226 
                 Chain 
                 CCGGCCTCCATCTCCTGCAGGTCTAGTCAGAGCCTCCTGCATAGTAATGGA 
               
               
                   
                   
                 TACAACTATTTGGATTGGTACCTGCAGAAGCCAGGGCAGTCTCCACAGTTC 
               
               
                   
                   
                 CTGATCTATTTGGGTTCTAATCGGGCCTCCGGGGTCCCTGACAGGTTCAGT 
               
               
                   
                   
                 GGCAGTGGATCAGGCACAGATTTTACACTGAAAATCAGCAGAGTGGAGG 
               
               
                   
                   
                 CTGAGGATGTTGGGGTTTATTACTGCATGCAAGCTCTACAAACTCCGTACA 
               
               
                   
                   
                 CTTTTGGCCAGGGGACCAAGCTGGAGATCAAACGAACTGTGGCTGCACCA 
               
               
                   
                   
                 AGCGTGTTCATCTTCCCCCCCAGCGACGAGCAGCTGAAGAGTGGCACCGC 
               
               
                   
                   
                 CAGCGTGGTGTGCCTGCTGAACAACTTCTACCCCCGGGAGGCCAAGGTGC 
               
               
                   
                   
                 AGTGGAAGGTGGACAACGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGT 
               
               
                   
                   
                 CACCGAGCAGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGA 
               
               
                   
                   
                 CCCTGAGCAAGGCCGACTACGAGAAGCATAAGGTGTACGCCTGCGAGGT 
               
               
                   
                   
                 GACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACAGGGGCG 
               
               
                   
                   
                 AGTGC 
               
            
           
           
               
            
               
                 942K11 Parental 
               
            
           
           
               
               
               
            
               
                 SEQ ID NO: 
                 HCDR1 
                 GGSISSYYWT 
               
               
                 227 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 HCDR2 
                 RVFTSESTNYNPSLKN 
               
               
                 228 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 HCDR3 
                 DRGTYLGGFDP 
               
               
                 229 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 HCDR1 
                 SYYWT 
               
               
                 230 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 HCDR2 
                 RVFTSESTNYNPSLKN 
               
               
                 228 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 HCDR3 
                 DRGTYLGGFDP 
               
               
                 229 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 HCDR1 
                 GGSISSY 
               
               
                 157 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 HCDR2 
                 FTSES 
               
               
                 231 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 HCDR3 
                 DRGTYLGGFDP 
               
               
                 229 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 HCDR1 
                 GGSISSYY 
               
               
                 159 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 HCDR2 
                 VFTSEST 
               
               
                 232 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 HCDR3 
                 ARDRGTYLGGFDP 
               
               
                 233 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 VH 
                 QVQLQESGPGLVKPSETLSLTCTVSGGSISSYYWTWIRQPAGKGLEWIGRVFT 
               
               
                 234 
                   
                 SESTNYNPSLKNRVTMSVDTSKNQFSLRLNSVTAADTAMYYCARDRGTYLGG 
               
               
                   
                   
                 FDPWGQGTLVTVSS 
               
               
                 SEQ ID NO: 
                 DNA VH 
                 CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGA 
               
               
                 235 
                   
                 CCCTGTCCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGTAGTTACTACTG 
               
               
                   
                   
                 GACCTGGATCCGGCAGCCCGCCGGGAAGGGACTGGAGTGGATTGGGCGT 
               
               
                   
                   
                 GTCTTTACCAGTGAGAGCACCAACTACAACCCCTCCCTCAAGAATCGAGTC 
               
               
                   
                   
                 ACCATGTCAGTAGACACGTCCAAGAACCAGTTCTCCCTGAGGCTGAATTCT 
               
               
                   
                   
                 GTGACCGCCGCGGACACGGCCATGTATTACTGTGCGAGAGACCGGGGGA 
               
               
                   
                   
                 CCTACCTAGGGGGGTTCGACCCCTGGGGCCAGGGAACCCTGGTCACCGTC 
               
               
                   
                   
                 TCCTCA 
               
               
                 SEQ ID NO: 
                 Heavy 
                 QVQLQESGPGLVKPSETLSLTCTVSGGSISSYYWTWIRQPAGKGLEWIGRVFT 
               
               
                 236 
                 Chain 
                 SESTNYNPSLKNRVTMSVDTSKNQFSLRLNSVTAADTAMYYCARDRGTYLGG 
               
               
                   
                   
                 FDPWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPCPVTV 
               
               
                   
                   
                 SWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNT 
               
               
                   
                   
                 KVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVV 
               
               
                   
                   
                 VAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL 
               
               
                   
                   
                 NGKEYKCKVSNKALAAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCL 
               
               
                   
                   
                 VKGFYPCDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG 
               
               
                   
                   
                 NVFSCSVMHEALHNHYTQKSLSLSPGK 
               
               
                 SEQ ID NO: 
                 DNA Heavy 
                 CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGA 
               
               
                 237 
                 Chain 
                 CCCTGTCCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGTAGTTACTACTG 
               
               
                   
                   
                 GACCTGGATCCGGCAGCCCGCCGGGAAGGGACTGGAGTGGATTGGGCGT 
               
               
                   
                   
                 GTCTTTACCAGTGAGAGCACCAACTACAACCCCTCCCTCAAGAATCGAGTC 
               
               
                   
                   
                 ACCATGTCAGTAGACACGTCCAAGAACCAGTTCTCCCTGAGGCTGAATTCT 
               
               
                   
                   
                 GTGACCGCCGCGGACACGGCCATGTATTACTGTGCGAGAGACCGGGGGA 
               
               
                   
                   
                 CCTACCTAGGGGGGTTCGACCCCTGGGGCCAGGGAACCCTGGTCACCGTC 
               
               
                   
                   
                 TCCTCAGCCTCCACCAAGGGCCCATCGGTGTTTCCCCTGGCCCCCAGCAGC 
               
               
                   
                   
                 AAGTCTACTTCCGGCGGAACTGCTGCCCTGGGTTGCCTGGTGAAGGACTA 
               
               
                   
                   
                 CTTCCCCTGTCCCGTGACAGTGTCCTGGAACTCTGGGGCTCTGACTTCCGG 
               
               
                   
                   
                 CGTGCACACCTTCCCCGCCGTGCTGCAGAGCAGCGGCCTGTACAGCCTGA 
               
               
                   
                   
                 GCAGCGTGGTGACAGTGCCCTCCAGCTCTCTGGGAACCCAGACCTATATCT 
               
               
                   
                   
                 GCAACGTGAACCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTGGA 
               
               
                   
                   
                 GCCCAAGAGCTGCGACAAGACCCACACCTGCCCCCCCTGCCCAGCTCCAG 
               
               
                   
                   
                 AACTGCTGGGAGGGCCTTCCGTGTTCCTGTTCCCCCCCAAGCCCAAGGACA 
               
               
                   
                   
                 CCCTGATGATCAGCAGGACCCCCGAGGTGACCTGCGTGGTGGTGGCCGTG 
               
               
                   
                   
                 TCCCACGAGGACCCAGAGGTGAAGTTCAACTGGTACGTGGACGGCGTGG 
               
               
                   
                   
                 AGGTGCACAACGCCAAGACCAAGCCCAGAGAGGAGCAGTACAACAGCAC 
               
               
                   
                   
                 CTACAGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGACTGGCTGAACG 
               
               
                   
                   
                 GCAAAGAATACAAGTGCAAAGTCTCCAACAAGGCCCTGGCTGCCCCAATC 
               
               
                   
                   
                 GAAAAGACAATCAGCAAGGCCAAGGGCCAGCCACGGGAGCCCCAGGTGT 
               
               
                   
                   
                 ACACCCTGCCCCCCAGCCGGGAGGAGATGACCAAGAACCAGGTGTCCCTG 
               
               
                   
                   
                 ACCTGTCTGGTGAAGGGCTTCTACCCCTGTGATATCGCCGTGGAGTGGGA 
               
               
                   
                   
                 GAGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCCAGTGCTGG 
               
               
                   
                   
                 ACAGCGACGGCAGCTTCTTCCTGTACAGCAAGCTGACCGTGGACAAGTCC 
               
               
                   
                   
                 AGGTGGCAGCAGGGCAACGTGTTCAGCTGCAGCGTGATGCACGAGGCCC 
               
               
                   
                   
                 TGCACAACCACTACACCCAGAAGTCCCTGAGCCTGAGCCCCGGCAAG 
               
               
                 SEQ ID NO: 
                 LCDR1 
                 RSSQSLLHSNGYNYLD 
               
               
                 216 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 LCDR2 
                 LGSNRAS 
               
               
                 217 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 LCDR3 
                 IQALQTPFT 
               
               
                 238 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 LCDR1 
                 RSSQSLLHSNGYNYLD 
               
               
                 216 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 LCDR2 
                 LGSNRAS 
               
               
                 217 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 LCDR3 
                 IQALQTPFT 
               
               
                 238 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 LCDR1 
                 SQSLLHSNGYNY 
               
               
                 219 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 LCDR2 
                 LGS 
               
               
                 220 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 LCDR3 
                 ALQTPF 
               
               
                 239 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 LCDR1 
                 QSLLHSNGYNY 
               
               
                 222 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 LCDR2 
                 LGS 
               
               
                 220 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 LCDR3 
                 IQALQTPFT 
               
               
                 238 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 VL 
                 DIVMTQSPLSLPVTPGEPASISCRSSQSLLHSNGYNYLDWYLQKPGQSPQLLIY 
               
               
                 240 
                   
                 LGSNRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCIQALQTPFTFGQGT 
               
               
                   
                   
                 KLEIK 
               
               
                 SEQ ID NO: 
                 DNA VL 
                 GATATTGTGATGACTCAGTCTCCACTCTCCCTGCCCGTCACCCCTGGAGAG 
               
               
                 241 
                   
                 CCGGCCTCCATCTCCTGCAGGTCTAGTCAGAGCCTCCTGCATAGTAATGGA 
               
               
                   
                   
                 TACAACTATTTGGATTGGTACCTGCAGAAGCCAGGGCAGTCTCCACAGCTC 
               
               
                   
                   
                 CTGATCTATTTGGGTTCTAATCGGGCCTCCGGGGTCCCTGACAGGTTCAGT 
               
               
                   
                   
                 GGCAGTGGATCAGGCACAGATTTTACACTGAAAATCAGCAGAGTGGAGG 
               
               
                   
                   
                 CTGAGGATGTTGGGGTTTATTACTGCATACAAGCTCTACAAACTCCGTTCA 
               
               
                   
                   
                 CTTTTGGCCAGGGGACCAAACTGGAGATCAAA 
               
               
                 SEQ ID NO: 
                 Light 
                 DIVMTQSPLSLPVTPGEPASISCRSSQSLLHSNGYNYLDWYLQKPGQSPQLLIY 
               
               
                 242 
                 Chain 
                 LGSNRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCIQALQTPFTFGQGT 
               
               
                   
                   
                 KLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQ 
               
               
                   
                   
                 SGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSF 
               
               
                   
                   
                 NRGEC 
               
               
                 SEQ ID NO: 
                 DNA Light 
                 GATATTGTGATGACTCAGTCTCCACTCTCCCTGCCCGTCACCCCTGGAGAG 
               
               
                 243 
                 Chain 
                 CCGGCCTCCATCTCCTGCAGGTCTAGTCAGAGCCTCCTGCATAGTAATGGA 
               
               
                   
                   
                 TACAACTATTTGGATTGGTACCTGCAGAAGCCAGGGCAGTCTCCACAGCTC 
               
               
                   
                   
                 CTGATCTATTTGGGTTCTAATCGGGCCTCCGGGGTCCCTGACAGGTTCAGT 
               
               
                   
                   
                 GGCAGTGGATCAGGCACAGATTTTACACTGAAAATCAGCAGAGTGGAGG 
               
               
                   
                   
                 CTGAGGATGTTGGGGTTTATTACTGCATACAAGCTCTACAAACTCCGTTCA 
               
               
                   
                   
                 CTTTTGGCCAGGGGACCAAACTGGAGATCAAACGTACGGTGGCCGCTCCC 
               
               
                   
                   
                 AGCGTGTTCATCTTCCCCCCCAGCGACGAGCAGCTGAAGAGTGGCACCGC 
               
               
                   
                   
                 CAGCGTGGTGTGCCTGCTGAACAACTTCTACCCCCGGGAGGCCAAGGTGC 
               
               
                   
                   
                 AGTGGAAGGTGGACAACGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGT 
               
               
                   
                   
                 CACCGAGCAGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGA 
               
               
                   
                   
                 CCCTGAGCAAGGCCGACTACGAGAAGCATAAGGTGTACGCCTGCGAGGT 
               
               
                   
                   
                 GACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACAGGGGCG 
               
               
                   
                   
                 AGTGC 
               
            
           
           
               
            
               
                 550E03 Parental 
               
            
           
           
               
               
               
            
               
                 SEQ ID NO: 
                 HCDR1 
                 GFSLSTSGMSVS 
               
               
                 244 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 HCDR2 
                 LIDWDDDKYYSTSLKT 
               
               
                 26 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 HCDR3 
                 MALRHAFDA 
               
               
                 245 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 HCDR1 
                 TSGMSVS 
               
               
                 141 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 HCDR2 
                 LIDWDDDKYYSTSLKT 
               
               
                 26 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 HCDR3 
                 MALRHAFDA 
               
               
                 245 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 HCDR1 
                 GFSLSTSGM 
               
               
                 246 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 HCDR2 
                 DWDDD 
               
               
                 30 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 HCDR3 
                 MALRHAFDA 
               
               
                 245 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 HCDR1 
                 GFSLSTSGMS 
               
               
                 247 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 HCDR2 
                 IDWDDDK 
               
               
                 32 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 HCDR3 
                 ARMALRHAFDA 
               
               
                 248 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 VH 
                 QVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGMSVSWIRQPPGKALEWLALID 
               
               
                 249 
                   
                 WDDDKYYSTSLKTRLTISKDTSKNQVVLTMTNMDPVDTATYYCARMALRHA 
               
               
                   
                   
                 FDAWGQGTMVTVSS 
               
               
                 SEQ ID NO: 
                 DNA VH 
                 CAGGTCACCTTGAGGGAGTCTGGTCCTGCGCTGGTGAAGCCCACACAGAC 
               
               
                 250 
                   
                 CCTCACACTGACCTGCACCTTCTCTGGGTTCTCACTCAGCACTAGTGGAAT 
               
               
                   
                   
                 GTCTGTGAGCTGGATCCGTCAGCCCCCAGGGAAGGCCCTGGAGTGGCTTG 
               
               
                   
                   
                 CACTCATTGATTGGGATGATGATAAATACTACAGCACATCTCTGAAGACCA 
               
               
                   
                   
                 GGCTCACCATCTCCAAGGACACCTCCAAAAACCAGGTGGTCCTTACAATGA 
               
               
                   
                   
                 CCAACATGGACCCTGTGGACACAGCCACGTATTATTGTGCACGGATGGCA 
               
               
                   
                   
                 CTACGTCATGCTTTTGATGCCTGGGGCCAAGGGACAATGGTCACCGTCTCT 
               
               
                   
                   
                 TCA 
               
               
                 SEQ ID NO: 
                 Heavy 
                 QVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGMSVSWIRQPPGKALEWLALID 
               
               
                 251 
                 Chain 
                 WDDDKYYSTSLKTRLTISKDTSKNQVVLTMTNMDPVDTATYYCARMALRHA 
               
               
                   
                   
                 FDAWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPCPVT 
               
               
                   
                   
                 VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN 
               
               
                   
                   
                 TKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
               
               
                   
                   
                 VVAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD 
               
               
                   
                   
                 WLNGKEYKCKVSNKALAAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSL 
               
               
                   
                   
                 TCLVKGFYPCDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW 
               
               
                   
                   
                 QQGNVFSCSVMHEALHNHYTQKSLSLSPGK 
               
               
                 SEQ ID NO: 
                 DNA Heavy 
                 CAGGTCACCTTGAGGGAGTCTGGTCCTGCGCTGGTGAAGCCCACACAGAC 
               
               
                 252 
                 Chain 
                 CCTCACACTGACCTGCACCTTCTCTGGGTTCTCACTCAGCACTAGTGGAAT 
               
               
                   
                   
                 GTCTGTGAGCTGGATCCGTCAGCCCCCAGGGAAGGCCCTGGAGTGGCTTG 
               
               
                   
                   
                 CACTCATTGATTGGGATGATGATAAATACTACAGCACATCTCTGAAGACCA 
               
               
                   
                   
                 GGCTCACCATCTCCAAGGACACCTCCAAAAACCAGGTGGTCCTTACAATGA 
               
               
                   
                   
                 CCAACATGGACCCTGTGGACACAGCCACGTATTATTGTGCACGGATGGCA 
               
               
                   
                   
                 CTACGTCATGCTTTTGATGCCTGGGGCCAAGGGACAATGGTCACCGTCTCT 
               
               
                   
                   
                 TCAGCCTCCACCAAGGGCCCATCGGTGTTTCCCCTGGCCCCCAGCAGCAAG 
               
               
                   
                   
                 TCTACTTCCGGCGGAACTGCTGCCCTGGGTTGCCTGGTGAAGGACTACTTC 
               
               
                   
                   
                 CCCTGTCCCGTGACAGTGTCCTGGAACTCTGGGGCTCTGACTTCCGGCGTG 
               
               
                   
                   
                 CACACCTTCCCCGCCGTGCTGCAGAGCAGCGGCCTGTACAGCCTGAGCAG 
               
               
                   
                   
                 CGTGGTGACAGTGCCCTCCAGCTCTCTGGGAACCCAGACCTATATCTGCAA 
               
               
                   
                   
                 CGTGAACCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTGGAGCCC 
               
               
                   
                   
                 AAGAGCTGCGACAAGACCCACACCTGCCCCCCCTGCCCAGCTCCAGAACT 
               
               
                   
                   
                 GCTGGGAGGGCCTTCCGTGTTCCTGTTCCCCCCCAAGCCCAAGGACACCCT 
               
               
                   
                   
                 GATGATCAGCAGGACCCCCGAGGTGACCTGCGTGGTGGTGGCCGTGTCCC 
               
               
                   
                   
                 ACGAGGACCCAGAGGTGAAGTTCAACTGGTACGTGGACGGCGTGGAGGT 
               
               
                   
                   
                 GCACAACGCCAAGACCAAGCCCAGAGAGGAGCAGTACAACAGCACCTAC 
               
               
                   
                   
                 AGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGACTGGCTGAACGGCA 
               
               
                   
                   
                 AAGAATACAAGTGCAAAGTCTCCAACAAGGCCCTGGCTGCCCCAATCGAA 
               
               
                   
                   
                 AAGACAATCAGCAAGGCCAAGGGCCAGCCACGGGAGCCCCAGGTGTACA 
               
               
                   
                   
                 CCCTGCCCCCCAGCCGGGAGGAGATGACCAAGAACCAGGTGTCCCTGACC 
               
               
                   
                   
                 TGTCTGGTGAAGGGCTTCTACCCCTGTGATATCGCCGTGGAGTGGGAGAG 
               
               
                   
                   
                 CAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCCAGTGCTGGACA 
               
               
                   
                   
                 GCGACGGCAGCTTCTTCCTGTACAGCAAGCTGACCGTGGACAAGTCCAGG 
               
               
                   
                   
                 TGGCAGCAGGGCAACGTGTTCAGCTGCAGCGTGATGCACGAGGCCCTGC 
               
               
                   
                   
                 ACAACCACTACACCCAGAAGTCCCTGAGCCTGAGCCCCGGCAAG 
               
               
                 SEQ ID NO: 
                 LCDR1 
                 TGSSSNIGAGYDVH 
               
               
                 253 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 LCDR2 
                 VNSNRPS 
               
               
                 254 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 LCDR3 
                 QSYDSSLSGWV 
               
               
                 255 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 LCDR1 
                 TGSSSNIGAGYDVH 
               
               
                 253 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 LCDR2 
                 VNSNRPS 
               
               
                 254 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 LCDR3 
                 QSYDSSLSGWV 
               
               
                 255 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 LCDR1 
                 SSSNIGAGYD 
               
               
                 256 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 LCDR2 
                 VNS 
               
               
                 257 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 LCDR3 
                 YDSSLSGW 
               
               
                 258 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 LCDR1 
                 SSNIGAGYD 
               
               
                 259 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 LCDR2 
                 VNS 
               
               
                 257 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 LCDR3 
                 QSYDSSLSGWV 
               
               
                 255 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 VL 
                 QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYVN 
               
               
                 260 
                   
                 SNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLSGWVFGGGT 
               
               
                   
                   
                 KLTVL 
               
               
                 SEQ ID NO: 
                 DNA VL 
                 CAGTCTGTGCTGACGCAGCCGCCCTCAGTGTCTGGGGCCCCAGGGCAGAG 
               
               
                 261 
                   
                 GGTCACCATCTCCTGCACTGGGAGCAGCTCCAACATCGGGGCAGGTTATG 
               
               
                   
                   
                 ATGTACACTGGTACCAGCAGCTTCCAGGAACAGCCCCCAAACTCCTCATCT 
               
               
                   
                   
                 ATGTTAACAGCAATCGGCCCTCAGGGGTCCCTGACCGATTCTCTGGCTCCA 
               
               
                   
                   
                 AGTCTGGCACCTCAGCCTCCCTGGCCATCACTGGGCTCCAGGCTGAGGAT 
               
               
                   
                   
                 GAGGCTGATTATTACTGCCAGTCCTATGACAGCAGCCTGAGTGGTTGGGT 
               
               
                   
                   
                 GTTCGGCGGAGGGACCAAGTTGACCGTCCTA 
               
               
                 SEQ ID NO: 
                 Light 
                 QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYVN 
               
               
                 262 
                 Chain 
                 SNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLSGWVFGGGT 
               
               
                   
                   
                 KLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVIVAWKADSSPV 
               
               
                   
                   
                 KAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAP 
               
               
                   
                   
                 TECS 
               
               
                 SEQ ID NO: 
                 DNA Light 
                 CAGTCTGTGCTGACGCAGCCGCCCTCAGTGTCTGGGGCCCCAGGGCAGAG 
               
               
                 263 
                 Chain 
                 GGTCACCATCTCCTGCACTGGGAGCAGCTCCAACATCGGGGCAGGTTATG 
               
               
                   
                   
                 ATGTACACTGGTACCAGCAGCTTCCAGGAACAGCCCCCAAACTCCTCATCT 
               
               
                   
                   
                 ATGTTAACAGCAATCGGCCCTCAGGGGTCCCTGACCGATTCTCTGGCTCCA 
               
               
                   
                   
                 AGTCTGGCACCTCAGCCTCCCTGGCCATCACTGGGCTCCAGGCTGAGGAT 
               
               
                   
                   
                 GAGGCTGATTATTACTGCCAGTCCTATGACAGCAGCCTGAGTGGTTGGGT 
               
               
                   
                   
                 GTTCGGCGGAGGGACCAAGTTGACCGTCCTAGGTCAGCCCAAGGCTGCCC 
               
               
                   
                   
                 CCTCCGTGACCCTGTTCCCCCCCAGCTCCGAGGAACTGCAGGCCAACAAG 
               
               
                   
                   
                 GCCACCCTGGTGTGCCTGATCAGCGACTTCTACCCTGGCGCCGTGACCGTG 
               
               
                   
                   
                 GCCTGGAAGGCCGACAGCAGCCCCGTGAAGGCCGGCGTGGAGACAACCA 
               
               
                   
                   
                 CCCCCAGCAAGCAGAGCAACAACAAGTACGCCGCCAGCAGCTACCTGAGC 
               
               
                   
                   
                 CTGACCCCCGAGCAGTGGAAGAGCCACAGAAGCTACAGCTGCCAGGTCAC 
               
               
                   
                   
                 CCACGAGGGCAGCACCGTGGAGAAAACCGTGGCCCCCACCGAGTGCAGC 
               
            
           
           
               
            
               
                 1G12 Hz 
               
            
           
           
               
               
               
            
               
                 SEQ ID NO: 
                 HCDR1 
                 GFSLTNYGVH 
               
               
                 264 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 HCDR2 
                 VIWRGESTDYNAAFMS 
               
               
                 265 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 HCDR3 
                 NGGSSGWYFDV 
               
               
                 266 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 HCDR1 
                 NYGVH 
               
               
                 267 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 HCDR2 
                 VIWRGESTDYNAAFMS 
               
               
                 265 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 HCDR3 
                 NGGSSGWYFDV 
               
               
                 266 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 HCDR1 
                 GFSLTNY 
               
               
                 268 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 HCDR2 
                 WRGES 
               
               
                 269 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 HCDR3 
                 NGGSSGWYFDV 
               
               
                 266 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 HCDR1 
                 GFSLTNYG 
               
               
                 270 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 HCDR2 
                 IWRGEST 
               
               
                 271 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 HCDR3 
                 ARNGGSSGWYFDV 
               
               
                 272 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 VH 
                 QVQLQESGPGLVKPSETLSLTCTVSGFSLTNYGVHWIRQPPGKGLEWIGVIW 
               
               
                 273 
                   
                 RGESTDYNAAFMSRVTISKDDSKSQVSLKLSSVTAADTAVYYCARNGGSSGW 
               
               
                   
                   
                 YFDVWGQGTTVIVSS 
               
               
                 SEQ ID NO: 
                 DNA VH 
                 CAAGTTCAGCTGCAAGAATCTGGCCCTGGCCTGGTCAAGCCTTCCGAGAC 
               
               
                 274 
                   
                 ACTGTCTCTGACCTGCACCGTGTCTGGCTTCTCCCTGACCAATTACGGCGT 
               
               
                   
                   
                 GCACTGGATCAGACAGCCTCCAGGCAAAGGCCTGGAATGGATCGGAGTG 
               
               
                   
                   
                 ATTTGGAGAGGCGAGTCCACCGACTACAACGCCGCCTTCATGTCCAGAGT 
               
               
                   
                   
                 GACCATCTCCAAGGACGACTCCAAGAGCCAGGTGTCCCTGAAGCTGTCCT 
               
               
                   
                   
                 CTGTGACCGCTGCTGATACCGCCGTGTACTACTGTGCCAGAAACGGCGGA 
               
               
                   
                   
                 TCCTCCGGCTGGTACTTTGATGTGTGGGGCCAGGGCACCACCGTGACAGT 
               
               
                   
                   
                 TAGTTCT 
               
               
                 SEQ ID NO: 
                 Heavy 
                 QVQLQESGPGLVKPSETLSLTCTVSGFSLTNYGVHWIRQPPGKGLEWIGVIW 
               
               
                 275 
                 Chain 
                 RGESTDYNAAFMSRVTISKDDSKSQVSLKLSSVTAADTAVYYCARNGGSSGW 
               
               
                   
                   
                 YFDVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPCPVT 
               
               
                   
                   
                 VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN 
               
               
                   
                   
                 TKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
               
               
                   
                   
                 VVAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD 
               
               
                   
                   
                 WLNGKEYKCKVSNKALAAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSL 
               
               
                   
                   
                 TCLVKGFYPCDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW 
               
               
                   
                   
                 QQGNVFSCSVMHEALHNHYTQKSLSLSPGK 
               
               
                 SEQ ID NO: 
                 DNA Heavy 
                 CAAGTTCAGCTGCAAGAATCTGGCCCTGGCCTGGTCAAGCCTTCCGAGAC 
               
               
                 276 
                 Chain 
                 ACTGTCTCTGACCTGCACCGTGTCTGGCTTCTCCCTGACCAATTACGGCGT 
               
               
                   
                   
                 GCACTGGATCAGACAGCCTCCAGGCAAAGGCCTGGAATGGATCGGAGTG 
               
               
                   
                   
                 ATTTGGAGAGGCGAGTCCACCGACTACAACGCCGCCTTCATGTCCAGAGT 
               
               
                   
                   
                 GACCATCTCCAAGGACGACTCCAAGAGCCAGGTGTCCCTGAAGCTGTCCT 
               
               
                   
                   
                 CTGTGACCGCTGCTGATACCGCCGTGTACTACTGTGCCAGAAACGGCGGA 
               
               
                   
                   
                 TCCTCCGGCTGGTACTTTGATGTGTGGGGCCAGGGCACCACCGTGACAGT 
               
               
                   
                   
                 TAGTTCTGCTAGCACCAAGGGCCCAAGTGTGTTTCCCCTGGCCCCCAGCAG 
               
               
                   
                   
                 CAAGTCTACTTCCGGCGGAACTGCTGCCCTGGGTTGCCTGGTGAAGGACT 
               
               
                   
                   
                 ACTTCCCCTGTCCCGTGACAGTGTCCTGGAACTCTGGGGCTCTGACTTCCG 
               
               
                   
                   
                 GCGTGCACACCTTCCCCGCCGTGCTGCAGAGCAGCGGCCTGTACAGCCTG 
               
               
                   
                   
                 AGCAGCGTGGTGACAGTGCCCTCCAGCTCTCTGGGAACCCAGACCTATAT 
               
               
                   
                   
                 CTGCAACGTGAACCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTG 
               
               
                   
                   
                 GAGCCCAAGAGCTGCGACAAGACCCACACCTGCCCCCCCTGCCCAGCTCC 
               
               
                   
                   
                 AGAACTGCTGGGAGGGCCTTCCGTGTTCCTGTTCCCCCCCAAGCCCAAGG 
               
               
                   
                   
                 ACACCCTGATGATCAGCAGGACCCCCGAGGTGACCTGCGTGGTGGTGGCC 
               
               
                   
                   
                 GTGTCCCACGAGGACCCAGAGGTGAAGTTCAACTGGTACGTGGACGGCG 
               
               
                   
                   
                 TGGAGGTGCACAACGCCAAGACCAAGCCCAGAGAGGAGCAGTACAACAG 
               
               
                   
                   
                 CACCTACAGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGACTGGCTGA 
               
               
                   
                   
                 ACGGCAAAGAATACAAGTGCAAAGTCTCCAACAAGGCCCTGGCTGCCCCA 
               
               
                   
                   
                 ATCGAAAAGACAATCAGCAAGGCCAAGGGCCAGCCACGGGAGCCCCAGG 
               
               
                   
                   
                 TGTACACCCTGCCCCCCAGCCGGGAGGAGATGACCAAGAACCAGGTGTCC 
               
               
                   
                   
                 CTGACCTGTCTGGTGAAGGGCTTCTACCCCTGTGATATCGCCGTGGAGTG 
               
               
                   
                   
                 GGAGAGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCCAGTGC 
               
               
                   
                   
                 TGGACAGCGACGGCAGCTTCTTCCTGTACAGCAAGCTGACCGTGGACAAG 
               
               
                   
                   
                 TCCAGGTGGCAGCAGGGCAACGTGTTCAGCTGCAGCGTGATGCACGAGG 
               
               
                   
                   
                 CCCTGCACAACCACTACACCCAGAAGTCCCTGAGCCTGAGCCCCGGCAAG 
               
               
                 SEQ ID NO: 
                 LCDR1 
                 KASQDVTSAVA 
               
               
                 277 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 LCDR2 
                 WTSTRHT 
               
               
                 278 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 LCDR3 
                 QQHYTTPLT 
               
               
                 279 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 LCDR1 
                 KASQDVTSAVA 
               
               
                 277 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 LCDR2 
                 WTSTRHT 
               
               
                 278 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 LCDR3 
                 QQHYTTPLT 
               
               
                 279 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 LCDR1 
                 SQDVTSA 
               
               
                 280 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 LCDR2 
                 WTS 
               
               
                 281 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 LCDR3 
                 HYTTPL 
               
               
                 282 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 LCDR1 
                 QDVTSA 
               
               
                 283 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 LCDR2 
                 WTS 
               
               
                 281 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 LCDR3 
                 QQHYTTPLT 
               
               
                 279 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 VL 
                 DIQLTQSPSFLSASVGDRVTITCKASQDVTSAVAWYQQKPGKAPKLLIYWTST 
               
               
                 284 
                   
                 RHTGVPSRFSGSGSGTEYTLTISSLQPEDFATYYCQQHYTTPLTFGQGTKLEIK 
               
               
                 SEQ ID NO: 
                 DNA VL 
                 GATATTCAGCTGACCCAGTCTCCTAGCTTCCTGTCCGCTTCTGTGGGCGAC 
               
               
                 285 
                   
                 AGAGTGACCATCACATGCAAGGCCTCTCAGGACGTGACCTCTGCCGTGGC 
               
               
                   
                   
                 TTGGTATCAGCAGAAGCCTGGCAAGGCCCCTAAGCTGCTGATCTACTGGA 
               
               
                   
                   
                 CCTCCACCAGACACACCGGCGTGCCCTCTAGATTTTCCGGCTCTGGCTCTG 
               
               
                   
                   
                 GCACCGAGTATACCCTGACAATCTCCAGCCTGCAGCCTGAGGACTTCGCCA 
               
               
                   
                   
                 CCTACTACTGCCAGCAGCACTACACCACACCTCTGACCTTTGGCCAGGGCA 
               
               
                   
                   
                 CCAAGCTGGAAATCAAG 
               
               
                 SEQ ID NO: 
                 Light 
                 DIQLTQSPSFLSASVGDRVTITCKASQDVTSAVAWYQQKPGKAPKLLIYWTST 
               
               
                 286 
                 Chain 
                 RHTGVPSRFSGSGSGTEYTLTISSLQPEDFATYYCQQHYTTPLTFGQGTKLEIKR 
               
               
                   
                   
                 TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQ 
               
               
                   
                   
                 ESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 
               
               
                 SEQ ID NO: 
                 DNA Light 
                 GATATTCAGCTGACCCAGTCTCCTAGCTTCCTGTCCGCTTCTGTGGGCGAC 
               
               
                 287 
                 Chain 
                 AGAGTGACCATCACATGCAAGGCCTCTCAGGACGTGACCTCTGCCGTGGC 
               
               
                   
                   
                 TTGGTATCAGCAGAAGCCTGGCAAGGCCCCTAAGCTGCTGATCTACTGGA 
               
               
                   
                   
                 CCTCCACCAGACACACCGGCGTGCCCTCTAGATTTTCCGGCTCTGGCTCTG 
               
               
                   
                   
                 GCACCGAGTATACCCTGACAATCTCCAGCCTGCAGCCTGAGGACTTCGCCA 
               
               
                   
                   
                 CCTACTACTGCCAGCAGCACTACACCACACCTCTGACCTTTGGCCAGGGCA 
               
               
                   
                   
                 CCAAGCTGGAAATCAAGCGTACGGTGGCCGCTCCCAGCGTGTTCATCTTCC 
               
               
                   
                   
                 CCCCCAGCGACGAGCAGCTGAAGAGTGGCACCGCCAGCGTGGTGTGCCT 
               
               
                   
                   
                 GCTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAGGTGGAC 
               
               
                   
                   
                 AACGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGTCACCGAGCAGGACA 
               
               
                   
                   
                 GCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCC 
               
               
                   
                   
                 GACTACGAGAAGCATAAGGTGTACGCCTGCGAGGTGACCCACCAGGGCC 
               
               
                   
                   
                 TGTCCAGCCCCGTGACCAAGAGCTTCAACAGGGGCGAGTGC 
               
            
           
           
               
            
               
                 1G12 mouse 
               
            
           
           
               
               
               
            
               
                 SEQ ID NO: 
                 HCDR1 
                 GFSLTNYGVH 
               
               
                 264 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 HCDR2 
                 VIWRGESTDYNAAFMS 
               
               
                 265 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 HCDR3 
                 NGGSSGWYFDV 
               
               
                 266 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 HCDR1 
                 NYGVH 
               
               
                 267 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 HCDR2 
                 VIWRGESTDYNAAFMS 
               
               
                 265 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 HCDR3 
                 NGGSSGWYFDV 
               
               
                 266 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 HCDR1 
                 GFSLTNY 
               
               
                 268 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 HCDR2 
                 WRGES 
               
               
                 269 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 HCDR3 
                 NGGSSGWYFDV 
               
               
                 266 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 HCDR1 
                 GFSLTNYG 
               
               
                 270 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 HCDR2 
                 IWRGEST 
               
               
                 271 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 HCDR3 
                 ARNGGSSGWYFDV 
               
               
                 272 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 VH 
                 QVQLQQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVI 
               
               
                 288 
                   
                 WRGESTDYNAAFMSRLSVTKDDSKSQVFFKMNSLQADDTAIYYCARNGGSS 
               
               
                   
                   
                 GWYFDVWGTGTTVTVSS 
               
               
                 SEQ ID NO: 
                 DNA VH 
                 CAGGTGCAGCTACAGCAGTCAGGACCTGGCCTAGTGCAGCCCTCACAGAG 
               
               
                 289 
                   
                 CCTGTCCATAACCTGCACAGTCTCTGGTTTCTCATTAACTAACTATGGTGTA 
               
               
                   
                   
                 CACTGGGTTCGCCAGTCTCCAGGAAAGGGTCTGGAGTGGCTGGGAGTGA 
               
               
                   
                   
                 TATGGAGAGGTGAAAGCACAGACTACAATGCAGCTTTCATGTCCAGACTG 
               
               
                   
                   
                 AGCGTCACCAAGGACGACTCCAAGAGCCAAGTTTTCTTTAAAATGAACAG 
               
               
                   
                   
                 TCTGCAAGCTGATGACACTGCCATATACTACTGTGCCAGAAATGGCGGTA 
               
               
                   
                   
                 GTAGCGGGTGGTACTTCGATGTCTGGGGCACAGGGACCACTGTCACCGTC 
               
               
                   
                   
                 TCCTCA 
               
               
                 SEQ ID NO: 
                 Heavy 
                 QVQLQQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVI 
               
               
                 290 
                 Chain 
                 WRGESTDYNAAFMSRLSVTKDDSKSQVFFKMNSLQADDTAIYYCARNGGSS 
               
               
                   
                   
                 GWYFDVWGTGTTVTVSSAKTTAPSVYPLAPVCGGTTGSSVTLGCLVKGYFPC 
               
               
                   
                   
                 PVTLTWNSGSLSSGVHTFPALLQSGLYTLSSSVTVTSNTWPSQTITCNVAHPA 
               
               
                   
                   
                 SSTKVDKKIEPRVPITQNPCPPLKECPPCAAPDLLGGPSVFIFPPKIKDVLMISLS 
               
               
                   
                   
                 PMVTCVVVAVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALP 
               
               
                   
                   
                 IQHQDWMSGKEFKCKVNNRALASPIEKTISKPRGPVRAPQVYVLPPPAEEMT 
               
               
                   
                   
                 KKEFSLTCMITGFLPCEIAVDWTSNGRTEQNYKNTATVLDSDGSYFMYSKLRV 
               
               
                   
                   
                 QKSTWERGSLFACSVVHEGLHNHLTTKTISRSLGK 
               
               
                 SEQ ID NO: 
                 DNA Heavy 
                 CAGGTGCAGCTACAGCAGTCAGGACCTGGCCTAGTGCAGCCCTCACAGAG 
               
               
                 291 
                 Chain 
                 CCTGTCCATAACCTGCACAGTCTCTGGTTTCTCATTAACTAACTATGGTGTA 
               
               
                   
                   
                 CACTGGGTTCGCCAGTCTCCAGGAAAGGGTCTGGAGTGGCTGGGAGTGA 
               
               
                   
                   
                 TATGGAGAGGTGAAAGCACAGACTACAATGCAGCTTTCATGTCCAGACTG 
               
               
                   
                   
                 AGCGTCACCAAGGACGACTCCAAGAGCCAAGTTTTCTTTAAAATGAACAG 
               
               
                   
                   
                 TCTGCAAGCTGATGACACTGCCATATACTACTGTGCCAGAAATGGCGGTA 
               
               
                   
                   
                 GTAGCGGGTGGTACTTCGATGTCTGGGGCACAGGGACCACTGTCACCGTC 
               
               
                   
                   
                 TCCTCAGCCAAAACAACAGCCCCATCGGTCTATCCACTGGCCCCTGTGTGT 
               
               
                   
                   
                 GGAGGTACAACTGGCTCCTCGGTGACTCTAGGATGCCTGGTCAAGGGTTA 
               
               
                   
                   
                 TTTCCCTTGTCCAGTGACCTTGACCTGGAACTCTGGATCCCTGTCCAGTGGT 
               
               
                   
                   
                 GTGCACACCTTCCCAGCTCTCCTGCAGTCTGGCCTCTACACCCTCAGCAGCT 
               
               
                   
                   
                 CAGTGACTGTAACCTCGAACACCTGGCCCAGCCAGACCATCACCTGCAATG 
               
               
                   
                   
                 TGGCCCACCCGGCAAGCAGCACCAAAGTGGACAAGAAAATTGAGCCCAG 
               
               
                   
                   
                 AGTGCCCATAACACAGAACCCCTGTCCTCCACTCAAAGAGTGTCCCCCATG 
               
               
                   
                   
                 CGCAGCTCCAGACCTCTTGGGTGGACCATCCGTCTTCATCTTCCCTCCAAA 
               
               
                   
                   
                 GATCAAGGATGTACTCATGATCTCCCTGAGCCCCATGGTCACATGTGTGGT 
               
               
                   
                   
                 GGTGGCTGTGAGCGAGGATGACCCAGACGTCCAGATCAGCTGGTTTGTGA 
               
               
                   
                   
                 ACAACGTGGAAGTACACACAGCTCAGACACAAACCCATAGAGAGGATTAC 
               
               
                   
                   
                 AACAGTACTCTCCGGGTGGTCAGTGCCCTCCCCATCCAGCACCAGGACTG 
               
               
                   
                   
                 GATGAGTGGCAAGGAGTTCAAATGCAAGGTCAACAACAGAGCCCTCGCAT 
               
               
                   
                   
                 CCCCCATCGAGAAAACCATCTCAAAACCCAGAGGGCCAGTAAGAGCTCCA 
               
               
                   
                   
                 CAGGTATATGTCTTGCCTCCACCAGCAGAAGAGATGACTAAGAAAGAGTT 
               
               
                   
                   
                 CAGTCTGACCTGCATGATCACAGGCTTCTTACCTTGTGAAATTGCTGTGGA 
               
               
                   
                   
                 vCTGGACCAGCAATGGGCGTACAGAGCAAAACTACAAGAACACCGCAACA 
               
               
                   
                   
                 GTCCTGGACTCTGATGGTTCTTACTTCATGTACAGCAAGCTCAGAGTACAA 
               
               
                   
                   
                 AAGAGCACTTGGGAAAGAGGAAGTCTTTTCGCCTGCTCAGTGGTCCACGA 
               
               
                   
                   
                 GGGTCTGCACAATCACCTTACGACTAAGACCATCTCCCGGTCTCTGGGTAA 
               
               
                   
                   
                 A 
               
               
                 SEQ ID NO: 
                 LCDR1 
                 KASQDVTSAVA 
               
               
                 277 
                 (Combined)  
                   
               
               
                 SEQ ID NO: 
                 LCDR2 
                 WTSTRHT 
               
               
                 278 
                 (Combined)  
                   
               
               
                 SEQ ID NO: 
                 LCDR3 
                 QQHYTTPLT 
               
               
                 279 
                 (Combined)  
                   
               
               
                 SEQ ID NO: 
                 LCDR1 
                 KASQDVTSAVA 
               
               
                 277 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 LCDR2 
                 WTSTRHT 
               
               
                 278 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 LCDR3 
                 QQHYTTPLT 
               
               
                 279 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 LCDR1 
                 SQDVTSA 
               
               
                 280 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 LCDR2 
                 WTS 
               
               
                 281 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 LCDR3 
                 HYTTPL 
               
               
                 282 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 LCDR1 
                 QDVTSA 
               
               
                 283 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 LCDR2 
                 WTS 
               
               
                 281 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 LCDR3 
                 QQHYTTPLT 
               
               
                 279 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 VL 
                 DIQMTQTHKFMSTSVGDRVSITCKASQDVTSAVAWYQQTPGQSPNLLIYWT 
               
               
                 292 
                   
                 STRHTGVPDRFTGSGSGTDYTLTISSVQAEDLALYYCQQHYTTPLTFGAGTKLE 
               
               
                   
                   
                 LK 
               
               
                 SEQ ID NO: 
                 DNA VL 
                 GACATTCAGATGACCCAGACTCACAAATTCATGTCCACATCAGTAGGAGAC 
               
               
                 293 
                   
                 AGGGTCAGCATCACCTGCAAGGCCAGTCAGGATGTGACTTCTGCTGTAGC 
               
               
                   
                   
                 CTGGTATCAACAAACACCAGGACAATCTCCTAATCTACTGATTTACTGGAC 
               
               
                   
                   
                 ATCCACCCGGCACACTGGAGTCCCTGATCGCTTCACAGGCAGTGGATCTG 
               
               
                   
                   
                 GGACAGATTATACTCTCACCATCAGCAGTGTGCAGGCTGAAGACCTGGCA 
               
               
                   
                   
                 CTTTATTACTGTCAGCAACATTATACCACTCCGCTCACGTTCGGTGCTGGGA 
               
               
                   
                   
                 CCAAGCTGGAGCTAAAA 
               
               
                 SEQ ID NO: 
                 Light 
                 DIQMTQTHKFMSTSVGDRVSITCKASQDVTSAVAWYQQTPGQSPNLLIYWT 
               
               
                 294 
                 Chain 
                 STRHTGVPDRFTGSGSGTDYTLTISSVQAEDLALYYCQQHYTTPLTFGAGTKLE 
               
               
                   
                   
                 LKRADAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNG 
               
               
                   
                   
                 VLNSWTDQDSKDSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKSFNR 
               
               
                   
                   
                 NEC 
               
               
                 SEQ ID NO: 
                 DNA Light 
                 GACATTCAGATGACCCAGACTCACAAATTCATGTCCACATCAGTAGGAGAC 
               
               
                 295 
                 Chain 
                 AGGGTCAGCATCACCTGCAAGGCCAGTCAGGATGTGACTTCTGCTGTAGC 
               
               
                   
                   
                 CTGGTATCAACAAACACCAGGACAATCTCCTAATCTACTGATTTACTGGAC 
               
               
                   
                   
                 ATCCACCCGGCACACTGGAGTCCCTGATCGCTTCACAGGCAGTGGATCTG 
               
               
                   
                   
                 GGACAGATTATACTCTCACCATCAGCAGTGTGCAGGCTGAAGACCTGGCA 
               
               
                   
                   
                 CTTTATTACTGTCAGCAACATTATACCACTCCGCTCACGTTCGGTGCTGGGA 
               
               
                   
                   
                 CCAAGCTGGAGCTAAAACGTGCCGATGCTGCACCAACTGTATCCATCTTCC 
               
               
                   
                   
                 CACCATCCAGTGAGCAGTTAACATCTGGAGGTGCCTCAGTCGTGTGCTTCT 
               
               
                   
                   
                 TGAACAACTTCTACCCCAAAGACATCAATGTCAAGTGGAAGATTGATGGC 
               
               
                   
                   
                 AGTGAACGACAAAATGGCGTCCTGAACAGTTGGACTGATCAGGACAGCA 
               
               
                   
                   
                 AAGACAGCACCTACAGCATGAGCAGCACCCTCACGTTGACCAAGGACGAG 
               
               
                   
                   
                 TATGAACGACATAACAGCTATACCTGTGAGGCCACTCACAAGACATCAACT 
               
               
                   
                   
                 TCACCCATTGTCAAGAGCTTCAACAGGAATGAGTGT 
               
            
           
           
               
            
               
                 1G12 
               
            
           
           
               
               
               
            
               
                 SEQ ID NO: 
                 HCDR1 
                 GFSLTNYGVH 
               
               
                 264 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 HCDR2 
                 VIWRGESTDYNAAFMS 
               
               
                 265 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 HCDR3 
                 NAGSSGWYFDV 
               
               
                 296 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 HCDR1 
                 NYGVH 
               
               
                 267 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 HCDR2 
                 VIWRGESTDYNAAFMS 
               
               
                 265 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 HCDR3 
                 NAGSSGWYFDV 
               
               
                 296 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 HCDR1 
                 GFSLTNY 
               
               
                 268 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 HCDR2 
                 WRGES 
               
               
                 269 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 HCDR3 
                 NAGSSGWYFDV 
               
               
                 296 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 HCDR1 
                 GFSLTNYG 
               
               
                 270 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 HCDR2 
                 IWRGEST 
               
               
                 271 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 HCDR3 
                 ARNAGSSGWYFDV 
               
               
                 297 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 VH 
                 QVQLQESGPGLVKPSETLSLTCTVSGFSLTNYGVHWIRQPPGKGLEWIGVIW 
               
               
                 298 
                   
                 RGESTDYNAAFMSRVTISKDDSKSQVSLKLSSVTAADTAVYYCARNAGSSGW 
               
               
                   
                   
                 YFDVWGQGTTVIVSS 
               
               
                 SEQ ID NO: 
                 DNA VH 
                 CAAGTTCAGCTGCAAGAATCTGGCCCTGGCCTGGTCAAGCCTTCCGAGAC 
               
               
                 299 
                   
                 ACTGTCTCTGACCTGCACCGTGTCTGGCTTCTCCCTGACCAATTACGGCGT 
               
               
                   
                   
                 GCACTGGATCAGACAGCCTCCAGGCAAAGGCCTGGAATGGATCGGAGTG 
               
               
                   
                   
                 ATTTGGAGAGGCGAGTCCACCGACTACAACGCCGCCTTCATGTCCAGAGT 
               
               
                   
                   
                 GACCATCTCCAAGGACGACTCCAAGAGCCAGGTGTCCCTGAAGCTGTCCT 
               
               
                   
                   
                 CTGTGACCGCTGCTGATACCGCCGTGTACTACTGTGCCAGAAACGCTGGCT 
               
               
                   
                   
                 CCTCCGGCTGGTACTTTGATGTGTGGGGCCAGGGCACCACCGTGACAGTT 
               
               
                   
                   
                 AGTTCT 
               
               
                 SEQ ID NO: 
                 Heavy 
                 QVQLQESGPGLVKPSETLSLTCTVSGFSLTNYGVHWIRQPPGKGLEWIGVIW 
               
               
                 300 
                 Chain 
                 RGESTDYNAAFMSRVTISKDDSKSQVSLKLSSVTAADTAVYYCARNAGSSGW 
               
               
                   
                   
                 YFDVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPCPVT 
               
               
                   
                   
                 VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN 
               
               
                   
                   
                 TKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
               
               
                   
                   
                 VVAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD 
               
               
                   
                   
                 WLNGKEYKCKVSNKALAAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSL 
               
               
                   
                   
                 TCLVKGFYPCDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW 
               
               
                   
                   
                 QQGNVFSCSVMHEALHNHYTQKSLSLSPGK 
               
               
                 SEQ ID NO: 
                 DNA Heavy 
                 CAAGTTCAGCTGCAAGAATCTGGCCCTGGCCTGGTCAAGCCTTCCGAGAC 
               
               
                 301 
                 Chain 
                 ACTGTCTCTGACCTGCACCGTGTCTGGCTTCTCCCTGACCAATTACGGCGT 
               
               
                   
                   
                 GCACTGGATCAGACAGCCTCCAGGCAAAGGCCTGGAATGGATCGGAGTG 
               
               
                   
                   
                 ATTTGGAGAGGCGAGTCCACCGACTACAACGCCGCCTTCATGTCCAGAGT 
               
               
                   
                   
                 GACCATCTCCAAGGACGACTCCAAGAGCCAGGTGTCCCTGAAGCTGTCCT 
               
               
                   
                   
                 CTGTGACCGCTGCTGATACCGCCGTGTACTACTGTGCCAGAAACGCTGGCT 
               
               
                   
                   
                 CCTCCGGCTGGTACTTTGATGTGTGGGGCCAGGGCACCACCGTGACAGTT 
               
               
                   
                   
                 AGTTCTGCTAGCACCAAGGGCCCAAGTGTGTTTCCCCTGGCCCCCAGCAGC 
               
               
                   
                   
                 AAGTCTACTTCCGGCGGAACTGCTGCCCTGGGTTGCCTGGTGAAGGACTA 
               
               
                   
                   
                 CTTCCCCTGTCCCGTGACAGTGTCCTGGAACTCTGGGGCTCTGACTTCCGG 
               
               
                   
                   
                 CGTGCACACCTTCCCCGCCGTGCTGCAGAGCAGCGGCCTGTACAGCCTGA 
               
               
                   
                   
                 GCAGCGTGGTGACAGTGCCCTCCAGCTCTCTGGGAACCCAGACCTATATCT 
               
               
                   
                   
                 GCAACGTGAACCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTGGA 
               
               
                   
                   
                 GCCCAAGAGCTGCGACAAGACCCACACCTGCCCCCCCTGCCCAGCTCCAG 
               
               
                   
                   
                 AACTGCTGGGAGGGCCTTCCGTGTTCCTGTTCCCCCCCAAGCCCAAGGACA 
               
               
                   
                   
                 CCCTGATGATCAGCAGGACCCCCGAGGTGACCTGCGTGGTGGTGGCCGTG 
               
               
                   
                   
                 TCCCACGAGGACCCAGAGGTGAAGTTCAACTGGTACGTGGACGGCGTGG 
               
               
                   
                   
                 AGGTGCACAACGCCAAGACCAAGCCCAGAGAGGAGCAGTACAACAGCAC 
               
               
                   
                   
                 CTACAGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGACTGGCTGAACG 
               
               
                   
                   
                 GCAAAGAATACAAGTGCAAAGTCTCCAACAAGGCCCTGGCTGCCCCAATC 
               
               
                   
                   
                 GAAAAGACAATCAGCAAGGCCAAGGGCCAGCCACGGGAGCCCCAGGTGT 
               
               
                   
                   
                 ACACCCTGCCCCCCAGCCGGGAGGAGATGACCAAGAACCAGGTGTCCCTG 
               
               
                   
                   
                 ACCTGTCTGGTGAAGGGCTTCTACCCCTGTGATATCGCCGTGGAGTGGGA 
               
               
                   
                   
                 GAGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCCAGTGCTGG 
               
               
                   
                   
                 ACAGCGACGGCAGCTTCTTCCTGTACAGCAAGCTGACCGTGGACAAGTCC 
               
               
                   
                   
                 AGGTGGCAGCAGGGCAACGTGTTCAGCTGCAGCGTGATGCACGAGGCCC 
               
               
                   
                   
                 TGCACAACCACTACACCCAGAAGTCCCTGAGCCTGAGCCCCGGCAAG 
               
               
                 SEQ ID NO: 
                 LCDR1 
                 KASQDVTSAVA 
               
               
                 277 
                 (Combined)  
                   
               
               
                 SEQ ID NO: 
                 LCDR2 
                 WTSTRHT 
               
               
                 278 
                 (Combined)  
                   
               
               
                 SEQ ID NO: 
                 LCDR3 
                 QQHYTTPLT 
               
               
                 279 
                 (Combined) 
                   
               
               
                 SEQ ID NO: 
                 LCDR1 
                 KASQDVTSAVA 
               
               
                 277 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 LCDR2 
                 WTSTRHT 
               
               
                 278 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 LCDR3 
                 QQHYTTPLT 
               
               
                 279 
                 (Kabat) 
                   
               
               
                 SEQ ID NO: 
                 LCDR1 
                 SQDVTSA 
               
               
                 280 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 LCDR2 
                 WTS 
               
               
                 281 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 LCDR3 
                 HYTTPL 
               
               
                 282 
                 (Chothia) 
                   
               
               
                 SEQ ID NO: 
                 LCDR1 
                 QDVTSA 
               
               
                 283 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 LCDR2 
                 WTS 
               
               
                 281 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 LCDR3 
                 QQHYTTPLT 
               
               
                 279 
                 (IMGT) 
                   
               
               
                 SEQ ID NO: 
                 VL 
                 DIQLTQSPSFLSASVGDRVTITCKASQDVTSAVAWYQQKPGKAPKLLIYWTST 
               
               
                 284 
                   
                 RHTGVPSRFSGSGSGTEYTLTISSLQPEDFATYYCQQHYTTPLTFGQGTKLEIK 
               
               
                 SEQ ID NO: 
                 DNA VL 
                 GATATTCAGCTGACCCAGTCTCCTAGCTTCCTGTCCGCTTCTGTGGGCGAC 
               
               
                 285 
                   
                 AGAGTGACCATCACATGCAAGGCCTCTCAGGACGTGACCTCTGCCGTGGC 
               
               
                   
                   
                 TTGGTATCAGCAGAAGCCTGGCAAGGCCCCTAAGCTGCTGATCTACTGGA 
               
               
                   
                   
                 CCTCCACCAGACACACCGGCGTGCCCTCTAGATTTTCCGGCTCTGGCTCTG 
               
               
                   
                   
                 GCACCGAGTATACCCTGACAATCTCCAGCCTGCAGCCTGAGGACTTCGCCA 
               
               
                   
                   
                 CCTACTACTGCCAGCAGCACTACACCACACCTCTGACCTTTGGCCAGGGCA 
               
               
                   
                   
                 CCAAGCTGGAAATCAAG 
               
               
                 SEQ ID NO: 
                 Light 
                 DIQLTQSPSFLSASVGDRVTITCKASQDVTSAVAWYQQKPGKAPKLLIYWTST 
               
               
                 286 
                 Chain 
                 RHTGVPSRFSGSGSGTEYTLTISSLQPEDFATYYCQQHYTTPLTFGQGTKLEIKR 
               
               
                   
                   
                 TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQ 
               
               
                   
                   
                 ESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 
               
               
                 SEQ ID NO: 
                 DNA Light 
                 GATATTCAGCTGACCCAGTCTCCTAGCTTCCTGTCCGCTTCTGTGGGCGAC 
               
               
                 287 
                 Chain 
                 AGAGTGACCATCACATGCAAGGCCTCTCAGGACGTGACCTCTGCCGTGGC 
               
               
                   
                   
                 TTGGTATCAGCAGAAGCCTGGCAAGGCCCCTAAGCTGCTGATCTACTGGA 
               
               
                   
                   
                 CCTCCACCAGACACACCGGCGTGCCCTCTAGATTTTCCGGCTCTGGCTCTG 
               
               
                   
                   
                 GCACCGAGTATACCCTGACAATCTCCAGCCTGCAGCCTGAGGACTTCGCCA 
               
               
                   
                   
                 CCTACTACTGCCAGCAGCACTACACCACACCTCTGACCTTTGGCCAGGGCA 
               
               
                   
                   
                 CCAAGCTGGAAATCAAGCGTACGGTGGCCGCTCCCAGCGTGTTCATCTTCC 
               
               
                   
                   
                 CCCCCAGCGACGAGCAGCTGAAGAGTGGCACCGCCAGCGTGGTGTGCCT 
               
               
                   
                   
                 GCTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAGGTGGAC 
               
               
                   
                   
                 AACGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGTCACCGAGCAGGACA 
               
               
                   
                   
                 GCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCC 
               
               
                   
                   
                 GACTACGAGAAGCATAAGGTGTACGCCTGCGAGGTGACCCACCAGGGCC 
               
               
                   
                   
                 TGTCCAGCCCCGTGACCAAGAGCTTCAACAGGGGCGAGTGC 
               
            
           
         
       
     
     Other anti-DC-SIGN antibodies or antibody fragments (e.g., antigen binding fragments) disclosed herein include amino acids that have been mutated, yet have at least 80, 85, 90, 95, 96, 97, 98, or 99 percent identity in the CDR regions with the CDR regions depicted in the sequences described in Table 8. In some embodiments, it includes mutant amino acid sequences wherein no more than 1, 2, 3, 4 or 5 amino acids have been mutated in the CDR regions when compared with the CDR regions depicted in the sequence described in Table 8. 
     Also provided herein are nucleic acid sequences that encode VH, VL, full length heavy chain, and full length light chain of antibodies and antigen binding fragments thereof that specifically bind to DC-SIGN, e.g., the nucleic acid sequences in Table 8. Such nucleic acid sequences can be optimized for expression in mammalian cells. 
     Other anti-DC-SIGN antibodies disclosed herein include those where the amino acids or nucleic acids encoding the amino acids have been mutated, yet have at least 80, 85, 90 95, 96, 97, 98, or 99 percent identity to the sequences described in Table 8. In some embodiments, antibodies or antigen binding fragments thereof include mutant amino acid sequences wherein no more than 1, 2, 3, 4 or 5 amino acids have been mutated in the variable regions when compared with the variable regions depicted in the sequence described in Table 8, while retaining substantially the same therapeutic activity. 
     Since each provided antibody binds to DC-SIGN, the VH, VL, full length light chain, and full length heavy chain sequences (amino acid sequences and the nucleotide sequences encoding the amino acid sequences) can be “mixed and matched” to create other DC-SIGN-binding antibodies disclosed herein. Such “mixed and matched” DC-SIGN-binding antibodies can be tested using binding assays known in the art (e.g., ELISAs, assays described in the Exemplification). When chains are mixed and matched, a VH sequence from a particular VH/VL pairing should be replaced with a structurally similar VH sequence. A full length heavy chain sequence from a particular full length heavy chain/full length light chain pairing should be replaced with a structurally similar full length heavy chain sequence. A VL sequence from a particular VH/VL pairing should be replaced with a structurally similar VL sequence. A full length light chain sequence from a particular full length heavy chain/full length light chain pairing should be replaced with a structurally similar full length light chain sequence. 
     Accordingly, in one embodiment, the invention provides an isolated monoclonal antibody or antigen binding region thereof having: a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 10; and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 21; wherein the antibody specifically binds to DC-SIGN. In one embodiment, the invention provides an isolated monoclonal antibody or antigen binding region thereof having: a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 34; and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 45; wherein the antibody specifically binds to DC-SIGN. In one embodiment, the invention provides an isolated monoclonal antibody or antigen binding region thereof having: a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 55; and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 64; wherein the antibody specifically binds to DC-SIGN. In another embodiment, the invention provides (i) an isolated monoclonal antibody having: a full length heavy chain comprising an amino acid sequence of any of SEQ ID NOs: 12, 36 or 57; and a full length light chain comprising an amino acid sequence of any of SEQ ID NOs: 23, 47 or 66; or (ii) a functional protein comprising an antigen binding portion thereof. 
     In another embodiment, the present disclosure provides DC-SIGN-binding antibodies that comprise the heavy chain CDR1, CDR2 and CDR3 and light chain CDR1, CDR2 and CDR3 as described in Table 8, or combinations thereof. The amino acid sequences of the VH CDR1s of the antibodies are shown in SEQ ID NOs: 1, 4, 5, 7, 25, 28, 29 and 31. The amino acid sequences of the VH CDR2s of the antibodies and are shown in SEQ ID NOs: 2, 6, 8, 26, 30 and 32. The amino acid sequences of the VH CDR3s of the antibodies are shown in SEQ ID NO: 3, 9, 27 and 33. The amino acid sequences of the VL CDR1s of the antibodies are shown in SEQ ID NOs: 14, 17, 20, 38, 41 and 44. The amino acid sequences of the VL CDR2s of the antibodies are shown in SEQ ID Nos: 15, 18, 39 and 42. The amino acid sequences of the VL CDR3s of the antibodies are shown in SEQ ID NOs: 16, 19, 40 and 43. 
     Given that each of the antibodies binds DC-SIGN and that antigen-binding specificity is provided primarily by the CDR1, CDR2 and CDR3 regions, the VH CDR1, CDR2 and CDR3 sequences and VL CDR1, CDR2 and CDR3 sequences can be “mixed and matched” (i.e., CDRs from different antibodies can be mixed and match, although each antibody must contain a VH CDR1, CDR2 and CDR3 and a VL CDR1, CDR2 and CDR3 to create other DC-SIGN-binding binding molecules disclosed herein. Such “mixed and matched” DC-SIGN-binding antibodies can be tested using the binding assays known in the art and those described in the Examples (e.g., ELISAs). When VH CDR sequences are mixed and matched, the CDR1, CDR2 and/or CDR3 sequence from a particular VH sequence should be replaced with a structurally similar CDR sequence(s). Likewise, when VL CDR sequences are mixed and matched, the CDR1, CDR2 and/or CDR3 sequence from a particular VL sequence should be replaced with a structurally similar CDR sequence(s). It will be readily apparent to the ordinarily skilled artisan that novel VH and VL sequences can be created by substituting one or more VH and/or VL CDR region sequences with structurally similar sequences from CDR sequences shown herein for monoclonal antibodies of the present disclosure. 
     Accordingly, the present disclosure provides an isolated monoclonal antibody or antigen binding region thereof comprising a heavy chain CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 1, 25, 49, 74, 88, 111, 138, 153, 178, 203, 227, 244, and 264; a heavy chain CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 2, 26, 139, 154, 179, 204, 228, and 265; a heavy chain CDR3 comprising an amino acid sequence of SEQ ID NO: 3, 27, 50, 140, 155, 180, 205, 229, 245, and 266; a light chain CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 14, 38, 59, 94, 166, 191, 216, 253, and 277; a light chain CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 15, 39, 95, 167, 192, 217, 254, and 278; and a light chain CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 16, 40, 60, 68, 82, 118, 124, 168, 193, 218, 238, 255, and 279; wherein the antibody specifically binds DC-SIGN. 
     In certain embodiments, an antibody that specifically binds to DC-SIGN is an antibody or antibody fragment (e.g., antigen binding fragment) that is described in Table 8. 
     In some embodiments, the antibody that specifically binds to human DC-SIGN comprises a heavy chain complementary determining region 1 (HCDR1) comprising the amino acid sequence of SEQ ID NO: 1; a heavy chain complementary determining region 2 (HCDR2) comprising the amino acid sequence of SEQ ID NO: 2; a heavy chain complementary determining region 3 (HCDR3) comprising the amino acid sequence of SEQ ID NO: 3; a light chain complementary determining region 1 (LCDR1) comprising the amino acid sequence of SEQ ID NO: 14; a light chain complementary determining region 2 (LCDR2) comprising the amino acid sequence of SEQ ID NO: 15; and a light chain complementary determining region 3 (LCDR3) comprising the amino acid sequence of SEQ ID NO: 16. 
     In some embodiments, the antibody that specifically binds to human DC-SIGN comprises a HCDR1 comprising the amino acid sequence of SEQ ID NO: 4; a HCDR2 comprising the amino acid sequence of SEQ ID NO: 2; a HCDR3 comprising the amino acid sequence of SEQ ID NO: 3; a LCDR1 comprising the amino acid sequence of SEQ ID NO: 14; a LCDR2 comprising the amino acid sequence of SEQ ID NO: 15; and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16. 
     In some embodiments, the antibody that specifically binds to human DC-SIGN comprises a HCDR1 comprising the amino acid sequence of SEQ ID NO: 5; a HCDR2 comprising the amino acid sequence of SEQ ID NO: 6; a HCDR3 comprising the amino acid sequence of SEQ ID NO: 3; a LCDR1 comprising the amino acid sequence of SEQ ID NO: 17; a LCDR2 comprising the amino acid sequence of SEQ ID NO: 18; and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 19. 
     In some embodiments, the antibody that specifically binds to human DC-SIGN comprises a HCDR1 comprising the amino acid sequence of SEQ ID NO: 7; a HCDR2 comprising the amino acid sequence of SEQ ID NO: 8; a HCDR3 comprising the amino acid sequence of SEQ ID NO: 9; a LCDR1 comprising the amino acid sequence of SEQ ID NO: 20; a LCDR2 comprising the amino acid sequence of SEQ ID NO: 18; and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16. 
     In some embodiments, the antibody that specifically binds to human DC-SIGN comprises a HCDR1 comprising the amino acid sequence of SEQ ID NO: 25; a HCDR2 comprising the amino acid sequence of SEQ ID NO: 26; a HCDR3 comprising the amino acid sequence of SEQ ID NO: 27; a LCDR1 comprising the amino acid sequence of SEQ ID NO: 38; a LCDR2 comprising the amino acid sequence of SEQ ID NO: 39; and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 40. 
     In some embodiments, the antibody that specifically binds to human DC-SIGN comprises a HCDR1 comprising the amino acid sequence of SEQ ID NO: 28; a HCDR2 comprising the amino acid sequence of SEQ ID NO: 26; a HCDR3 comprising the amino acid sequence of SEQ ID NO: 27; a LCDR1 comprising the amino acid sequence of SEQ ID NO: 38; a LCDR2 comprising the amino acid sequence of SEQ ID NO: 39; and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 40. 
     In some embodiments, the antibody that specifically binds to human DC-SIGN comprises a HCDR1 comprising the amino acid sequence of SEQ ID NO: 29; a HCDR2 comprising the amino acid sequence of SEQ ID NO: 30; a HCDR3 comprising the amino acid sequence of SEQ ID NO: 27; a LCDR1 comprising the amino acid sequence of SEQ ID NO: 41; a LCDR2 comprising the amino acid sequence of SEQ ID NO: 42; and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 43. 
     In some embodiments, the antibody that specifically binds to human DC-SIGN comprises a HCDR1 comprising the amino acid sequence of SEQ ID NO: 31; a HCDR2 comprising the amino acid sequence of SEQ ID NO: 32; a HCDR3 comprising the amino acid sequence of SEQ ID NO: 33; a LCDR1 comprising the amino acid sequence of SEQ ID NO: 44; a LCDR2 comprising the amino acid sequence of SEQ ID NO: 42; and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 40. 
     In some embodiments, the antibody that specifically binds to human DC-SIGN comprises a HCDR1 comprising the amino acid sequence of SEQ ID NO: 49; a HCDR2 comprising the amino acid sequence of SEQ ID NO: 26; a HCDR3 comprising the amino acid sequence of SEQ ID NO: 50; a LCDR1 comprising the amino acid sequence of SEQ ID NO: 59; a LCDR2 comprising the amino acid sequence of SEQ ID NO: 39; and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 60. 
     In some embodiments, the antibody that specifically binds to human DC-SIGN comprises a HCDR1 comprising the amino acid sequence of SEQ ID NO: 51; a HCDR2 comprising the amino acid sequence of SEQ ID NO: 26; a HCDR3 comprising the amino acid sequence of SEQ ID NO: 50; a LCDR1 comprising the amino acid sequence of SEQ ID NO: 59; a LCDR2 comprising the amino acid sequence of SEQ ID NO: 39; and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 60. 
     In some embodiments, the antibody that specifically binds to human DC-SIGN comprises a HCDR1 comprising the amino acid sequence of SEQ ID NO: 52; a HCDR2 comprising the amino acid sequence of SEQ ID NO: 30; a HCDR3 comprising the amino acid sequence of SEQ ID NO: 50; a LCDR1 comprising the amino acid sequence of SEQ ID NO: 61; a LCDR2 comprising the amino acid sequence of SEQ ID NO: 42; and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 62. 
     In some embodiments, the antibody that specifically binds to human DC-SIGN comprises a HCDR1 comprising the amino acid sequence of SEQ ID NO: 53; a HCDR2 comprising the amino acid sequence of SEQ ID NO: 32; a HCDR3 comprising the amino acid sequence of SEQ ID NO: 54; a LCDR1 comprising the amino acid sequence of SEQ ID NO: 63; a LCDR2 comprising the amino acid sequence of SEQ ID NO: 42; and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 60. 
     In some embodiments, the antibody that specifically binds to human DC-SIGN comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 10, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 21. 
     In some embodiments, the antibody that specifically binds to human DC-SIGN comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 34, and a light chain comprising the amino acid sequence of SEQ ID NO: 45. 
     In some embodiments, the antibody that specifically binds to human DC-SIGN comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 55, and a light chain comprising the amino acid sequence of SEQ ID NO: 64. 
     In some embodiments, the antibody that specifically binds to human DC-SIGN comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 34, and a light chain comprising the amino acid sequence of SEQ ID NO: 70. 
     In some embodiments, the antibody that specifically binds to human DC-SIGN comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 78, and a light chain comprising the amino acid sequence of SEQ ID NO: 84. 
     In some embodiments, the antibody that specifically binds to human DC-SIGN comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 90, and a light chain comprising the amino acid sequence of SEQ ID NO: 99. 
     In some embodiments, the antibody that specifically binds to human DC-SIGN comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 103, and a light chain comprising the amino acid sequence of SEQ ID NO: 107. 
     In some embodiments, the antibody that specifically binds to human DC-SIGN comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 114, and a light chain comprising the amino acid sequence of SEQ ID NO: 120. 
     In some embodiments, the antibody that specifically binds to human DC-SIGN comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 55, and a light chain comprising the amino acid sequence of SEQ ID NO: 126. 
     In some embodiments, the antibody that specifically binds to human DC-SIGN comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 78, and a light chain comprising the amino acid sequence of SEQ ID NO: 130. 
     In some embodiments, the antibody that specifically binds to human DC-SIGN comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 90, and a light chain comprising the amino acid sequence of SEQ ID NO: 134. 
     In some embodiments, the antibody that specifically binds to human DC-SIGN comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 145, and a light chain comprising the amino acid sequence of SEQ ID NO: 149. 
     In some embodiments, the antibody that specifically binds to human DC-SIGN comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 162, and a light chain comprising the amino acid sequence of SEQ ID NO: 174. 
     In some embodiments, the antibody that specifically binds to human DC-SIGN comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 187, and a light chain comprising the amino acid sequence of SEQ ID NO: 199. 
     In some embodiments, the antibody that specifically binds to human DC-SIGN comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 212, and a light chain comprising the amino acid sequence of SEQ ID NO: 223. 
     In some embodiments, the antibody that specifically binds to human DC-SIGN comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 234, and a light chain comprising the amino acid sequence of SEQ ID NO: 240. 
     In some embodiments, the antibody that specifically binds to human DC-SIGN comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 249, and a light chain comprising the amino acid sequence of SEQ ID NO: 260. 
     In some embodiments, the antibody that specifically binds to human DC-SIGN comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 273, and a light chain comprising the amino acid sequence of SEQ ID NO: 284. 
     In some embodiments, the antibody that specifically binds to human DC-SIGN comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 288, and a light chain comprising the amino acid sequence of SEQ ID NO: 292. 
     In some embodiments, the antibody that specifically binds to human DC-SIGN comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 298, and a light chain comprising the amino acid sequence of SEQ ID NO: 284. 
     In some embodiments, the present disclosure provides antibodies or antibody fragments (e.g., antigen binding fragments) that specifically bind an epitope in human DC-SIGN. In some embodiments, the present disclosure provides antibodies or antibody fragments (e.g., antigen binding fragments) that specifically bind to an epitope in human DC-SIGN, wherein the epitope comprises amino acid sequence of SEQ ID NOs: 320-323. 
     In some embodiments, the present disclosure provides antibodies or antibody fragments (e.g., antigen binding fragments) that specifically bind to human DC-SIGN, but not human L-SIGN. For example, the present disclosure provides antibodies or antibody fragments (e.g., antigen binding fragments) that specifically bind to human DC-SIGN at an affinity that is at least 1×, at least 2×, at least 3×, at least 4×, at least 5×, at least 10×, at least 20×, at least 50×, at least 100×, at least 1,000× higher than its affinity to human L-SIGN. 
     Once a desired epitope on an antigen is determined, it is possible to generate antibodies to that epitope, e.g., using the techniques described in the present invention. Alternatively, during the discovery process, the generation and characterization of antibodies may elucidate information about desirable epitopes. From this information, it is then possible to competitively screen antibodies for binding to the same epitope. An approach to achieve this is to conduct cross-competition studies to find antibodies that competitively bind with one another, e.g., the antibodies compete for binding to the antigen. A high throughput process for “binning” antibodies based upon their cross-competition is described in International Patent Application No. WO 2003/48731. As will be appreciated by one of skill in the art, practically anything to which an antibody can specifically bind could be an epitope. An epitope can comprises those residues to which the antibody binds. 
     The present invention also provides anti-DC-SIGN antibodies or antigen binding fragments thereof that comprise modifications in the constant regions of the heavy chain, light chain, or both the heavy and light chain wherein particular amino acid residues have mutated to cysteines, also referred to herein at “CysMab” or “Cys” antibodies. As discussed herein, drug moieties may be conjugated site specifically and with control over the number of drug moieties (“DAR Controlled”) to cysteine residues on antibodies. Cysteine modifications to antibodies for the purposes of site specifically controlling immunoconjugation are disclosed, for example, in WO2014/124316, which is incorporated herein by reference in its entirety. 
     In some embodiments, the anti-DC-SIGN antibodies have been modified at positions 152 and/or 375 of the heavy chain, wherein the positions are defined according to the EU numbering system. Namely, the modifications are E152C and/or S375C. In some embodiments, the anti-DC-SIGN antibodies have been modified at position 152 of the heavy chain, wherein the positions are defined according to the EU numbering system. Namely, the modification is E152C. In some embodiments, the anti-DC-SIGN antibodies have been modified at position 375 of the heavy chain, wherein the positions are defined according to the EU numbering system. Namely, the modification is S375C. In other embodiments, the anti-DC-SIGN antibodies have been modified at position 360 of the heavy chain and position 107 of the kappa light chain, wherein the positions are defined according to the EU numbering system. Namely, the modifications are K360C and K107C. 
     The present invention also provides nucleic acid sequences that encode the VH, VL, the full length heavy chain, and the full length light chain of the antibodies that specifically bind to P-cadherin. Such nucleic acid sequences can be optimized for expression in mammalian cells. 
     Identification of Epitopes and Antibodies that Bind to the Same Epitope 
     The present invention also provides antibodies and antibody fragments (e.g., antigen binding fragments) that specifically bind to the same epitope as the anti-DC-SIGN antibodies described in Table 8, or cross compete with the antibodies described in Table 8. Additional antibodies and antibody fragments (e.g., antigen binding fragments) can therefore be identified based on their ability to cross-compete (e.g., to competitively inhibit the binding of, in a statistically significant manner) with other antibodies of the invention in DC-SIGN binding assays, for example, via BIACORE or assays known to persons skilled in the art for measuring binding. The ability of a test antibody to inhibit the binding of antibodies and antibody fragments (e.g., antigen binding fragments) of the present invention to a DC-SIGN (e.g., human DC-SIGN) demonstrates that the test antibody can compete with that antibody or antibody fragment (e.g., antigen binding fragments) for binding to DC-SIGN; such an antibody may, according to non-limiting theory, bind to the same or a related (e.g., a structurally similar or spatially proximal or overlapping) epitope on the DC-SIGN protein as the antibody or antibody fragment (e.g., antigen binding fragments) with which it competes. In certain embodiments, the antibodies that bind to the same epitope on DC-SIGN as the antibodies or antibody fragments (e.g., antigen binding fragments) described in Table 8 are human or humanized monoclonal antibodies. Such human or humanized monoclonal antibodies can be prepared and isolated as described herein. 
     Modification of Framework or Fc Region 
     Antibodies and antibody conjugates disclosed herein may comprise modified antibodies or antigen binding fragments thereof that comprise modifications to framework residues within VH and/or VL, e.g. to improve the properties of the antibody/antibody conjugate. 
     In some embodiments, framework modifications are made to decrease immunogenicity of an antibody. For example, one approach is to “back-mutate” one or more framework residues to a corresponding germline sequence. Such residues can be identified by comparing antibody framework sequences to germline sequences from which the antibody is derived. To “match” framework region sequences to desired germline configuration, residues can be “back-mutated” to a corresponding germline sequence by, for example, site-directed mutagenesis. Such “back-mutated” antibodies are also intended to be encompassed by the invention. 
     Another type of framework modification involves mutating one or more residues within a framework region, or even within one or more CDR regions, to remove T-cell epitopes to thereby reduce potential immunogenicity of the antibody. This approach is also referred to as “deimmunization” and is described in further detail in U.S. Patent Publication No. 20030153043 by Carr et al. 
     In addition or alternative to modifications made within a framework or CDR regions, antibodies disclosed herein may be engineered to include modifications within the Fc region, typically to alter one or more functional properties of the antibody, such as serum half-life, complement fixation, Fc receptor binding, and/or antigen-dependent cellular cytotoxicity. 
     Furthermore, an antibody disclosed herein may be chemically modified (e.g., one or more chemical moieties can be attached to the antibody) or be modified to alter its glycosylation, again to alter one or more functional properties of the antibody. Each of these embodiments is described in further detail below. 
     In one embodiment, the hinge region of CH 1  is modified such that the number of cysteine residues in the hinge region is altered, e.g., increased or decreased. This approach is described further in U.S. Pat. No. 5,677,425 by Bodmer et al. The number of cysteine residues in the hinge region of CH 1  is altered to, for example, facilitate assembly of the light and heavy chains or to increase or decrease the stability of the antibody. 
     In some embodiments antibodies or antibody fragments (e.g., antigen binding fragment) useful in antibody conjugates disclosed herein include modified or engineered antibodies, such as an antibody modified to introduce one or more cysteine residues as sites for conjugation to a drug moiety (Junutula J R, et al.: Nat Biotechnol 2008, 26:925-932). In one embodiment, the invention provides a modified antibody or antibody fragment thereof comprising a substitution of one or more amino acids with cysteine at the positions described herein. Sites for cysteine substitution are in the constant regions of the antibody and are thus applicable to a variety of antibodies, and the sites are selected to provide stable and homogeneous conjugates. A modified antibody or fragment can have two or more cysteine substitutions, and these substitutions can be used in combination with other antibody modification and conjugation methods as described herein. Methods for inserting cysteine at specific locations of an antibody are known in the art, see, e.g., Lyons et al, (1990) Protein Eng., 3:703-708, WO 2011/005481, WO2014/124316, WO 2015/138615. In certain embodiments a modified antibody or antibody fragment comprises a substitution of one or more amino acids with cysteine on its constant region selected from positions 117, 119, 121, 124, 139, 152, 153, 155, 157, 164, 169, 171, 174, 189, 205, 207, 246, 258, 269, 274, 286, 288, 290, 292, 293, 320, 322, 326, 333, 334, 335, 337, 344, 355, 360, 375, 382, 390, 392, 398, 400 and 422 of a heavy chain of the antibody or antibody fragment, and wherein the positions are numbered according to the EU system. In some embodiments a modified antibody or antibody fragment comprises a substitution of one or more amino acids with cysteine on its constant region selected from positions 107, 108, 109, 114, 129, 142, 143, 145, 152, 154, 156, 159, 161, 165, 168, 169, 170, 182, 183, 197, 199, and 203 of a light chain of the antibody or antibody fragment, wherein the positions are numbered according to the EU system, and wherein the light chain is a human kappa light chain. In certain embodiments a modified antibody or antibody fragment thereof comprises a combination of substitution of two or more amino acids with cysteine on its constant regions wherein the combinations comprise substitutions at positions 375 of an antibody heavy chain, position 152 of an antibody heavy chain, position 360 of an antibody heavy chain, or position 107 of an antibody light chain and wherein the positions are numbered according to the EU system. In certain embodiments a modified antibody or antibody fragment thereof comprises a substitution of one amino acid with cysteine on its constant regions wherein the substitution is position 375 of an antibody heavy chain, position 152 of an antibody heavy chain, position 360 of an antibody heavy chain, position 107 of an antibody light chain, position 165 of an antibody light chain or position 159 of an antibody light chain and wherein the positions are numbered according to the EU system, and wherein the light chain is a kappa chain. 
     In particular embodiments a modified antibody or antibody fragment thereof comprises a combination of substitution of two amino acids with cysteine on its constant regions, wherein the modified antibody or antibody fragment thereof comprises cysteines at positions 152 and 375 of an antibody heavy chain, wherein the positions are numbered according to the EU system. 
     In other particular embodiments a modified antibody or antibody fragment thereof comprises a substitution of one amino acid with cysteine at position 360 of an antibody heavy chain and wherein the positions are numbered according to the EU system. 
     In other particular embodiments a modified antibody or antibody fragment thereof comprises a substitution of one amino acid with cysteine at position 107 of an antibody light chain and wherein the positions are numbered according to the EU system, and wherein the light chain is a kappa chain. 
     In additional embodiments antibodies or antibody fragments (e.g., antigen binding fragment) useful in antibody conjugates disclosed herein include modified or engineered antibodies, such as an antibody modified to introduce one or more other reactive amino acid (other than cysteine), including Pcl (pyrroline-carboxy-lysine), pyrrolysine, peptide tags (such as S6, A1 and ybbR tags), and non-natural amino acids, in place of at least one amino acid of the native sequence, thus providing a reactive site on the antibody or antigen binding fragment for conjugation to a drug moiety of Formula (I) or subformulae thereof. For example, the antibodies or antibody fragments can be modified to incorporate Pcl or pyrrolysine (W. Ou et al. (2011) PNAS 108 (26), 10437-10442; WO2014124258) or unnatural amino acids (J. Y. Axup, et al. Proc Natl Acad Sci USA, 109 (2012), pp. 16101-16106; for review, see C. C. Liu and P. G. Schultz (2010) Annu Rev Biochem 79, 413-444; C. H. Kim, et al., (2013) Curr Opin Chem Biol. 17, 412-419) as sites for conjugation to a drug. Similarly, peptide tags for enzymatic conjugation methods can be introduced into an antibody (Strop P. et al. Chem Biol. 2013, 20(2):161-7; Rabuka D., Curr Opin Chem Biol. 2010 December; 14(6):790-6; Rabuka D, et al., Nat Protoc. 2012, 7(6):1052-67). One other example is the use of 4′-phosphopantetheinyl transferases (PPTase) for the conjugation of Coenzyme A analogs (WO2013184514; Grinewald J, et al., Bioconjug Chem. 2015 Dec. 16; 26(12):2554-62). Methods for conjugating such modified or engineered antibodies with payloads or linker-payload combinations are known in the art. 
     In another embodiment, an Fc hinge region of an antibody is mutated to decrease the biological half-life of the antibody. More specifically, one or more amino acid mutations are introduced into the CH2-CH3 domain interface region of the Fc-hinge fragment such that the antibody has impaired Staphylococcyl Protein A (SpA) binding relative to native Fc-hinge domain SpA binding. This approach is described in further detail in U.S. Pat. No. 6,165,745 by Ward et al. 
     In yet other embodiments, an Fc region is altered by replacing at least one amino acid residue with a different amino acid residue to alter the effector functions of the antibody. For example, one or more amino acids can be replaced with a different amino acid residue such that the antibody has an altered affinity for an effector ligand but retains the antigen-binding ability of the parent antibody. The effector ligand to which affinity is altered can be, for example, an Fc receptor or the C1 component of complement. This approach is described in, e.g., U.S. Pat. Nos. 5,624,821 and 5,648,260, both by Winter et al. 
     In another embodiment, one or more amino acids selected from amino acid residues can be replaced with a different amino acid residue such that the antibody has altered Clq binding and/or reduced or abolished complement dependent cytotoxicity (CDC). This approach is described in, e.g., U.S. Pat. No. 6,194,551 by Idusogie et al. 
     In another embodiment, one or more amino acid residues are altered to thereby alter the ability of the antibody to fix complement. This approach is described in, e.g., the PCT Publication WO 94/29351 by Bodmer et al. Allotypic amino acid residues include, but are not limited to, constant region of a heavy chain of the IgG1, IgG2, and IgG3 subclasses as well as constant region of a light chain of the kappa isotype as described by Jefferis et al., MAbs. 1:332-338 (2009). 
     In a further embodiment, the Fc region is modified to “silence” the effector function of the antibody, for example, reduce or eliminate the ability of the antibody to mediate antibody dependent cellular cytotoxicity (ADCC) and/or antibody dependent cellular phagocytosis (ADCP). This can be achieve, for example, by introducing a mutation in the Fc region of the antibodies. Such mutations have been described in the art: LALA and N297A (Strohl, W., 2009, Curr. Opin. Biotechnol. vol. 20(6):685-691); and D265A (Baudino et al., 2008, J. Immunol. 181: 6664-69; Strohl, W., supra). Examples of silent Fc IgG1 antibodies comprise the so-called LALA mutant comprising L234A and L235A mutation in the IgG1 Fc amino acid sequence. Another example of a silent IgG1 antibody comprises the D265A mutation. Another silent IgG1 antibody comprises the so-called DAPA mutant comprising D265A and P329A mutations in the IgG1 Fc amino acid sequence. Another silent IgG1 antibody comprises the N297A mutation, which results in aglycosylated/non-glycosylated antibodies. 
     In yet another embodiment, the Fc region is modified to increase the ability of the antibody to mediate antibody dependent cellular cytotoxicity (ADCC) and/or antibody dependent cellular phagocytosis (ADCP), for example, by modifying one or more amino acid residues to increase the affinity of the antibody for an activating Fcγ receptor, or to decrease the affinity of the antibody for an inhibitory Fcγ receptor. Human activating Fcγ receptors include FcγRIa, FcγRIIa, FcγRIIIa, and FcγRIIIb, and human inhibitory Fcγ receptor includes FcγRIIb. This approach is described in, e.g., the PCT Publication WO 00/42072 by Presta. Moreover, binding sites on human IgG1 for FcγRI, FcγRII, FcγRIII and FcRn have been mapped and variants with improved binding have been described (see Shields et al., J. Biol. Chem. 276:6591-6604, 2001). Optimization of Fc-mediated effector functions of monoclonal antibodies such as increased ADCC/ADCP function has been described (see Strohl, W. R., Current Opinion in Biotechnology 2009; 20:685-691.) In some embodiments, an antibody conjugate comprises an immunoglobulin heavy chain comprising a mutation or combination of mutations conferring enhanced ADCC/ADCP function, e.g., one or more mutations selected from G236A, S239D, F243L, P2471, D280H, K290S, R292P, S298A, S298D, S298V, Y300L, V3051, A330L, 1332E, E333A, K334A, A339D, A339Q, A339T, P396L (all positions by EU numbering). 
     In another embodiment, the Fc region is modified to increase the ability of the antibody to mediate ADCC and/or ADCP, for example, by modifying one or more amino acids to increase the affinity fo the antibody for an activating receptor that would typically not recognize the parent antibody, such as FcαRI. This approach is descried in, e.g., Borrok et al., mAbs. 7(4):743-751. In particular embodiments, an antibody conjugate comprises an immunoglobulin heavy chain comprising a mutation or a fusion of one or more antibody sequences conferring enhanced ADCC and/or ADCP function. 
     In still another embodiment, glycosylation of an antibody is modified. For example, an aglycosylated antibody can be made (i.e., the antibody lacks glycosylation). Glycosylation can be altered to, for example, increase the affinity of the antibody for “antigen.” Such carbohydrate modifications can be accomplished by, for example, altering one or more sites of glycosylation within the antibody sequence. For example, one or more amino acid substitutions can be made that result in elimination of one or more variable region framework glycosylation sites to thereby eliminate glycosylation at that site. Such aglycosylation may increase the affinity of the antibody for antigen. Such an approach is described in, e.g., U.S. Pat. Nos. 5,714,350 and 6,350,861 by Co et al. 
     Additionally or alternatively, an antibody can be made that has an altered type of glycosylation, such as a hypofucosylated antibody having reduced amounts of fucosyl residues or an antibody having increased bisecting GlcNac structures. Such altered glycosylation patterns have been demonstrated to increase the ADCC ability of antibodies. Such carbohydrate modifications can be accomplished by, for example, expressing the antibody in a host cell with altered glycosylation machinery. Cells with altered glycosylation machinery have been described in the art and can be used as host cells in which to express recombinant antibodies of the invention to thereby produce an antibody with altered glycosylation. For example, EP 1,176,195 by Hang et al. describes a cell line with a functionally disrupted FUT8 gene, which encodes a fucosyl transferase, such that antibodies expressed in such a cell line exhibit hypofucosylation. PCT Publication WO 03/035835 by Presta describes a variant CHO cell line, Lecl3 cells, with reduced ability to attach fucose to Asn(297)-linked carbohydrates, also resulting in hypofucosylation of antibodies expressed in that host cell (see also Shields et al., (2002) J. Biol. Chem. 277:26733-26740). PCT Publication WO 99/54342 by Umana et al. describes cell lines engineered to express glycoprotein-modifying glycosyl transferases (e.g., beta(1,4)-N acetylglucosaminyltransferase III (GnTIII)) such that antibodies expressed in the engineered cell lines exhibit increased bisecting GlcNac structures which results in increased ADCC activity of the antibodies (see also Umana et al., Nat. Biotech. 17:176-180, 1999). 
     In another embodiment, the antibody is modified to increase its biological half-life. Various approaches are possible. For example, one or more of the following mutations can be introduced: T252L, T254S, T256F, as described in U.S. Pat. No. 6,277,375 to Ward. Alternatively, to increase the biological half-life, the antibody can be altered within the CH1 or CL region to contain a salvage receptor binding epitope taken from two loops of a CH2 domain of an Fc region of an IgG, as described in U.S. Pat. Nos. 5,869,046 and 6,121,022 by Presta et al. 
     Production of Anti-DC-SIGN Antibodies 
     Anti-DC-SIGN antibodies and antibody fragments (e.g., antigen binding fragments) thereof can be produced by any means known in the art, including but not limited to, recombinant expression, chemical synthesis, and enzymatic digestion of antibody tetramers, whereas full-length monoclonal antibodies can be obtained by, e.g., hybridoma or recombinant production. Recombinant expression can be from any appropriate host cells known in the art, for example, mammalian host cells, bacterial host cells, yeast host cells, insect host cells, etc. 
     Also provided herein are polynucleotides encoding antibodies described herein, e.g., polynucleotides encoding heavy or light chain variable regions or segments comprising complementarity determining regions as described herein. In some embodiments, a polynucleotide encoding the heavy chain variable regions has at least 85%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% nucleic acid sequence identity with a polynucleotide of SEQ ID NO: 11, 35, 56, 79, 91, 104, 115, 146, 163, 188, 213, 235, 250, 274, 289, or 299. In some embodiments, a polynucleotide encoding the light chain variable regions has at least 85%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% nucleic acid sequence identity with a polynucleotide of SEQ ID NO: 22, 46, 65, 71, 85, 100, 108, 121, 127, 131, 135, 150, 175, 200, 224, 241, 261, 285, or 293. 
     In some embodiments, a polynucleotide encoding the heavy chain has at least 85%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% nucleic acid sequence identity with a polynucleotide of any of SEQ ID NOs: 13, 37, 58, 81, 93, 106, 117, 148, 165, 190, 215, 237, 252, 276, 291, or 301. In some embodiments, a polynucleotide encoding the light chain has at least 85%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% nucleic acid sequence identity with a polynucleotide of SEQ ID NO: 24, 48, 67, 73, 87, 102, 110, 123, 129, 133, 137, 152, 177, 202, 226, 243, 263, 287, or 295. 
     Some polynucleotides disclosed herein encode a variable region of an anti-DC-SIGN antibody. Some polynucleotides disclosed herein encode both a variable region and a constant region of an anti-DC-SIGN antibody. Some polynucleotide sequences encode a polypeptide that comprises variable regions of both a heavy chain and a light chain of an anti-DC-SIGN antibody. Some polynucleotides encode two polypeptide segments that respectively are substantially identical to the variable regions of a heavy chain and a light chain of any anti-DC-SIGN antibodies disclosed herein. 
     Polynucleotide sequences can be produced by de novo solid-phase DNA synthesis or by PCR mutagenesis of an existing sequence encoding an antibody or its binding fragment. Direct chemical synthesis of nucleic acids can be accomplished by methods known in the art, such as the phosphotriester method of Narang et al., Meth. Enzymol. 68:90, 1979; the phosphodiester method of Brown et al., Meth. Enzymol. 68:109, 1979; the diethylphosphoramidite method of Beaucage et al., Tetra. Lett., 22:1859, 1981; and the solid support method of U.S. Pat. No. 4,458,066. Introducing mutations to a polynucleotide sequence by PCR can be performed as described in, e.g., PCR Technology: Principles and Applications for DNA Amplification, H. A. Erlich (Ed.), Freeman Press, NY, NY, 1992; PCR Protocols: A Guide to Methods and Applications, Innis et al. (Ed.), Academic Press, San Diego, Calif., 1990; Mattila et al., Nucleic Acids Res. 19:967, 1991; and Eckert et al., PCR Methods and Applications 1:17, 1991. 
     Also provided are expression vectors and host cells for producing antibodies described herein. Various expression vectors can be employed to express polynucleotides encoding antibody chains or binding fragments. Both viral-based and nonviral expression vectors can be used to produce antibodies in a mammalian host cell. 
     Nonviral vectors and systems include plasmids, episomal vectors, typically with an expression cassette for expressing a protein or RNA, and human artificial chromosomes (see, e.g., Harrington et al., Nat Genet 15:345, 1997). For example, nonviral vectors useful for expression of polynucleotides and polypeptides in mammalian (e.g., human) cells include pThioHis A, B &amp; C, pCDNATM3.1/His, pEBVHis A, B &amp; C (Invitrogen, San Diego, Calif.), MPSV vectors, and numerous other vectors known in the art for expressing other proteins. Useful viral vectors include vectors based on retroviruses, adenoviruses, adenoassociated viruses, herpes viruses, vectors based on SV40, papilloma virus, HBP Epstein Barr virus, vaccinia virus vectors and Semliki Forest virus (SFV). See, Brent et al., supra; Smith, Annu. Rev. Microbiol. 49:807, 1995; and Rosenfeld et al., Cell 68:143, 1992. 
     Choice of expression vector depends on the intended host cells in which a vector is to be expressed. Typically, expression vectors contain a promoter and other regulatory sequences (e.g., enhancers) that are operably linked to polynucleotides encoding an antibody chain or fragment. In some embodiments, an inducible promoter is employed to prevent expression of inserted sequences except under inducing conditions. Inducible promoters include, e.g., arabinose, lacZ, metallothionein promoter or a heat shock promoter. Cultures of transformed organisms can be expanded under noninducing conditions without biasing the population for coding sequences whose expression products are better tolerated by host cells. In addition to promoters, other regulatory elements may also be required or desired for efficient expression of an antibody chain or fragment. Elements typically include an ATG initiation codon and adjacent ribosome binding site or other sequences. In addition, efficiency of expression may be enhanced by the inclusion of enhancers appropriate to the cell system in use (see, e.g., Scharf et al., Results Probl. Cell Differ. 20:125, 1994; and Bittner et al., Meth. Enzymol., 153:516, 1987). For example, an SV40 enhancer or CMV enhancer may be used to increase expression in mammalian host cells. 
     Expression vectors may also provide a secretion signal sequence position to form a fusion protein with polypeptides encoded by inserted antibody sequences. More often, inserted antibody sequences are linked to a signal sequence before inclusion in the vector. Vectors to be used to receive sequences encoding antibody light and heavy chain variable domains sometimes also encode constant regions or parts thereof. Such vectors allow expression of variable regions as fusion proteins with constant regions, thereby leading to production of intact antibodies or fragments thereof. Typically, such constant regions are human. 
     Host cells for harboring and expressing antibody chains can be either prokaryotic or eukaryotic.  E. coli  is one prokaryotic host useful for cloning and expressing polynucleotides of the present disclosure. Other microbial hosts suitable for use include bacilli, such as  Bacillus subtilis , and other enterobacteriaceae, such as  Salmonella, Serratia , and various  Pseudomonas  species. In these prokaryotic hosts, one can also make expression vectors, which typically contain expression control sequences compatible with the host cell (e.g., an origin of replication). In addition, any number of a variety of well-known promoters will be present, such as a lactose promoter system, a tryptophan (trp) promoter system, a beta-lactamase promoter system, or a promoter system from phage lambda. The promoters typically control expression, optionally with an operator sequence, and have ribosome binding site sequences and the like, for initiating and completing transcription and translation. Other microbes, such as yeast, can also be employed to express polypeptides, including antibodies. Insect cells in combination with baculovirus vectors can also be used. 
     In some particular embodiments, mammalian host cells are used to express and produce polypeptides of the present disclosure. For example, they can be either a hybridoma cell line expressing endogenous immunoglobulin genes (e.g., myeloma hybridoma clones) or a mammalian cell line harboring an exogenous expression vector (e.g., the SP2/0 myeloma cells). These include any normal mortal or normal or abnormal immortal animal or human cell. For example, a number of suitable host cell lines capable of secreting intact immunoglobulins have been developed, including various CHO cell lines, Cos cell lines, HeLa cells, myeloma cell lines, transformed B-cells and hybridomas. Use of mammalian tissue cell culture to express polypeptides is discussed generally in, e.g., Winnacker, From Genes to Clones, VCH Publishers, N.Y., N.Y., 1987. Expression vectors for mammalian host cells can include expression control sequences, such as an origin of replication, a promoter, and an enhancer (see, e.g., Queen et al., Immunol. Rev. 89:49-68, 1986), and necessary processing information sites, such as ribosome binding sites, RNA splice sites, polyadenylation sites, and transcriptional terminator sequences. Expression vectors usually contain promoters derived from mammalian genes or from mammalian viruses. Suitable promoters may be constitutive, cell type-specific, stage-specific, and/or modulatable or regulatable. Useful promoters include, but are not limited to, a metallothionein promoter, a constitutive adenovirus major late promoter, a dexamethasoneinducible MMTV promoter, a SV40 promoter, a MRP polIII promoter, a constitutive MPSV promoter, a tetracycline-inducible CMV promoter (such as the human immediate-early CMV promoter), a constitutive CMV promoter, and promoter-enhancer combinations known in the art. 
     Methods for introducing expression vectors containing polynucleotide sequences of interest vary depending on the type of cellular host. For example, calcium chloride transfection is commonly utilized for prokaryotic cells, whereas calcium phosphate treatment or electroporation may be used for other cellular hosts (see generally Sambrook et al., supra). Other methods include, e.g., electroporation, calcium phosphate treatment, liposome-mediated transformation, injection and microinjection, ballistic methods, virosomes, immunoliposomes, polycation:nucleic acid conjugates, naked DNA, artificial virions, fusion to the herpes virus structural protein VP22 (Elliot and O&#39;Hare, Cell 88:223, 1997), agent-enhanced uptake of DNA, and ex vivo transduction. For long-term, high-yield production of recombinant proteins, stable expression will often be desired. For example, cell lines which stably express antibody chains or binding fragments can be prepared using expression vectors disclosed herein which contain viral origins of replication or endogenous expression elements and a selectable marker gene. Following introduction of the vector, cells may be allowed to grow for 1-2 days in an enriched media before they are switched to selective media. The purpose of the selectable marker is to confer resistance to selection, and its presence allows growth of cells which successfully express the introduced sequences in selective media. Resistant, stably transfected cells can be proliferated using tissue culture techniques appropriate to the cell type. 
     Therapeutic Uses and Methods of Treatment 
     Provided antibody conjugates are useful in a variety of applications including, but not limited to, treatment of cancer. In certain embodiments, antibody conjugates provided herein are useful for inhibiting tumor growth, reducing tumor volume, inducing differentiation, and/or reducing the tumorigenicity of a tumor. The methods of use can be in vitro, ex vivo, or in vivo methods. 
     In some embodiments, provided herein are methods of treating, preventing, or ameliorating a disease, e.g., a cancer, in a subject in need thereof, e.g., a human patient, by administering to the subject any of the antibody conjugates described herein. Also provided is use of the antibody conjugates of the invention to treat or prevent disease in a subject, e.g., a human patient. Additionally provided is use of antibody conjugates in treatment or prevention of disease in a subject. In some embodiments provided are antibody conjugates for use in manufacture of a medicament for treatment or prevention of disease in a subject. In certain embodiments, the disease treated with antibody conjugates is a cancer. 
     In one aspect, the immunoconjugates described herein can be used to treat a solid tumor. Examples of solid tumors include malignancies, e.g., sarcomas, adenocarcinomas, blastomas, and carcinomas, of the various organ systems, such as those affecting liver, lung, breast, lymphoid, biliarintestinal (e.g., colon), genitourinary tract (e.g., renal, urothelial cells), prostate and pharynx. Adenocarcinomas include malignancies such as most colon cancers, rectal cancer, renal-cell carcinoma, liver cancer, small cell lung cancer, non-small cell carcinoma of the lung, cancer of the small intestine and cancer of the esophagus. In one embodiment, the cancer is a melanoma, e.g., an advanced stage melanoma. Examples of other cancers that can be treated include bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, colorectal cancer, cancer of the anal region, cancer of the peritoneum, stomach or gastric cancer, esophageal cancer, salivary gland carcinoma, testicular cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, penile carcinoma, glioblastoma, neuroblastoma, cervical cancer, Hodgkin Disease, non-Hodgkin lymphoma, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, chronic or acute leukemias including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, solid tumors of childhood, lymphocytic lymphoma, cancer of the bladder, cancer of the kidney or ureter, carcinoma of the renal pelvis, neoplasm of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axis tumor, brain stem glioma, pituitary adenoma, Kaposi&#39;s sarcoma, neuroendocrine tumors (including carcinoid tumors, gastrinoma, and islet cell cancer), mesothelioma, schwannoma (including acoustic neuroma), meningioma, epidermoid cancer, squamous cell cancer, T-cell lymphoma, environmentally induced cancers including those induced by asbestos, and combinations of said cancers. 
     In another aspect, the immunoconjugates described herein can be used to treat a hematological cancer. Hematological cancers include leukemia, lymphoma, and malignant lymphoproliferative conditions that affect blood, bone marrow and the lymphatic system. 
     Leukemia can be classified as acute leukemia and chronic leukemia. Acute leukemia can be further classified as acute myelogenous leukemia (AML) and acute lymphoid leukemia (ALL). Chronic leukemia includes chronic myelogenous leukemia (CML) and chronic lymphoid leukemia (CLL). Other related conditions include myelodysplastic syndromes (MDS, formerly known as “preleukemia”) which are a diverse collection of hematological conditions united by ineffective production (or dysplasia) of myeloid blood cells and risk of transformation to AML. 
     Lymphoma is a group of blood cell tumors that develop from lymphocytes. Exemplary lymphomas include non-Hodgkin lymphoma and Hodgkin lymphoma. 
     In some embodiments, the cancer is a hematologic cancer including but is not limited to, e.g., acute leukemias including but not limited to, e.g., B-cell acute lymphoid leukemia (“BALL”), T-cell acute lymphoid leukemia (“TALL”), acute lymphoid leukemia (ALL); one or more chronic leukemias including but not limited to, e.g., chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL); additional hematologic cancers or hematologic conditions including, but not limited to, e.g., B cell prolymphocytic leukemia, blastic plasmacytoid dendritic cell neoplasm, Burkitt&#39;s lymphoma, diffuse large B cell lymphoma, Follicular lymphoma, Hairy cell leukemia, small cell- or a large cell-follicular lymphoma, malignant lymphoproliferative conditions, MALT lymphoma, mantle cell lymphoma, Marginal zone lymphoma, multiple myeloma, myelodysplasia and myelodysplastic syndrome, non-Hodgkin lymphoma, plasmablastic lymphoma, plasmacytoid dendritic cell neoplasm, Waldenstrom macroglobulinemia, and “preleukemia” which are a diverse collection of hematological conditions united by ineffective production (or dysplasia) of myeloid blood cells, and the like. Further a disease associated with a tumor antigen expression includes, but not limited to, e.g., atypical and/or non-classical cancers, malignancies, precancerous conditions or proliferative diseases expressing a tumor antigen as described herein. Metastatic lesions of the aforementioned cancers can also be treated or prevented using the methods and compositions of the invention. 
     Method of administration of such antibody conjugates include, but are not limited to, parenteral (e.g., intravenous) administration, e.g., injection as a bolus or continuous infusion over a period of time, oral administration, intramuscular administration, intratumoral administration, intramuscular administration, intraperitoneal administration, intracerobrospinal administration, subcutaneous administration, intra-articular administration, intrasynovial administration, injection to lymph nodes, or intrathecal administration. 
     For treatment of disease, appropriate dosage of antibody conjugates of the present invention depends on various factors, such as the type of disease to be treated, the severity and course of the disease, the responsiveness of the disease, previous therapy, patient&#39;s clinical history, and so on. Antibody conjugates can be administered one time or over a series of treatments lasting from several days to several months, or until a cure is effected or a diminution of the disease state is achieved (e.g., reduction in tumor size). Optimal dosing schedules can be calculated from measurements of drug accumulation in the body of the patient and will vary depending on the relative potency of a particular antibody conjugate. In some embodiments, dosage is from 0.01 mg to 20 mg (e.g., 0.01 mg, 0.02 mg, 0.03 mg, 0.04 mg, 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, or 20 mg) per kg of body weight, and can be given once or more daily, weekly, monthly or yearly. In certain embodiments, the antibody conjugate of the present invention is given once every two weeks or once every three weeks. In certain embodiments, the antibody conjugate of the present invention is given only once. The treating physician can estimate repetition rates for dosing based on measured residence times and concentrations of the drug in bodily fluids or tissues. 
     Combination Therapy 
     In certain instances, an antibody conjugate of the present invention can be combined with other therapeutic agents, such as other anti-cancer agents, anti-allergic agents, anti-nausea agents (or anti-emetics), pain relievers, cytoprotective agents, and combinations thereof. 
     General chemotherapeutic agents considered for use in combination therapies include anastrozole (Arimidex®), bicalutamide (Casodex®), bleomycin sulfate (Blenoxane®), busulfan (Myleran®), busulfan injection (Busulfex®), capecitabine (Xeloda®), N4-pentoxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin (Paraplatin®), carmustine (BiCNU®), chlorambucil (Leukeran®), cisplatin (Platinol®), cladribine (Leustatin®), cyclophosphamide (Cytoxan® or Neosar®), cytarabine, cytosine arabinoside (Cytosar-U®), cytarabine liposome injection (DepoCyt®), dacarbazine (DTIC-Dome®), dactinomycin (Actinomycin D, Cosmegan), daunorubicin hydrochloride (Cerubidine®), daunorubicin citrate liposome injection (DaunoXome®), dexamethasone, docetaxel (Taxotere®), doxorubicin hydrochloride (Adriamycin®, Rubex®), etoposide (Vepesid®), fludarabine phosphate (Fludara®), 5-fluorouracil (Adrucil®, Efudex®), flutamide (Eulexin®), tezacitibine, Gemcitabine (difluorodeoxycitidine), hydroxyurea (Hydrea®), Idarubicin (Idamycin®), ifosfamide (IFEX®), irinotecan (Camptosar®), L-asparaginase (ELSPAR®), leucovorin calcium, melphalan (Alkeran®), 6-mercaptopurine (Purinethol®), methotrexate (Folex®), mitoxantrone (Novantrone®), mylotarg, paclitaxel (Taxol®), phoenix (Yttrium90/MX-DTPA), pentostatin, polifeprosan 20 with carmustine implant (Gliadel®), tamoxifen citrate (Nolvadex®), teniposide (Vumon®), 6-thioguanine, thiotepa, tirapazamine (Tirazone®), topotecan hydrochloride for injection (Hycamptin®), vinblastine (Velban®), vincristine (Oncovin®), vinorelbine (Navelbine®), epirubicin (Ellence®), oxaliplatin (Eloxatin®), exemestane (Aromasin®), letrozole (Femara®), and fulvestrant (Faslodex®). 
     The term “pharmaceutical combination” as used herein refers to either a fixed combination in one dosage unit form, or non-fixed combination or a kit of parts for the combined administration where two or more therapeutic agents may be administered independently at the same time or separately within time intervals, especially where these time intervals allow that the combination partners show a cooperative, e.g. synergistic effect. 
     The term “combination therapy” refers to the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in the present disclosure. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients. Alternatively, such administration encompasses co-administration in multiple, or in separate containers (e.g., capsules, powders, and liquids) for each active ingredient. Powders and/or liquids may be reconstituted or diluted to a desired dose prior to administration. In addition, such administration also encompasses use of each type of therapeutic agent in a sequential manner, either at approximately the same time or at different times. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein. 
     The combination therapy can provide “synergy” and prove “synergistic”, i.e., the effect achieved when the active ingredients used together is greater than the sum of the effects that results from using the compounds separately. A synergistic effect can be attained when the active ingredients are: (1) co-formulated and administered or delivered simultaneously in a combined, unit dosage formulation; (2) delivered by alternation or in parallel as separate formulations; or (3) by some other regimen. When delivered in alternation therapy, a synergistic effect can be attained when the compounds are administered or delivered sequentially, e.g., by different injections in separate syringes. In general, during alternation therapy, an effective dosage of each active ingredient is administered sequentially, i.e., serially, whereas in combination therapy, effective dosages of two or more active ingredients are administered together. 
     In one embodiment, the present invention provides a method of treating cancer by administering to a subject in need thereof antibody conjugate of the present invention in combination with one or more anti-HER2 antibodies, e.g., trastuzumab, pertuzumab, margetuximab, or HT-19 described above, or with other anti-HER2 conjugates, e.g., ado-trastuzumab emtansine (also known as Kadcyla®, or T-DM1). 
     In one embodiment, the present invention provides a method of treating cancer by administering to a subject in need thereof antibody conjugate of the present invention in combination with one or more tyrosine kinase inhibitors, including but not limited to, EGFR inhibitors, Her3 inhibitors, IGFR inhibitors, and Met inhibitors. 
     For example, tyrosine kinase inhibitors include but are not limited to, Erlotinib hydrochloride (Tarceva®); Linifanib (N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N′-(2-fluoro-5-methylphenyl)urea, also known as ABT 869, available from Genentech); Sunitinib malate (Sutent®); Bosutinib (4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinoline-3-carbonitrile, also known as SKI-606, and described in U.S. Pat. No. 6,780,996); Dasatinib (Sprycel®); Pazopanib (Votrient®); Sorafenib (Nexavar®); Zactima (ZD6474); and Imatinib or Imatinib mesylate (Gilvec® and Gleevec®). 
     Epidermal growth factor receptor (EGFR) inhibitors include but are not limited to, Erlotinib hydrochloride (Tarceva®), Gefitinib (Iressa®); N-[4-[(3-Chloro-4-fluorophenyl)amino]-7-[[(3″S″)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4(dimethylamino)-2-butenamide, Tovok®); Vandetanib (Caprelsa®); Lapatinib (Tykerb®); (3R,4R)-4-Amino-1-((4-((3-methoxyphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)methyl)piperidin-3-ol (BMS690514); Canertinib dihydrochloride (CI-1033); 6-[4-[(4-Ethyl-1-piperazinyl)methyl]phenyl]-N-[(1R)-1-phenylethyl]-7H-Pyrrolo[2,3-d]pyrimidin-4-amine (AEE788, CAS 497839-62-0); Mubritinib (TAK165); Pelitinib (EKB569); Afatinib (Gilotrif®); Neratinib (HKI-272); N-[4-[[1-[(3-Fluorophenyl)methyl]-1H-indazol-5-yl]amino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl]-carbamic acid, (3S)-3-morpholinylmethyl ester (BMS599626); N-(3,4-Dichloro-2-fluorophenyl)-6-methoxy-7-[[(3β,5β,6α)-octahydro-2-methylcyclopenta[c]pyrrol-5-yl]methoxy]-4-quinazolinamine (XL647, CAS 781613-23-8); and 4-[4-[[(1R)-1-Phenylethyl]amino]-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenol (PKI 166, CAS187724-61-4). 
     EGFR antibodies include but are not limited to, Cetuximab (Erbitux®); Panitumumab (Vectibix®); Matuzumab (EMD-72000); Nimotuzumab (hR3); Zalutumumab; TheraCIM h-R3; MDX0447 (CAS 339151-96-1); and ch806 (mAb-806, CAS 946414-09-1). 
     Other HER2 inhibitors include but are not limited to, Neratinib (HKI-272, (2E)-N-[4-[[3-chloro-4-[(pyridin-2-yl) methoxy]phenyl]amino]-3-cyano-7-ethoxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide, and described PCT Publication No. WO 05/028443); Lapatinib or Lapatinib ditosylate (Tykerb®); (3R,4R)-4-amino-1-((4-((3-methoxyphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)methyl)piperidin-3-ol (BMS690514); (2E)-N-[4-[(3-Chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4-(dimethylamino)-2-butenamide (BIBW-2992, CAS 850140-72-6); N-[4-[[1-[(3-Fluorophenyl)methyl]-1H-indazol-5-yl]amino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl]-carbamic acid, (3S)-3-morpholinylmethyl ester (BMS 599626, CAS 714971-09-2); Canertinib dihydrochloride (PD183805 or CI-1033); and N-(3,4-Dichloro-2-fluorophenyl)-6-methoxy-7-[[(3a□,5□,6a□)-octahydro-2-methylcyclopenta[c]pyrrol-5-yl]methoxy]-4-quinazolinamine (XL647, CAS 781613-23-8). 
     HER3 inhibitors include but are not limited to, LJM716, MM-121, AMG-888, RG7116, REGN-1400, AV-203, MP-RM-1, MM-111, and MEHD-7945A. 
     MET inhibitors include but are not limited to, Cabozantinib (XL184, CAS 849217-68-1); Foretinib (GSK1363089, formerly XL880, CAS 849217-64-7); Tivantinib (ARQ197, CAS 1000873-98-2); 1-(2-Hydroxy-2-methylpropyl)-N-(5-(7-methoxyquinolin-4-yloxy)pyridin-2-yl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (AMG 458); Cryzotinib (Xalkori®, PF-02341066); (3Z)-5-(2,3-Dihydro-1H-indol-1-ylsulfonyl)-3-({3,5-dimethyl-4-[(4-methylpiperazin-1-yl)carbonyl]-1H-pyrrol-2-yl}methylene)-1,3-dihydro-2H-indol-2-one (SU 11271); (3Z)-N-(3-Chlorophenyl)-3-({3,5-dimethyl-4-[(4-methylpiperazin-1-yl)carbonyl]-1H-pyrrol-2-yl}methylene)-N-methyl-2-oxoindoline-5-sulfonamide (SU 11274); (3Z)-N-(3-Chlorophenyl)-3-{[3,5-dimethyl-4-(3-morpholin-4-ylpropyl)-1H-pyrrol-2-yl]methylene}-N-methyl-2-oxoindoline-5-sulfonamide (SU 11606); 6-[Difluoro[6-(1-methyl-1H-pyrazol-4-yl)-1,2,4-triazolo[4,3-b]pyridazin-3-yl]methyl]-quinoline (JNJ38877605, CAS 943540-75-8); 2-[4-[1-(Quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl]-1H-pyrazol-1-yl]ethanol (PF04217903, CAS 956905-27-4); N-((2R)-1,4-Dioxan-2-ylmethyl)-N-methyl-N′-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]sulfamide (MK2461, CAS 917879-39-1); 6-[[6-(1-Methyl-1H-pyrazol-4-yl)-1,2,4-triazolo[4,3-b]pyridazin 3-yl]thio]-quinoline (SGX523, CAS 1022150-57-7); and (3Z)-5-[[(2,6-Dichlorophenyl)methyl]sulfonyl]-3-[[3,5-dimethyl-4-[[(2R)-2-(1-pyrrolidinylmethyl)-1-pyrrolidinyl]carbonyl]-1H-pyrrol-2-yl]methylene]-1,3-dihydro-2H-indol-2-one (PHA665752, CAS 477575-56-7). 
     IGFR inhibitors include but are not limited to, BMS-754807, XL-228, OSI-906, GSK0904529A, A-928605, AXL1717, KW-2450, MK0646, AMG479, IMCA12, MEDI-573, and B1836845. See e.g., Yee, JNCI, 104; 975 (2012) for review. 
     In another embodiment, the present invention provides a method of treating cancer by administering to a subject in need thereof antibody conjugate of the present invention in combination with one or more proliferation signaling pathway inhibitors, including but not limited to, MEK inhibitors, BRAF inhibitors, PI3K/Akt inhibitors, SHP2 inhibitors, and also mTOR inhibitors, and CDK inhibitors. 
     For example, mitogen-activated protein kinase (MEK) inhibitors include but are not limited to, XL-518 (also known as GDC-0973, Cas No. 1029872-29-4, available from ACC Corp.); 2-[(2-Chloro-4-iodophenyl)amino]-N-(cyclopropylmethoxy)-3,4-difluoro-benzamide (also known as CI-1040 or PD184352 and described in PCT Publication No. WO2000035436); N-[(2R)-2,3-Dihydroxypropoxy]-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-benzamide (also known as PD0325901 and described in PCT Publication No. WO2002006213); 2,3-Bis[amino[(2-aminophenyl)thio]methylene]-butanedinitrile (also known as U0126 and described in U.S. Pat. No. 2,779,780); N-[3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]-6-methoxyphenyl]-1-[(2R)-2,3-dihydroxypropyl]-cyclopropanesulfonamide (also known as RDEA119 or BAY869766 and described in PCT Publication No. WO2007014011); (3S,4R,5Z,8S,9S,11E)-14-(Ethylamino)-8,9,16-trihydroxy-3,4-dimethyl-3,4,9,19-tetrahydro-1H-2-benzoxacyclotetradecine-1,7(8H)-dione] (also known as E6201 and described in PCT Publication No. WO2003076424); 2′-Amino-3′-methoxyflavone (also known as PD98059 available from Biaffin GmbH &amp; Co., KG, Germany); Vemurafenib (PLX-4032, CAS 918504-65-1); (R)-3-(2,3-Dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (TAK-733, CAS 1035555-63-5); Pimasertib (AS-703026, CAS 1204531-26-9); and Trametinib dimethyl sulfoxide (GSK-1120212, CAS 1204531-25-80). 
     BRAF inhibitors include, but are not limited to, Vemurafenib (or Zelboraf®), GDC-0879, PLX-4720 (available from Symansis), Dabrafenib (or GSK2118436), LGX 818, CEP-32496, UI-152, RAF 265, Regorafenib (BAY 73-4506), CCT239065, or Sorafenib (or Sorafenib Tosylate, or Nexavar®), or Ipilimumab (or MDX-010, MDX-101, or Yervoy). 
     Phosphoinositide 3-kinase (PI3K) inhibitors include, but are not limited to, 4-[2-(1H-Indazol-4-yl)-6-[[4-(methylsulfonyl)piperazin-1-yl]methyl]thieno[3,2-d]pyrimidin-4-yl]morpholine (also known as GDC0941, RG7321, GNE0941, Pictrelisib, or Pictilisib; and described in PCT Publication Nos. WO 09/036082 and WO 09/055730); 2-Methyl-2-[4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydroimidazo[4,5-c]quinolin-1-yl]phenyl]propionitrile (also known as BEZ 235 or NVP-BEZ 235, and described in PCT Publication No. WO 06/122806); 4-(trifluoromethyl)-5-(2,6-dimorpholinopyrimidin-4-yl)pyridin-2-amine (also known as BKM120 or NVP-BKM120, and described in PCT Publication No. WO2007/084786); Tozasertib (VX680 or MK-0457, CAS 639089-54-6); (5Z)-5-[[4-(4-Pyridinyl)-6-quinolinyl]methylene]-2,4-thiazolidinedione (GSK1059615, CAS 958852-01-2); (1E,4S,4aR,5R,6aS,9aR)-5-(Acetyloxy)-1-[(di-2-propenylamino)methylene]-4,4a,5,6,6a,8,9,9a-octahydro-11-hydroxy-4-(methoxymethyl)-4a,6a-dimethylcyclopenta[5,6]naphtho[1,2-c]pyran-2,7,10(1H)-trione (PX866, CAS 502632-66-8); 8-Phenyl-2-(morpholin-4-yl)-chromen-4-one (LY294002, CAS 154447-36-6); (S)-N1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1,2-dicarboxamide (also known as BYL719 or Alpelisib); 2-(4-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanamide (also known as GDC0032, RG7604, or Taselisib). 
     mTOR inhibitors include but are not limited to, Temsirolimus (Torisel®); Ridaforolimus (formally known as deferolimus, (1R,2R,4S)-4-[(2R)-2 [(1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28Z,30S,32S,35R)-1,18-dihydroxy-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-2,3,10,14,20-pentaoxo-11,36-dioxa-4-azatricyclo[30.3.1.04,9] hexatriaconta-16,24,26,28-tetraen-12-yl]propyl]-2-methoxycyclohexyl dimethylphosphinate, also known as AP23573 and MK8669, and described in PCT Publication No. WO 03/064383); Everolimus (Afinitor® or RAD001); Rapamycin (AY22989, Sirolimus®); Simapimod (CAS 164301-51-3); (5-{2,4-Bis[(3S)-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl}-2-methoxyphenyl)methanol (AZD8055); 2-Amino-8-[trans-4-(2-hydroxyethoxy)cyclohexyl]-6-(6-methoxy-3-pyridinyl)-4-methyl-pyrido[2,3-d]pyrimidin-7(8H)-one (PF04691502, CAS 1013101-36-4); and N 2 -[1,4-dioxo-4-[[4-(4-oxo-8-phenyl-4H-1-benzopyran-2-yl)morpholinium-4-yl]methoxy]butyl]-L-arginylglycyl-L-□-aspartylL-serine-(SEQ ID NO: 932), inner salt (SF1126, CAS 936487-67-1). 
     CDK inhibitors include but are not limited to, Palbociclib (also known as PD-0332991, Ibrance®, 6-Acetyl-8-cyclopentyl-5-methyl-2-{[5-(1-piperazinyl)-2-pyridinyl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one). 
     In yet another embodiment, the present invention provides a method of treating cancer by administering to a subject in need thereof antibody conjugate of the present invention in combination with one or more pro-apoptotics, including but not limited to, IAP inhibitors, BCL2 inhibitors, MCL1 inhibitors, TRAIL agents, CHK inhibitors. 
     For examples, IAP inhibitors include but are not limited to, LCL161, GDC-0917, AEG-35156, AT406, and TL32711. Other examples of IAP inhibitors include but are not limited to those disclosed in WO04/005284, WO 04/007529, WO05/097791, WO 05/069894, WO 05/069888, WO 05/094818, US2006/0014700, US2006/0025347, WO 06/069063, WO 06/010118, WO 06/017295, and WO08/134679, all of which are incorporated herein by reference. 
     BCL-2 inhibitors include but are not limited to, 4-[4-[[2-(4-Chlorophenyl)-5,5-dimethyl-1-cyclohexen-1-yl]methyl]-1-piperazinyl]-N-[[4-[[(1R)-3-(4-morpholinyl)-1-[(phenylthio)methyl]propyl]amino]-3-[(trifluoromethyl)sulfonyl]phenyl]sulfonyl]benzamide (also known as ABT-263 and described in PCT Publication No. WO 09/155386); Tetrocarcin A; Antimycin; Gossypol ((−)BL-193); Obatoclax; Ethyl-2-amino-6-cyclopentyl-4-(1-cyano-2-ethoxy-2-oxoethyl)-4Hchromone-3-carboxylate (HA14-1); Oblimersen (G3139, Genasense®); Bak BH3 peptide; (−)-Gossypol acetic acid (AT-101); 4-[4-[(4′-Chloro[1,1′-biphenyl]-2-yl)methyl]-1-piperazinyl]-N-[[4-[[(1R)-3-(dimethylamino)-1-[(phenylthio)methyl]propyl]amino]-3-nitrophenyl]sulfonyl]-benzamide (ABT-737, CAS 852808-04-9); and Navitoclax (ABT-263, CAS 923564-51-6). 
     Proapoptotic receptor agonists (PARAs) including DR4 (TRAILR1) and DR5 (TRAILR2), including but are not limited to, Dulanermin (AMG-951, RhApo2L/TRAIL); Mapatumumab (HRS-ETR1, CAS 658052-09-6); Lexatumumab (HGS-ETR2, CAS 845816-02-6); Apomab (Apomab®); Conatumumab (AMG655, CAS 896731-82-1); and Tigatuzumab (CS1008, CAS 946415-34-5, available from Daiichi Sankyo). 
     Checkpoint Kinase (CHK) inhibitors include but are not limited to, 7-Hydroxystaurosporine (UCN-01); 6-Bromo-3-(1-methyl-1H-pyrazol-4-yl)-5-(3R)-3-piperidinylpyrazolo[1,5-a]pyrimidin-7-amine (SCH900776, CAS 891494-63-6); 5-(3-Fluorophenyl)-3-ureidothiophene-2-carboxylic acid N-[(S)-piperidin-3-yl]amide (AZD7762, CAS 860352-01-8); 4-[((3S)-1-Azabicyclo[2.2.2]oct-3-yl)amino]-3-(1H-benzimidazol-2-yl)-6-chloroquinolin-2(1H)-one (CHIR 124, CAS 405168-58-3); 7-Aminodactinomycin (7-AAD), Isogranulatimide, debromohymenialdisine; N-[5-Bromo-4-methyl-2-[(2S)-2-morpholinylmethoxy]-phenyl]-N′-(5-methyl-2-pyrazinyl)urea (LY2603618, CAS 911222-45-2); Sulforaphane (CAS 4478-93-7, 4-Methylsulfinylbutyl isothiocyanate); 9,10,11,12-Tetrahydro-9,12-epoxy-1H-diindolo[1,2,3-fg:3′,2′,1′-kI]pyrrolo[3,4-i][1,6]benzodiazocine-1,3(2H)-dione (SB-218078, CAS 135897-06-2); and TAT-S216A (YGRKKRRQRRRLYRSPAMPENL (SEQ ID NO: 929)), and CBP501 ((d-Bpa)sws(d-Phe-F5)(d-Cha)rrrqrr). 
     In a further embodiment, the present invention provides a method of treating cancer by administering to a subject in need thereof antibody conjugate of the present invention in combination with one or more immunomodulators (e.g., one or more of an activator of a costimulatory molecule or an inhibitor of an immune checkpoint molecule). 
     In certain embodiments, the immunomodulator is an activator of a costimulatory molecule. In one embodiment, the agonist of the costimulatory molecule is selected from an agonist (e.g., an agonistic antibody or antigen-binding fragment thereof, or a soluble fusion) of OX40, CD2, CD27, CDS, ICAM-1, LFA-1 (CD11a/CD18), ICOS (CD278), 4-1BB (CD137), GITR, CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3 or CD83 ligand. 
     GITR Aqonists 
     In certain embodiments, the agonist of the costimulatory molecule is a GITR agonist. In some embodiments, the GITR agonist is GWN323 (NVS), BMS-986156, MK-4166 or MK-1248 (Merck), TRX518 (Leap Therapeutics), INCAGN1876 (Incyte/Agenus), AMG 228 (Amgen) or INBRX-110 (Inhibrx). 
     Exemplary GITR Aqonists 
     In one embodiment, the GITR agonist is an anti-GITR antibody molecule. In one embodiment, the GITR agonist is an anti-GITR antibody molecule as described in WO 2016/057846, published on Apr. 14, 2016, entitled “Compositions and Methods of Use for Augmented Immune Response and Cancer Therapy,” incorporated by reference in its entirety. 
     In one embodiment, the anti-GITR antibody molecule comprises at least one, two, three, four, five or six complementarity determining regions (CDRs) (or collectively all of the CDRs) from a heavy and light chain variable region comprising an amino acid sequence shown in Table 9 (e.g., from the heavy and light chain variable region sequences of MAB7 disclosed in Table 9), or encoded by a nucleotide sequence shown in Table 9. In some embodiments, the CDRs are according to the Kabat definition (e.g., as set out in Table 9). In some embodiments, the CDRs are according to the Chothia definition (e.g., as set out in Table 9). In one embodiment, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six or more changes, e.g., amino acid substitutions (e.g., conservative amino acid substitutions) or deletions, relative to an amino acid sequence shown in Table 9, or encoded by a nucleotide sequence shown in Table 9. 
     In one embodiment, the anti-GITR antibody molecule comprises a heavy chain variable region (VH) comprising a VHCDR1 amino acid sequence of SEQ ID NO: 909, a VHCDR2 amino acid sequence of SEQ ID NO: 911, and a VHCDR3 amino acid sequence of SEQ ID NO: 913; and a light chain variable region (VL) comprising a VLCDR1 amino acid sequence of SEQ ID NO: 914, a VLCDR2 amino acid sequence of SEQ ID NO: 916, and a VLCDR3 amino acid sequence of SEQ ID NO: 918, each disclosed in Table 9. 
     In one embodiment, the anti-GITR antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 901, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 901. In one embodiment, the anti-GITR antibody molecule comprises a VL comprising the amino acid sequence of SEQ ID NO: 902, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 902. In one embodiment, the anti-GITR antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 901 and a VL comprising the amino acid sequence of SEQ ID NO: 902. 
     In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 905, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 905. In one embodiment, the antibody molecule comprises a VL encoded by the nucleotide sequence of SEQ ID NO: 906, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 906. In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 905 and a VL encoded by the nucleotide sequence of SEQ ID NO: 906. 
     In one embodiment, the anti-GITR antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 903, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 903. In one embodiment, the anti-GITR antibody molecule comprises a light chain comprising the amino acid sequence of SEQ ID NO: 904, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 904. In one embodiment, the anti-GITR antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 903 and a light chain comprising the amino acid sequence of SEQ ID NO: 904. 
     In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 907, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 907. In one embodiment, the antibody molecule comprises a light chain encoded by the nucleotide sequence of SEQ ID NO: 908, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 908. In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 907 and a light chain encoded by the nucleotide sequence of SEQ ID NO: 908. 
     The antibody molecules described herein can be made by vectors, host cells, and methods described in WO 2016/057846, incorporated by reference in its entirety. 
     
       
         
           
               
             
               
                 TABLE 9 
               
               
                   
               
               
                 Amino acid and nucleotide sequences of exemplary anti-GITR antibody molecule 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
            
               
                 MAB7 
               
            
           
           
               
               
               
            
               
                 SEQ ID NO: 901 
                 VH 
                 EVQLVESGGGLVQSGGSLRLSCAASGFSLSSYGVDW 
               
               
                   
                   
                 VRQAPGKGLEWVGVIWGGGGTYYASSLMGRFTISRD 
               
               
                   
                   
                 NSKNTLYLQMNSLRAEDTAVYYCARHAYGHDGGFAM 
               
               
                   
                   
                 DYWGQGTLVTVSS 
               
               
                   
               
               
                 SEQ ID NO: 902 
                 VL 
                 EIVMTQSPATLSVSPGERATLSCRASESVSSNVAWYQ 
               
               
                   
                   
                 QRPGQAPRLLIYGASNRATGIPARFSGSGSGTDFTLTI 
               
               
                   
                   
                 SRLEPEDFAVYYCGQSYSYPFTFGQGTKLEIK 
               
               
                   
               
               
                 SEQ ID NO: 903 
                 Heavy 
                 EVQLVESGGGLVQSGGSLRLSCAASGFSLSSYGVDW 
               
               
                   
                 Chain 
                 VRQAPGKGLEWVGVIWGGGGTYYASSLMGRFTISRD 
               
               
                   
                   
                 NSKNTLYLQMNSLRAEDTAVYYCARHAYGHDGGFAM 
               
               
                   
                   
                 DYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTA 
               
               
                   
                   
                 ALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS 
               
               
                   
                   
                 GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKR 
               
               
                   
                   
                 VEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL 
               
               
                   
                   
                 MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNA 
               
               
                   
                   
                 KTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKV 
               
               
                   
                   
                 SNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKN 
               
               
                   
                   
                 QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVL 
               
               
                   
                   
                 DSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN 
               
               
                   
                   
                 HYTQKSLSLSPGK 
               
               
                   
               
               
                 SEQ ID NO: 904 
                 Light 
                 EIVMTQSPATLSVSPGERATLSCRASESVSSNVAWYQ 
               
               
                   
                 Chain 
                 QRPGQAPRLLIYGASNRATGIPARFSGSGSGTDFTLTI 
               
               
                   
                   
                 SRLEPEDFAVYYCGQSYSYPFTFGQGTKLEIKRTVAA 
               
               
                   
                   
                 PSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWK 
               
               
                   
                   
                 VDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADY 
               
               
                   
                   
                 EKHKVYACEVTHQGLSSPVTKSFNRGEC 
               
               
                   
               
               
                 SEQ ID NO: 905 
                 DNA 
                 GAGGTGCAGCTGGTGGAATCTGGCGGCGGACTGG 
               
               
                   
                 VH 
                 TGCAGTCCGGCGGCTCTCTGAGACTGTCTTGCGCT 
               
               
                   
                   
                 GCCTCCGGCTTCTCCCTGTCCTCTTACGGCGTGGA 
               
               
                   
                   
                 CTGGGTGCGACAGGCCCCTGGCAAGGGCCTGGAA 
               
               
                   
                   
                 TGGGTGGGAGTGATCTGGGGCGGAGGCGGCACCT 
               
               
                   
                   
                 ACTACGCCTCTTCCCTGATGGGCCGGTTCACCATCT 
               
               
                   
                   
                 CCCGGGACAACTCCAAGAACACCCTGTACCTGCAG 
               
               
                   
                   
                 ATGAACTCCCTGCGGGCCGAGGACACCGCCGTGTA 
               
               
                   
                   
                 CTACTGCGCCAGACACGCCTACGGCCACGACGGC 
               
               
                   
                   
                 GGCTTCGCCATGGATTATTGGGGCCAGGGCACCCT 
               
               
                   
                   
                 GGTGACAGTGTCCTCC 
               
               
                   
               
               
                 SEQ ID NO: 906 
                 DNA 
                 GAGATCGTGATGACCCAGTCCCCCGCCACCCTGTC 
               
               
                   
                 VL 
                 TGTGTCTCCCGGCGAGAGAGCCACCCTGAGCTGCA 
               
               
                   
                   
                 GAGCCTCCGAGTCCGTGTCCTCCAACGTGGCCTGG 
               
               
                   
                   
                 TATCAGCAGAGACCTGGTCAGGCCCCTCGGCTGCT 
               
               
                   
                   
                 GATCTACGGCGCCTCTAACCGGGCCACCGGCATCC 
               
               
                   
                   
                 CTGCCAGATTCTCCGGCTCCGGCAGCGGCACCGAC 
               
               
                   
                   
                 TTCACCCTGACCATCTCCCGGCTGGAACCCGAGGA 
               
               
                   
                   
                 CTTCGCCGTGTACTACTGCGGCCAGTCCTACTCATA 
               
               
                   
                   
                 CCCCTTCACCTTCGGCCAGGGCACCAAGCTGGAAA 
               
               
                   
                   
                 TCAAG 
               
               
                   
               
               
                 SEQ ID NO: 907 
                 DNA 
                 GAGGTGCAGCTGGTGGAATCTGGCGGCGGACTGG 
               
               
                   
                 Heavy 
                 TGCAGTCCGGCGGCTCTCTGAGACTGTCTTGCGCT 
               
               
                   
                 Chain 
                 GCCTCCGGCTTCTCCCTGTCCTCTTACGGCGTGGA 
               
               
                   
                   
                 CTGGGTGCGACAGGCCCCTGGCAAGGGCCTGGAA 
               
               
                   
                   
                 TGGGTGGGAGTGATCTGGGGCGGAGGCGGCACCT 
               
               
                   
                   
                 ACTACGCCTCTTCCCTGATGGGCCGGTTCACCATCT 
               
               
                   
                   
                 CCCGGGACAACTCCAAGAACACCCTGTACCTGCAG 
               
               
                   
                   
                 ATGAACTCCCTGCGGGCCGAGGACACCGCCGTGTA 
               
               
                   
                   
                 CTACTGCGCCAGACACGCCTACGGCCACGACGGC 
               
               
                   
                   
                 GGCTTCGCCATGGATTATTGGGGCCAGGGCACCCT 
               
               
                   
                   
                 GGTGACAGTGTCCTCCGCTAGCACCAAGGGCCCAA 
               
               
                   
                   
                 GTGTGTTTCCCCTGGCCCCCAGCAGCAAGTCTACTT 
               
               
                   
                   
                 CCGGCGGAACTGCTGCCCTGGGTTGCCTGGTGAAG 
               
               
                   
                   
                 GACTACTTCCCCGAGCCCGTGACAGTGTCCTGGAA 
               
               
                   
                   
                 CTCTGGGGCTCTGACTTCCGGCGTGCACACCTTCC 
               
               
                   
                   
                 CCGCCGTGCTGCAGAGCAGCGGCCTGTACAGCCT 
               
               
                   
                   
                 GAGCAGCGTGGTGACAGTGCCCTCCAGCTCTCTGG 
               
               
                   
                   
                 GAACCCAGACCTATATCTGCAACGTGAACCACAAGC 
               
               
                   
                   
                 CCAGCAACACCAAGGTGGACAAGAGAGTGGAGCCC 
               
               
                   
                   
                 AAGAGCTGCGACAAGACCCACACCTGCCCCCCCTG 
               
               
                   
                   
                 CCCAGCTCCAGAACTGCTGGGAGGGCCTTCCGTGT 
               
               
                   
                   
                 TCCTGTTCCCCCCCAAGCCCAAGGACACCCTGATG 
               
               
                   
                   
                 ATCAGCAGGACCCCCGAGGTGACCTGCGTGGTGGT 
               
               
                   
                   
                 GGACGTGTCCCACGAGGACCCAGAGGTGAAGTTCA 
               
               
                   
                   
                 ACTGGTACGTGGACGGCGTGGAGGTGCACAACGC 
               
               
                   
                   
                 CAAGACCAAGCCCAGAGAGGAGCAGTACAACAGCA 
               
               
                   
                   
                 CCTACAGGGTGGTGTCCGTGCTGACCGTGCTGCAC 
               
               
                   
                   
                 CAGGACTGGCTGAACGGCAAAGAATACAAGTGCAA 
               
               
                   
                   
                 AGTCTCCAACAAGGCCCTGCCAGCCCCAATCGAAA 
               
               
                   
                   
                 AGACAATCAGCAAGGCCAAGGGCCAGCCACGGGA 
               
               
                   
                   
                 GCCCCAGGTGTACACCCTGCCCCCCAGCCGGGAG 
               
               
                   
                   
                 GAGATGACCAAGAACCAGGTGTCCCTGACCTGTCT 
               
               
                   
                   
                 GGTGAAGGGCTTCTACCCCAGCGATATCGCCGTGG 
               
               
                   
                   
                 AGTGGGAGAGCAACGGCCAGCCCGAGAACAACTAC 
               
               
                   
                   
                 AAGACCACCCCCCCAGTGCTGGACAGCGACGGCA 
               
               
                   
                   
                 GCTTCTTCCTGTACAGCAAGCTGACCGTGGACAAGT 
               
               
                   
                   
                 CCAGGTGGCAGCAGGGCAACGTGTTCAGCTGCAGC 
               
               
                   
                   
                 GTGATGCACGAGGCCCTGCACAACCACTACACCCA 
               
               
                   
                   
                 GAAGTCCCTGAGCCTGAGCCCCGGCAAG 
               
               
                   
               
               
                 SEQ ID NO: 908 
                 DNA 
                 GAGATCGTGATGACCCAGTCCCCCGCCACCCTGTC 
               
               
                   
                 Light 
                 TGTGTCTCCCGGCGAGAGAGCCACCCTGAGCTGCA 
               
               
                   
                 Chain 
                 GAGCCTCCGAGTCCGTGTCCTCCAACGTGGCCTGG 
               
               
                   
                   
                 TATCAGCAGAGACCTGGTCAGGCCCCTCGGCTGCT 
               
               
                   
                   
                 GATCTACGGCGCCTCTAACCGGGCCACCGGCATCC 
               
               
                   
                   
                 CTGCCAGATTCTCCGGCTCCGGCAGCGGCACCGAC 
               
               
                   
                   
                 TTCACCCTGACCATCTCCCGGCTGGAACCCGAGGA 
               
               
                   
                   
                 CTTCGCCGTGTACTACTGCGGCCAGTCCTACTCATA 
               
               
                   
                   
                 CCCCTTCACCTTCGGCCAGGGCACCAAGCTGGAAA 
               
               
                   
                   
                 TCAAGCGTACGGTGGCCGCTCCCAGCGTGTTCATC 
               
               
                   
                   
                 TTCCCCCCCAGCGACGAGCAGCTGAAGAGCGGCAC 
               
               
                   
                   
                 CGCCAGCGTGGTGTGCCTGCTGAACAACTTCTACC 
               
               
                   
                   
                 CCCGGGAGGCCAAGGTGCAGTGGAAGGTGGACAA 
               
               
                   
                   
                 CGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGTC 
               
               
                   
                   
                 ACCGAGCAGGACAGCAAGGACTCCACCTACAGCCT 
               
               
                   
                   
                 GAGCAGCACCCTGACCCTGAGCAAGGCCGACTACG 
               
               
                   
                   
                 AGAAGCATAAGGTGTACGCCTGCGAGGTGACCCAC 
               
               
                   
                   
                 CAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAA 
               
               
                   
                   
                 CAGGGGCGAGTGC 
               
               
                   
               
               
                 SEQ ID NO: 909 
                 HCDR1 
                 SYGVD 
               
               
                 KABAT) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 910 
                 HCDR1 
                 GFSLSSY 
               
               
                 (CHOTHIA) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 911 
                 HCDR2 
                 VIWGGGGTYYASSLMG 
               
               
                 (KABAT) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 912 
                 HCDR2 
                 WGGGG 
               
               
                 (CHOTHIA) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 913 
                 HCDR3 
                 HAYGHDGGFAMDY 
               
               
                 (KABAT) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 913 
                 HCDR3 
                 HAYGHDGGFAMDY 
               
               
                 (CHOTHIA) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 914 
                 LCDR1 
                 RASESVSSNVA 
               
               
                 (KABAT) 
                   
                   
               
               
                 SEQ ID NO: 915 
                 LCDR1 
                 SESVSSN 
               
               
                 (CHOTHIA) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 916 
                 LCDR2 
                 GASNRAT 
               
               
                 (KABAT) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 917 
                 LCDR2 
                 GAS 
               
               
                 (CHOTHIA) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 918 
                 LCDR3 
                 GQSYSYPFT 
               
               
                 (KABAT) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 919 
                 LCDR3 
                 SYSYPF 
               
               
                 (CHOTHIA) 
               
               
                   
               
            
           
         
       
     
     Other Exemplary GITR Agonists 
     In one embodiment, the anti-GITR antibody molecule is BMS-986156 (Bristol-Myers Squibb), also known as BMS 986156 or BMS986156. BMS-986156 and other anti-GITR antibodies are disclosed, e.g., in U.S. Pat. No. 9,228,016 and WO 2016/196792, incorporated by reference in their entirety. In one embodiment, the anti-GITR antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of BMS-986156, e.g., as disclosed in Table 10. 
     In one embodiment, the anti-GITR antibody molecule is MK-4166 or MK-1248 (Merck). MK-4166, MK-1248, and other anti-GITR antibodies are disclosed, e.g., in U.S. Pat. No. 8,709,424, WO 2011/028683, WO 2015/026684, and Mahne et al.  Cancer Res.  2017; 77(5):1108-1118, incorporated by reference in their entirety. In one embodiment, the anti-GITR antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of MK-4166 or MK-1248. 
     In one embodiment, the anti-GITR antibody molecule is TRX518 (Leap Therapeutics). TRX518 and other anti-GITR antibodies are disclosed, e.g., in U.S. Pat. Nos. 7,812,135, 8,388,967, 9,028,823, WO 2006/105021, and Ponte J et al. (2010)  Clinical Immunology;  135:596, incorporated by reference in their entirety. In one embodiment, the anti-GITR antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of TRX518. 
     In one embodiment, the anti-GITR antibody molecule is INCAGN1876 (Incyte/Agenus). INCAGN1876 and other anti-GITR antibodies are disclosed, e.g., in US 2015/0368349 and WO 2015/184099, incorporated by reference in their entirety. In one embodiment, the anti-GITR antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of INCAGN1876. 
     In one embodiment, the anti-GITR antibody molecule is AMG 228 (Amgen). AMG 228 and other anti-GITR antibodies are disclosed, e.g., in U.S. Pat. No. 9,464,139 and WO 2015/031667, incorporated by reference in their entirety. In one embodiment, the anti-GITR antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of AMG 228. 
     In one embodiment, the anti-GITR antibody molecule is INBRX-110 (Inhibrx). INBRX-110 and other anti-GITR antibodies are disclosed, e.g., in US 2017/0022284 and WO 2017/015623, incorporated by reference in their entirety. In one embodiment, the GITR agonist comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of INBRX-110. 
     In one embodiment, the GITR agonist (e.g., a fusion protein) is MEDI 1873 (MedImmune), also known as MEDI1873. MEDI 1873 and other GITR agonists are disclosed, e.g., in US 2017/0073386, WO 2017/025610, and Ross et al.  Cancer Res  2016; 76(14 Suppl): Abstract nr 561, incorporated by reference in their entirety. In one embodiment, the GITR agonist comprises one or more of an IgG Fc domain, a functional multimerization domain, and a receptor binding domain of a glucocorticoid-induced TNF receptor ligand (GITRL) of MEDI 1873. 
     Further known GITR agonists (e.g., anti-GITR antibodies) include those described, e.g., in WO 2016/054638, incorporated by reference in its entirety. 
     In one embodiment, the anti-GITR antibody is an antibody that competes for binding with, and/or binds to the same epitope on GITR as, one of the anti-GITR antibodies described herein. 
     In one embodiment, the GITR agonist is a peptide that activates the GITR signaling pathway. In one embodiment, the GITR agonist is an immunoadhesin binding fragment (e.g., an immunoadhesin binding fragment comprising an extracellular or GITR binding portion of GITRL) fused to a constant region (e.g., an Fc region of an immunoglobulin sequence). 
     
       
         
           
               
             
               
                 TABLE 10 
               
               
                   
               
               
                 Amino acid sequence of other exemplary 
               
               
                  anti-GITR antibody molecules 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
            
               
                 BMS-986156 
               
            
           
           
               
               
               
            
               
                 SEQ ID NO: 920 
                 VH 
                 QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMH 
               
               
                   
                   
                 WVRQAPGKGLEWVAVIWYEGSNKYYADSVKGRFTI 
               
               
                   
                   
                 SRDNSKNTLYLQMNSLRAEDTAVYYCARGGSMVRG 
               
               
                   
                   
                 DYYYGMDVWGQGTTVTVSS 
               
               
                   
               
               
                 SEQ ID NO: 921 
                 VL 
                 AIQLTQSPSSLSASVGDRVTITCRASQGISSALAW 
               
               
                   
                   
                 YQQKPGKAPKLLIYDASSLESGVPSRFSGSGSGTD 
               
               
                   
                   
                 FTLTISSLQPEDFATYYCQQFNSYPYTFGQGTKLE 
               
               
                   
                   
                 IK 
               
               
                   
               
            
           
         
       
     
     In certain embodiments, the immunomodulator is an inhibitor of an immune checkpoint molecule. In one embodiment, the immunomodulator is an inhibitor of PD-1, PD-L1, PD-L2, CTLA4, TIM3, LAG3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 and/or TGFRbeta. In one embodiment, the inhibitor of an immune checkpoint molecule inhibits PD-1, PD-L1, LAG-3, TIM-3 or CTLA4, or any combination thereof. The term “inhibition” or “inhibitor” includes a reduction in a certain parameter, e.g., an activity, of a given molecule, e.g., an immune checkpoint inhibitor. For example, inhibition of an activity, e.g., a PD-1 or PD-L1 activity, of at least 5%, 10%, 20%, 30%, 40%, 50% or more is included by this term. Thus, inhibition need not be 100%. 
     Inhibition of an inhibitory molecule can be performed at the DNA, RNA or protein level. In some embodiments, an inhibitory nucleic acid (e.g., a dsRNA, siRNA or shRNA), can be used to inhibit expression of an inhibitory molecule. In other embodiments, the inhibitor of an inhibitory signal is a polypeptide e.g., a soluble ligand (e.g., PD-1-Ig or CTLA-4 Ig), or an antibody or antigen-binding fragment thereof, that binds to the inhibitory molecule; e.g., an antibody or fragment thereof (also referred to herein as “an antibody molecule”) that binds to PD-1, PD-L1, PD-L2, CTLA4, TIM3, LAG3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 and/or TGFR beta, or a combination thereof. 
     In one embodiment, the antibody molecule is a full antibody or fragment thereof (e.g., a Fab, F(ab′) 2 , Fv, or a single chain Fv fragment (scFv)). In yet other embodiments, the antibody molecule has a heavy chain constant region (Fc) selected from, e.g., the heavy chain constant regions of IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgD, and IgE; particularly, selected from, e.g., the heavy chain constant regions of IgG1, IgG2, IgG3, and IgG4, more particularly, the heavy chain constant region of IgG1 or IgG4 (e.g., human IgG1 or IgG4). In one embodiment, the heavy chain constant region is human IgG1 or human IgG4. In one embodiment, the constant region is altered, e.g., mutated, to modify the properties of the antibody molecule (e.g., to increase or decrease one or more of Fc receptor binding, antibody glycosylation, the number of cysteine residues, effector cell function, or complement function). 
     In certain embodiments, the antibody molecule is in the form of a bispecific or multispecific antibody molecule. In one embodiment, the bispecific antibody molecule has a first binding specificity to PD-1 or PD-L1 and a second binding specificity, e.g., a second binding specificity to TIM-3, LAG-3, or PD-L2. In one embodiment, the bispecific antibody molecule binds to PD-1 or PD-L1 and TIM-3. In another embodiment, the bispecific antibody molecule binds to PD-1 or PD-L1 and LAG-3. In another embodiment, the bispecific antibody molecule binds to PD-1 and PD-L1. In yet another embodiment, the bispecific antibody molecule binds to PD-1 and PD-L2. In another embodiment, the bispecific antibody molecule binds to TIM-3 and LAG-3. Any combination of the aforesaid molecules can be made in a multispecific antibody molecule, e.g., a trispecific antibody that includes a first binding specificity to PD-1 or PD-1, and a second and third binding specifities to two or more of: TIM-3, LAG-3, or PD-L2. 
     In certain embodiments, the immunomodulator is an inhibitor of PD-1, e.g., human PD-1. In another embodiment, the immunomodulator is an inhibitor of PD-L1, e.g., human PD-L1. In one embodiment, the inhibitor of PD-1 or PD-L1 is an antibody molecule to PD-1 or PD-L1. The PD-1 or PD-L1 inhibitor can be administered alone, or in combination with other immunomodulators, e.g., in combination with an inhibitor of LAG-3, TIM-3 or CTLA4. In an exemplary embodiment, the inhibitor of PD-1 or PD-L1, e.g., the anti-PD-1 or PD-L1 antibody molecule, is administered in combination with a LAG-3 inhibitor, e.g., an anti-LAG-3 antibody molecule. In another embodiment, the inhibitor of PD-1 or PD-L1, e.g., the anti-PD-1 or PD-L1 antibody molecule, is administered in combination with a TIM-3 inhibitor, e.g., an anti-TIM-3 antibody molecule. In yet other embodiments, the inhibitor of PD-1 or PD-L1, e.g., the anti-PD-1 antibody molecule, is administered in combination with a LAG-3 inhibitor, e.g., an anti-LAG-3 antibody molecule, and a TIM-3 inhibitor, e.g., an anti-TIM-3 antibody molecule. 
     Other combinations of immunomodulators with a PD-1 inhibitor (e.g., one or more of PD-L2, CTLA4, TIM3, LAG3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 and/or TGFR) are also within the present invention. Any of the antibody molecules known in the art or disclosed herein can be used in the aforesaid combinations of inhibitors of checkpoint molecule. 
     PD-1 Inhibitors 
     In some embodiments, the antibody conjugate of the present invention is administered in combination with a PD-1 inhibitor. In some embodiments, the PD-1 inhibitor is selected from PDR001 (Novartis), Nivolumab (Bristol-Myers Squibb), Pembrolizumab (Merck &amp; Co), Pidilizumab (CureTech), MEDI0680 (Medimmune), REGN2810 (Regeneron), TSR-042 (Tesaro), PF-06801591 (Pfizer), BGB-A317 (Beigene), BGB-108 (Beigene), INCSHR1210 (Incyte), or AMP-224 (Amplimmune). 
     Exemplary PD-1 Inhibitors 
     In one embodiment, the PD-1 inhibitor is an anti-PD-1 antibody molecule. In one embodiment, the PD-1 inhibitor is an anti-PD-1 antibody molecule as described in US 2015/0210769, published on Jul. 30, 2015, entitled “Antibody Molecules to PD-1 and Uses Thereof,” incorporated by reference in its entirety. 
     In one embodiment, the anti-PD-1 antibody molecule comprises at least one, two, three, four, five or six complementarity determining regions (CDRs) (or collectively all of the CDRs) from a heavy and light chain variable region comprising an amino acid sequence shown in Table 11 (e.g., from the heavy and light chain variable region sequences of BAP049-Clone-E or BAP049-Clone-B disclosed in Table 11), or encoded by a nucleotide sequence shown in Table 11. In some embodiments, the CDRs are according to the Kabat definition (e.g., as set out in Table 11). In some embodiments, the CDRs are according to the Chothia definition (e.g., as set out in Table 11). In some embodiments, the CDRs are according to the combined CDR definitions of both Kabat and Chothia (e.g., as set out in Table 11). In one embodiment, the combination of Kabat and Chothia CDR of VH CDR1 comprises the amino acid sequence GYTFTTYWMH (SEQ ID NO: 541). In one embodiment, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six or more changes, e.g., amino acid substitutions (e.g., conservative amino acid substitutions) or deletions, relative to an amino acid sequence shown in Table 11, or encoded by a nucleotide sequence shown in Table 11. 
     In one embodiment, the anti-PD-1 antibody molecule comprises a heavy chain variable region (VH) comprising a VHCDR1 amino acid sequence of SEQ ID NO: 501, a VHCDR2 amino acid sequence of SEQ ID NO: 502, and a VHCDR3 amino acid sequence of SEQ ID NO: 503; and a light chain variable region (VL) comprising a VLCDR1 amino acid sequence of SEQ ID NO: 510, a VLCDR2 amino acid sequence of SEQ ID NO: 511, and a VLCDR3 amino acid sequence of SEQ ID NO: 512, each disclosed in Table 11. 
     In one embodiment, the antibody molecule comprises a VH comprising a VHCDR1 encoded by the nucleotide sequence of SEQ ID NO: 524, a VHCDR2 encoded by the nucleotide sequence of SEQ ID NO: 525, and a VHCDR3 encoded by the nucleotide sequence of SEQ ID NO: 526; and a VL comprising a VLCDR1 encoded by the nucleotide sequence of SEQ ID NO: 529, a VLCDR2 encoded by the nucleotide sequence of SEQ ID NO: 530, and a VLCDR3 encoded by the nucleotide sequence of SEQ ID NO: 531, each disclosed in Table 11. 
     In one embodiment, the anti-PD-1 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 506, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 506. In one embodiment, the anti-PD-1 antibody molecule comprises a VL comprising the amino acid sequence of SEQ ID NO: 520, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 520. In one embodiment, the anti-PD-1 antibody molecule comprises a VL comprising the amino acid sequence of SEQ ID NO: 516, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 516. In one embodiment, the anti-PD-1 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 506 and a VL comprising the amino acid sequence of SEQ ID NO: 520. In one embodiment, the anti-PD-1 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 506 and a VL comprising the amino acid sequence of SEQ ID NO: 516. 
     In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 507, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 507. In one embodiment, the antibody molecule comprises a VL encoded by the nucleotide sequence of SEQ ID NO: 521 or 517, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 521 or 517. In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 507 and a VL encoded by the nucleotide sequence of SEQ ID NO: 521 or 517. 
     In one embodiment, the anti-PD-1 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 508, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 508. In one embodiment, the anti-PD-1 antibody molecule comprises a light chain comprising the amino acid sequence of SEQ ID NO: 522, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 522. In one embodiment, the anti-PD-1 antibody molecule comprises a light chain comprising the amino acid sequence of SEQ ID NO: 518, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 518. In one embodiment, the anti-PD-1 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 508 and a light chain comprising the amino acid sequence of SEQ ID NO: 522. In one embodiment, the anti-PD-1 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 508 and a light chain comprising the amino acid sequence of SEQ ID NO: 518. 
     In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 509, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 509. In one embodiment, the antibody molecule comprises a light chain encoded by the nucleotide sequence of SEQ ID NO: 523 or 519, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 523 or 519. In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 509 and a light chain encoded by the nucleotide sequence of SEQ ID NO: 523 or 519. 
     The antibody molecules described herein can be made by vectors, host cells, and methods described in US 2015/0210769, incorporated by reference in its entirety. 
     
       
         
           
               
             
               
                 TABLE 11 
               
               
                   
               
               
                 Amino acid and nucleotide sequences of exemplary anti-PD-1 antibody molecules 
               
               
                   
               
             
            
               
                 BAP049-Clone-B HC 
               
            
           
           
               
               
               
            
               
                 SEQ ID NO: 501 
                 HCDR1 
                 TYWMH 
               
               
                 (Kabat) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 502 
                 HCDR2 
                 NIYPGTGGSNFDEKFKN 
               
               
                 (Kabat) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 503 
                 HCDR3 
                 WTTGTGAY 
               
               
                 (Kabat) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 504 
                 HCDR1 
                 GYTFTTY 
               
               
                 (Chothia) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 505 
                 HCDR2 
                 YPGTGG 
               
               
                 (Chothia) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 503 
                 HCDR3 
                 WTTGTGAY 
               
               
                 (Chothia) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 506 
                 VH 
                 EVQLVQSGAEVKKPGESLRISCKGSGYTFTTYWMHWVRQ 
               
               
                   
                   
                 ATGQGLEWMGNIYPGTGGSNFDEKFKNRVTITADKSTSTA 
               
               
                   
                   
                 YMELSSLRSEDTAVYYCTRWTTGTGAYWGQGTTVTVSS 
               
               
                   
               
               
                 SEQ ID NO: 507 
                 DNA 
                 GAGGTGCAGCTGGTGCAGTCAGGCGCCGAAGTGAAGAA 
               
               
                   
                 VH 
                 GCCCGGCGAGTCACTGAGAATTAGCTGTAAAGGTTCAG 
               
               
                   
                   
                 GCTACACCTTCACTACCTACTGGATGCACTGGGTCCGCC 
               
               
                   
                   
                 AGGCTACCGGTCAAGGCCTCGAGTGGATGGGTAATATC 
               
               
                   
                   
                 TACCCCGGCACCGGCGGCTCTAACTTCGACGAGAAGTT 
               
               
                   
                   
                 TAAGAATAGAGTGACTATCACCGCCGATAAGTCTACTAG 
               
               
                   
                   
                 CACCGCCTATATGGAACTGTCTAGCCTGAGATCAGAGGA 
               
               
                   
                   
                 CACCGCCGTCTACTACTGCACTAGGTGGACTACCGGCA 
               
               
                   
                   
                 CAGGCGCCTACTGGGGTCAAGGCACTACCGTGACCGTG 
               
               
                   
                   
                 TCTAGC 
               
               
                   
               
               
                 SEQ ID NO: 508 
                 Heavy 
                 EVQLVQSGAEVKKPGESLRISCKGSGYTFTTYWMHWVRQ 
               
               
                   
                 chain 
                 ATGQGLEWMGNIYPGTGGSNFDEKFKNRVTITADKSTSTA 
               
               
                   
                   
                 YMELSSLRSEDTAVYYCTRWTTGTGAYWGQGTTVTVSSA 
               
               
                   
                   
                 STKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSW 
               
               
                   
                   
                 NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYT 
               
               
                   
                   
                 CNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFL 
               
               
                   
                   
                 FPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGV 
               
               
                   
                   
                 EVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCK 
               
               
                   
                   
                 VSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQV 
               
               
                   
                   
                 SLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS 
               
               
                   
                   
                 FFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSL 
               
               
                   
                   
                 SLG 
               
               
                   
               
               
                 SEQ ID NO: 509 
                 DNA 
                 GAGGTGCAGCTGGTGCAGTCAGGCGCCGAAGTGAAGAA 
               
               
                   
                 heavy 
                 GCCCGGCGAGTCACTGAGAATTAGCTGTAAAGGTTCAG 
               
               
                   
                 chain 
                 GCTACACCTTCACTACCTACTGGATGCACTGGGTCCGCC 
               
               
                   
                   
                 AGGCTACCGGTCAAGGCCTCGAGTGGATGGGTAATATC 
               
               
                   
                   
                 TACCCCGGCACCGGCGGCTCTAACTTCGACGAGAAGTT 
               
               
                   
                   
                 TAAGAATAGAGTGACTATCACCGCCGATAAGTCTACTAG 
               
               
                   
                   
                 CACCGCCTATATGGAACTGTCTAGCCTGAGATCAGAGGA 
               
               
                   
                   
                 CACCGCCGTCTACTACTGCACTAGGTGGACTACCGGCA 
               
               
                   
                   
                 CAGGCGCCTACTGGGGTCAAGGCACTACCGTGACCGTG 
               
               
                   
                   
                 TCTAGCGCTAGCACTAAGGGCCCGTCCGTGTTCCCCCT 
               
               
                   
                   
                 GGCACCTTGTAGCCGGAGCACTAGCGAATCCACCGCTG 
               
               
                   
                   
                 CCCTCGGCTGCCTGGTCAAGGATTACTTCCCGGAGCCC 
               
               
                   
                   
                 GTGACCGTGTCCTGGAACAGCGGAGCCCTGACCTCCGG 
               
               
                   
                   
                 AGTGCACACCTTCCCCGCTGTGCTGCAGAGCTCCGGGC 
               
               
                   
                   
                 TGTACTCGCTGTCGTCGGTGGTCACGGTGCCTTCATCTA 
               
               
                   
                   
                 GCCTGGGTACCAAGACCTACACTTGCAACGTGGACCAC 
               
               
                   
                   
                 AAGCCTTCCAACACTAAGGTGGACAAGCGCGTCGAATC 
               
               
                   
                   
                 GAAGTACGGCCCACCGTGCCCGCCTTGTCCCGCGCCG 
               
               
                   
                   
                 GAGTTCCTCGGCGGTCCCTCGGTCTTTCTGTTCCCACC 
               
               
                   
                   
                 GAAGCCCAAGGACACTTTGATGATTTCCCGCACCCCTGA 
               
               
                   
                   
                 AGTGACATGCGTGGTCGTGGACGTGTCACAGGAAGATC 
               
               
                   
                   
                 CGGAGGTGCAGTTCAATTGGTACGTGGATGGCGTCGAG 
               
               
                   
                   
                 GTGCACAACGCCAAAACCAAGCCGAGGGAGGAGCAGTT 
               
               
                   
                   
                 CAACTCCACTTACCGCGTCGTGTCCGTGCTGACGGTGC 
               
               
                   
                   
                 TGCATCAGGACTGGCTGAACGGGAAGGAGTACAAGTGC 
               
               
                   
                   
                 AAAGTGTCCAACAAGGGACTTCCTAGCTCAATCGAAAAG 
               
               
                   
                   
                 ACCATCTCGAAAGCCAAGGGACAGCCCCGGGAACCCCA 
               
               
                   
                   
                 AGTGTATACCCTGCCACCGAGCCAGGAAGAAATGACTAA 
               
               
                   
                   
                 GAACCAAGTCTCATTGACTTGCCTTGTGAAGGGCTTCTA 
               
               
                   
                   
                 CCCATCGGATATCGCCGTGGAATGGGAGTCCAACGGCC 
               
               
                   
                   
                 AGCCGGAAAACAACTACAAGACCACCCCTCCGGTGCTG 
               
               
                   
                   
                 GACTCAGACGGATCCTTCTTCCTCTACTCGCGGCTGACC 
               
               
                   
                   
                 GTGGATAAGAGCAGATGGCAGGAGGGAAATGTGTTCAG 
               
               
                   
                   
                 CTGTTCTGTGATGCATGAAGCCCTGCACAACCACTACAC 
               
               
                   
                   
                 TCAGAAGTCCCTGTCCCTCTCCCTGGGA 
               
               
                   
               
            
           
           
               
            
               
                 BAP049-Clone-B LC 
               
            
           
           
               
               
               
            
               
                 SEQ ID NO: 510 
                 LCDR1 
                 KSSQSLLDSGNQKNFLT 
               
               
                 (Kabat) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 511 
                 LCDR2 
                 WASTRES 
               
               
                 (Kabat) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 512 
                 LCDR3 
                 QNDYSYPYT 
               
               
                 (Kabat) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 513 
                 LCDR1 
                 SQSLLDSGNQKNF 
               
               
                 (Chothia) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 514 
                 LCDR2 
                 WAS 
               
               
                 (Chothia) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 515 
                 LCDR3 
                 DYSYPY 
               
               
                 (Chothia) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 516 
                 VL 
                 EIVLTQSPATLSLSPGERATLSCKSSQSLLDSGNQKNFLTW 
               
               
                   
                   
                 YQQKPGKAPKLLIYWASTRESGVPSRFSGSGSGTDFTFTIS 
               
               
                   
                   
                 SLQPEDIATYYCQNDYSYPYTFGQGTKVEIK 
               
               
                   
               
               
                 SEQ ID NO: 517 
                 DNA 
                 GAGATCGTCCTGACTCAGTCACCCGCTACCCTGAGCCT 
               
               
                   
                 VL 
                 GAGCCCTGGCGAGCGGGCTACACTGAGCTGTAAATCTA 
               
               
                   
                   
                 GTCAGTCACTGCTGGATAGCGGTAATCAGAAGAACTTCC 
               
               
                   
                   
                 TGACCTGGTATCAGCAGAAGCCCGGTAAAGCCCCTAAG 
               
               
                   
                   
                 CTGCTGATCTACTGGGCCTCTACTAGAGAATCAGGCGTG 
               
               
                   
                   
                 CCCTCTAGGTTTAGCGGTAGCGGTAGTGGCACCGACTT 
               
               
                   
                   
                 CACCTTCACTATCTCTAGCCTGCAGCCCGAGGATATCGC 
               
               
                   
                   
                 TACCTACTACTGTCAGAACGACTATAGCTACCCCTACAC 
               
               
                   
                   
                 CTTCGGTCAAGGCACTAAGGTCGAGATTAAG 
               
               
                   
               
               
                 SEQ ID NO: 518 
                 Light 
                 EIVLTQSPATLSLSPGERATLSCKSSQSLLDSGNQKNFLTW 
               
               
                   
                 chain 
                 YQQKPGKAPKLLIYWASTRESGVPSRFSGSGSGTDFTFTIS 
               
               
                   
                   
                 SLQPEDIATYYCQNDYSYPYTFGQGTKVEIKRTVAAPSVFIF 
               
               
                   
                   
                 PPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSG 
               
               
                   
                   
                 NSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVT 
               
               
                   
                   
                 HQGLSSPVTKSFNRGEC 
               
               
                   
               
               
                 SEQ ID NO: 519 
                 DNA 
                 GAGATCGTCCTGACTCAGTCACCCGCTACCCTGAGCCT 
               
               
                   
                 light 
                 GAGCCCTGGCGAGCGGGCTACACTGAGCTGTAAATCTA 
               
               
                   
                 chain 
                 GTCAGTCACTGCTGGATAGCGGTAATCAGAAGAACTTCC 
               
               
                   
                   
                 TGACCTGGTATCAGCAGAAGCCCGGTAAAGCCCCTAAG 
               
               
                   
                   
                 CTGCTGATCTACTGGGCCTCTACTAGAGAATCAGGCGTG 
               
               
                   
                   
                 CCCTCTAGGTTTAGCGGTAGCGGTAGTGGCACCGACTT 
               
               
                   
                   
                 CACCTTCACTATCTCTAGCCTGCAGCCCGAGGATATCGC 
               
               
                   
                   
                 TACCTACTACTGTCAGAACGACTATAGCTACCCCTACAC 
               
               
                   
                   
                 CTTCGGTCAAGGCACTAAGGTCGAGATTAAGCGTACGG 
               
               
                   
                   
                 TGGCCGCTCCCAGCGTGTTCATCTTCCCCCCCAGCGAC 
               
               
                   
                   
                 GAGCAGCTGAAGAGCGGCACCGCCAGCGTGGTGTGCC 
               
               
                   
                   
                 TGCTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAG 
               
               
                   
                   
                 TGGAAGGTGGACAACGCCCTGCAGAGCGGCAACAGCCA 
               
               
                   
                   
                 GGAGAGCGTCACCGAGCAGGACAGCAAGGACTCCACCT 
               
               
                   
                   
                 ACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGAC 
               
               
                   
                   
                 TACGAGAAGCATAAGGTGTACGCCTGCGAGGTGACCCA 
               
               
                   
                   
                 CCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACA 
               
               
                   
                   
                 GGGGCGAGTGC 
               
               
                   
               
            
           
           
               
            
               
                 BAP049-Clone-E HC 
               
            
           
           
               
               
               
            
               
                 SEQ ID NO: 501 
                 HCDR1 
                 TYWMH 
               
               
                 (Kabat) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 502 
                 HCDR2 
                 NIYPGTGGSNFDEKFKN 
               
               
                 (Kabat) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 503 
                 HCDR3 
                 WTTGTGAY 
               
               
                 (Kabat) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 504 
                 HCDR1 
                 GYTFTTY 
               
               
                 (Chothia) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 505 
                 HCDR2 
                 YPGTGG 
               
               
                 (Chothia) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 503 
                 HCDR3 
                 WTTGTGAY 
               
               
                 (Chothia) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 506 
                 VH 
                 EVQLVQSGAEVKKPGESLRISCKGSGYTFTTYWMHWVRQ 
               
               
                   
                   
                 ATGQGLEWMGNIYPGTGGSNFDEKFKNRVTITADKSTSTA 
               
               
                   
                   
                 YMELSSLRSEDTAVYYCTRWTTGTGAYWGQGTTVTVSS 
               
               
                   
               
               
                 SEQ ID NO: 507 
                 DNA 
                 GAGGTGCAGCTGGTGCAGTCAGGCGCCGAAGTGAAGAA 
               
               
                   
                 VH 
                 GCCCGGCGAGTCACTGAGAATTAGCTGTAAAGGTTCAG 
               
               
                   
                   
                 GCTACACCTTCACTACCTACTGGATGCACTGGGTCCGCC 
               
               
                   
                   
                 AGGCTACCGGTCAAGGCCTCGAGTGGATGGGTAATATC 
               
               
                   
                   
                 TACCCCGGCACCGGCGGCTCTAACTTCGACGAGAAGTT 
               
               
                   
                   
                 TAAGAATAGAGTGACTATCACCGCCGATAAGTCTACTAG 
               
               
                   
                   
                 CACCGCCTATATGGAACTGTCTAGCCTGAGATCAGAGGA 
               
               
                   
                   
                 CACCGCCGTCTACTACTGCACTAGGTGGACTACCGGCA 
               
               
                   
                   
                 CAGGCGCCTACTGGGGTCAAGGCACTACCGTGACCGTG 
               
               
                   
                   
                 TCTAGC 
               
               
                   
               
               
                 SEQ ID NO: 508 
                 Heavy 
                 EVQLVQSGAEVKKPGESLRISCKGSGYTFTTYWMHWVRQ 
               
               
                   
                 chain 
                 ATGQGLEWMGNIYPGTGGSNFDEKFKNRVTITADKSTSTA 
               
               
                   
                   
                 YMELSSLRSEDTAVYYCTRWTTGTGAYWGQGTTVTVSSA 
               
               
                   
                   
                 STKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSW 
               
               
                   
                   
                 NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYT 
               
               
                   
                   
                 CNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFL 
               
               
                   
                   
                 FPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGV 
               
               
                   
                   
                 EVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCK 
               
               
                   
                   
                 VSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQV 
               
               
                   
                   
                 SLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS 
               
               
                   
                   
                 FFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSL 
               
               
                   
                   
                 SLG 
               
               
                   
               
               
                 SEQ ID NO: 509 
                 DNA 
                 GAGGTGCAGCTGGTGCAGTCAGGCGCCGAAGTGAAGAA 
               
               
                   
                 heavy 
                 GCCCGGCGAGTCACTGAGAATTAGCTGTAAAGGTTCAG 
               
               
                   
                 chain 
                 GCTACACCTTCACTACCTACTGGATGCACTGGGTCCGCC 
               
               
                   
                   
                 AGGCTACCGGTCAAGGCCTCGAGTGGATGGGTAATATC 
               
               
                   
                   
                 TACCCCGGCACCGGCGGCTCTAACTTCGACGAGAAGTT 
               
               
                   
                   
                 TAAGAATAGAGTGACTATCACCGCCGATAAGTCTACTAG 
               
               
                   
                   
                 CACCGCCTATATGGAACTGTCTAGCCTGAGATCAGAGGA 
               
               
                   
                   
                 CACCGCCGTCTACTACTGCACTAGGTGGACTACCGGCA 
               
               
                   
                   
                 CAGGCGCCTACTGGGGTCAAGGCACTACCGTGACCGTG 
               
               
                   
                   
                 TCTAGCGCTAGCACTAAGGGCCCGTCCGTGTTCCCCCT 
               
               
                   
                   
                 GGCACCTTGTAGCCGGAGCACTAGCGAATCCACCGCTG 
               
               
                   
                   
                 CCCTCGGCTGCCTGGTCAAGGATTACTTCCCGGAGCCC 
               
               
                   
                   
                 GTGACCGTGTCCTGGAACAGCGGAGCCCTGACCTCCGG 
               
               
                   
                   
                 AGTGCACACCTTCCCCGCTGTGCTGCAGAGCTCCGGGC 
               
               
                   
                   
                 TGTACTCGCTGTCGTCGGTGGTCACGGTGCCTTCATCTA 
               
               
                   
                   
                 GCCTGGGTACCAAGACCTACACTTGCAACGTGGACCAC 
               
               
                   
                   
                 AAGCCTTCCAACACTAAGGTGGACAAGCGCGTCGAATC 
               
               
                   
                   
                 GAAGTACGGCCCACCGTGCCCGCCTTGTCCCGCGCCG 
               
               
                   
                   
                 GAGTTCCTCGGCGGTCCCTCGGTCTTTCTGTTCCCACC 
               
               
                   
                   
                 GAAGCCCAAGGACACTTTGATGATTTCCCGCACCCCTGA 
               
               
                   
                   
                 AGTGACATGCGTGGTCGTGGACGTGTCACAGGAAGATC 
               
               
                   
                   
                 CGGAGGTGCAGTTCAATTGGTACGTGGATGGCGTCGAG 
               
               
                   
                   
                 GTGCACAACGCCAAAACCAAGCCGAGGGAGGAGCAGTT 
               
               
                   
                   
                 CAACTCCACTTACCGCGTCGTGTCCGTGCTGACGGTGC 
               
               
                   
                   
                 TGCATCAGGACTGGCTGAACGGGAAGGAGTACAAGTGC 
               
               
                   
                   
                 AAAGTGTCCAACAAGGGACTTCCTAGCTCAATCGAAAAG 
               
               
                   
                   
                 ACCATCTCGAAAGCCAAGGGACAGCCCCGGGAACCCCA 
               
               
                   
                   
                 AGTGTATACCCTGCCACCGAGCCAGGAAGAAATGACTAA 
               
               
                   
                   
                 GAACCAAGTCTCATTGACTTGCCTTGTGAAGGGCTTCTA 
               
               
                   
                   
                 CCCATCGGATATCGCCGTGGAATGGGAGTCCAACGGCC 
               
               
                   
                   
                 AGCCGGAAAACAACTACAAGACCACCCCTCCGGTGCTG 
               
               
                   
                   
                 GACTCAGACGGATCCTTCTTCCTCTACTCGCGGCTGACC 
               
               
                   
                   
                 GTGGATAAGAGCAGATGGCAGGAGGGAAATGTGTTCAG 
               
               
                   
                   
                 CTGTTCTGTGATGCATGAAGCCCTGCACAACCACTACAC 
               
               
                   
                   
                 TCAGAAGTCCCTGTCCCTCTCCCTGGGA 
               
               
                   
               
            
           
           
               
            
               
                 BAP049-Clone-E LC 
               
            
           
           
               
               
               
            
               
                 SEQ ID NO: 510 
                 LCDR1 
                 KSSQSLLDSGNQKNFLT 
               
               
                 (Kabat) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 511 
                 LCDR2 
                 WASTRES 
               
               
                 (Kabat) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 512 
                 LCDR3 
                 QNDYSYPYT 
               
               
                 (Kabat) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 513 
                 LCDR1 
                 SQSLLDSGNQKNF 
               
               
                 (Chothia) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 514 
                 LCDR2 
                 WAS 
               
               
                 (Chothia) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 515 
                 LCDR3 
                 DYSYPY 
               
               
                 (Chothia) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 520 
                 VL 
                 EIVLTQSPATLSLSPGERATLSCKSSQSLLDSGNQKNFLTW 
               
               
                   
                   
                 YQQKPGQAPRLLIYWASTRESGVPSRFSGSGSGTDFTFTI 
               
               
                   
                   
                 SSLEAEDAATYYCQNDYSYPYTFGQGTKVEIK 
               
               
                   
               
               
                 SEQ ID NO: 521 
                 DNA 
                 GAGATCGTCCTGACTCAGTCACCCGCTACCCTGAGCCT 
               
               
                   
                 VL 
                 GAGCCCTGGCGAGCGGGCTACACTGAGCTGTAAATCTA 
               
               
                   
                   
                 GTCAGTCACTGCTGGATAGCGGTAATCAGAAGAACTTCC 
               
               
                   
                   
                 TGACCTGGTATCAGCAGAAGCCCGGTCAAGCCCCTAGA 
               
               
                   
                   
                 CTGCTGATCTACTGGGCCTCTACTAGAGAATCAGGCGTG 
               
               
                   
                   
                 CCCTCTAGGTTTAGCGGTAGCGGTAGTGGCACCGACTT 
               
               
                   
                   
                 CACCTTCACTATCTCTAGCCTGGAAGCCGAGGACGCCG 
               
               
                   
                   
                 CTACCTACTACTGTCAGAACGACTATAGCTACCCCTACA 
               
               
                   
                   
                 CCTTCGGTCAAGGCACTAAGGTCGAGATTAAG 
               
               
                   
               
               
                 SEQ ID NO: 522 
                 Light 
                 EIVLTQSPATLSLSPGERATLSCKSSQSLLDSGNQKNFLTW 
               
               
                   
                 chain 
                 YQQKPGQAPRLLIYWASTRESGVPSRFSGSGSGTDFTFTI 
               
               
                   
                   
                 SSLEAEDAATYYCQNDYSYPYTFGQGTKVEIKRTVAAPSVF 
               
               
                   
                   
                 IFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQS 
               
               
                   
                   
                 GNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEV 
               
               
                   
                   
                 THQGLSSPVTKSFNRGEC 
               
               
                   
               
               
                 SEQ ID NO: 523 
                 DNA 
                 GAGATCGTCCTGACTCAGTCACCCGCTACCCTGAGCCT 
               
               
                   
                 light 
                 GAGCCCTGGCGAGCGGGCTACACTGAGCTGTAAATCTA 
               
               
                   
                 chain 
                 GTCAGTCACTGCTGGATAGCGGTAATCAGAAGAACTTCC 
               
               
                   
                   
                 TGACCTGGTATCAGCAGAAGCCCGGTCAAGCCCCTAGA 
               
               
                   
                   
                 CTGCTGATCTACTGGGCCTCTACTAGAGAATCAGGCGTG 
               
               
                   
                   
                 CCCTCTAGGTTTAGCGGTAGCGGTAGTGGCACCGACTT 
               
               
                   
                   
                 CACCTTCACTATCTCTAGCCTGGAAGCCGAGGACGCCG 
               
               
                   
                   
                 CTACCTACTACTGTCAGAACGACTATAGCTACCCCTACA 
               
               
                   
                   
                 CCTTCGGTCAAGGCACTAAGGTCGAGATTAAGCGTACG 
               
               
                   
                   
                 GTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCCAGCGA 
               
               
                   
                   
                 CGAGCAGCTGAAGAGCGGCACCGCCAGCGTGGTGTGC 
               
               
                   
                   
                 CTGCTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCA 
               
               
                   
                   
                 GTGGAAGGTGGACAACGCCCTGCAGAGCGGCAACAGC 
               
               
                   
                   
                 CAGGAGAGCGTCACCGAGCAGGACAGCAAGGACTCCAC 
               
               
                   
                   
                 CTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCG 
               
               
                   
                   
                 ACTACGAGAAGCATAAGGTGTACGCCTGCGAGGTGACC 
               
               
                   
                   
                 CACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAA 
               
               
                   
                   
                 CAGGGGCGAGTGC 
               
               
                   
               
            
           
           
               
            
               
                 BAP049-Clone-B HC 
               
            
           
           
               
               
               
            
               
                 SEQ ID NO: 524 
                 HCDR1 
                 ACCTACTGGATGCAC 
               
               
                 (Kabat) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 525 
                 HCDR2 
                 AATATCTACCCCGGCACCGGCGGCTCTAACTTCGACGA 
               
               
                 (Kabat) 
                 ,  
                 GAAGTTTAAGAAT 
               
               
                   
               
               
                 SEQ ID NO: 526 
                 HCDR3 
                 TGGACTACCGGCACAGGCGCCTAC 
               
               
                 (Kabat) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 527 
                 HCDR1 
                 GGCTACACCTTCACTACCTAC 
               
               
                 (Chothia) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 528 
                 HCDR2 
                 TACCCCGGCACCGGCGGC 
               
               
                 (Chothia) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 526 
                 HCDR3 
                 TGGACTACCGGCACAGGCGCCTAC 
               
               
                 (Chothia) 
                   
                   
               
               
                   
               
               
                 BAP049-Clone-B LC 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 529 
                 LCDR1 
                 AAATCTAGTCAGTCACTGCTGGATAGCGGTAATCAGAAG 
               
               
                 (Kabat) 
                   
                 AACTTCCTGACC 
               
               
                   
               
               
                 SEQ ID NO: 530 
                 LCDR2 
                 TGGGCCTCTACTAGAGAATCA 
               
               
                 (Kabat) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 531 
                 LCDR3 
                 CAGAACGACTATAGCTACCCCTACACC 
               
               
                 (Kabat) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 532 
                 LCDR1 
                 AGTCAGTCACTGCTGGATAGCGGTAATCAGAAGAACTTC 
               
               
                 (Chothia) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 533 
                 LCDR2 
                 TGGGCCTCT 
               
               
                 (Chothia) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 534 
                 LCDR3 
                 GACTATAGCTACCCCTAC 
               
               
                 (Chothia) 
                   
                   
               
               
                   
               
               
                 BAP049-Clone-E HC 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 524 
                 HCDR1 
                 ACCTACTGGATGCAC 
               
               
                 (Kabat) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 525 
                 HCDR2 
                 AATATCTACCCCGGCACCGGCGGCTCTAACTTCGACGA 
               
               
                 (Kabat) 
                   
                 GAAGTTTAAGAAT 
               
               
                   
               
               
                 SEQ ID NO: 526 
                 HCDR3 
                 TGGACTACCGGCACAGGCGCCTAC 
               
               
                 (Kabat) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 527 
                 HCDR1 
                 GGCTACACCTTCACTACCTAC 
               
               
                 (Chothia) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 528 
                 HCDR2 
                 TACCCCGGCACCGGCGGC 
               
               
                 (Chothia) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 526 
                 HCDR3 
                 TGGACTACCGGCACAGGCGCCTAC 
               
               
                 (Chothia) 
                   
                   
               
               
                   
               
               
                 BAP049-Clone-E LC 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 529 
                 LCDR1 
                 AAATCTAGTCAGTCACTGCTGGATAGCGGTAATCAGAAG 
               
               
                 (Kabat) 
                   
                 AACTTCCTGACC 
               
               
                   
               
               
                 SEQ ID NO: 530 
                 LCDR2 
                 TGGGCCTCTACTAGAGAATCA 
               
               
                 (Kabat) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 531 
                 LCDR3 
                 CAGAACGACTATAGCTACCCCTACACC 
               
               
                 (Kabat) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 532 
                 LCDR1 
                 AGTCAGTCACTGCTGGATAGCGGTAATCAGAAGAACTTC 
               
               
                 (Chothia) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 533 
                 LCDR2 
                 TGGGCCTCT 
               
               
                 (Chothia) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 534 
                 LCDR3 
                 GACTATAGCTACCCCTAC 
               
               
                 (Chothia) 
               
               
                   
               
            
           
         
       
     
     Other Exemplary PD-1 Inhibitors 
     selected from In some embodiments, the anti-PD-1 antibody is Nivolumab (CAS Registry Number: 946414-94-4). Alternative names for Nivolumab include MDX-1106, MDX-1106-04, ONO-4538, BMS-936558 or OPDIVO®. Nivolumab is a fully human IgG4 monoclonal antibody which specifically blocks PD1. Nivolumab (clone 5C4) and other human monoclonal antibodies that specifically bind to PD1 are disclosed in U.S. Pat. No. 8,008,449 and PCT Publication No. WO2006/121168, incorporated by reference in their entirety. In one embodiment, the anti-PD-1 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of Nivolumab, e.g., as disclosed in Table 12. 
     In other embodiments, the anti-PD-1 antibody is Pembrolizumab. Pembrolizumab (Trade name KEYTRUDA formerly Lambrolizumab, also known as Merck 3745, MK-3475 or SCH-900475) is a humanized IgG4 monoclonal antibody that binds to PD1. Pembrolizumab is disclosed, e.g., in Hamid, O. et al. (2013) New England Journal of Medicine 369 (2): 134-44, PCT Publication No. WO2009/114335, and U.S. Pat. No. 8,354,509, incorporated by reference in their entirety. In one embodiment, the anti-PD-1 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of Pembrolizumab, e.g., as disclosed in Table 12. 
     In some embodiments, the anti-PD-1 antibody is Pidilizumab. Pidilizumab (CT-011; Cure Tech) is a humanized IgG1k monoclonal antibody that binds to PD1. Pidilizumab and other humanized anti-PD-1 monoclonal antibodies are disclosed in PCT Publication No. WO2009/101611, incorporated by reference in their entirety. In one embodiment, the anti-PD-1 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of Pidilizumab, e.g., as disclosed in Table 12. 
     Other anti-PD1 antibodies are disclosed in U.S. Pat. No. 8,609,089, US Publication No. 2010028330, and/or US Publication No. 20120114649, incorporated by reference in their entirety. Other anti-PD1 antibodies include AMP 514 (Amplimmune). 
     In one embodiment, the anti-PD-1 antibody molecule is MEDI0680 (Medimmune), also known as AMP-514. MEDI0680 and other anti-PD-1 antibodies are disclosed in U.S. Pat. No. 9,205,148 and WO 2012/145493, incorporated by reference in their entirety. In one embodiment, the anti-PD-1 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of MEDI0680. 
     In one embodiment, the anti-PD-1 antibody molecule is REGN2810 (Regeneron). In one embodiment, the anti-PD-1 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of REGN2810. 
     In one embodiment, the anti-PD-1 antibody molecule is PF-06801591 (Pfizer). In one embodiment, the anti-PD-1 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of PF-06801591. 
     In one embodiment, the anti-PD-1 antibody molecule is BGB-A317 or BGB-108 (Beigene). In one embodiment, the anti-PD-1 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of BGB-A317 or BGB-108. 
     In one embodiment, the anti-PD-1 antibody molecule is INCSHR1210 (Incyte), also known as INCSHR01210 or SHR-1210. In one embodiment, the anti-PD-1 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of INCSHR1210. 
     In one embodiment, the anti-PD-1 antibody molecule is TSR-042 (Tesaro), also known as ANB011. In one embodiment, the anti-PD-1 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of TSR-042. 
     Further known anti-PD-1 antibodies include those described, e.g., in WO 2015/112800, WO 2016/092419, WO 2015/085847, WO 2014/179664, WO 2014/194302, WO 2014/209804, WO 2015/200119, U.S. Pat. Nos. 8,735,553, 7,488,802, 8,927,697, 8,993,731, and 9,102,727, incorporated by reference in their entirety. 
     In one embodiment, the anti-PD-1 antibody is an antibody that competes for binding with, and/or binds to the same epitope on PD-1 as, one of the anti-PD-1 antibodies described herein. 
     In one embodiment, the PD-1 inhibitor is a peptide that inhibits the PD-1 signaling pathway, e.g., as described in U.S. Pat. No. 8,907,053, incorporated by reference in its entirety. In some embodiments, the PD-1 inhibitor is an immunoadhesin (e.g., an immunoadhesin comprising an extracellular or PD-1 binding portion of PD-L1 or PD-L2 fused to a constant region (e.g., an Fc region of an immunoglobulin sequence). In some embodiments, the PD-1 inhibitor is AMP-224 (B7-DCIg (Amplimmune), e.g., disclosed in WO 2010/027827 and WO 2011/066342, incorporated by reference in their entirety). 
     
       
         
           
               
             
               
                 TABLE 12 
               
               
                   
               
               
                 Amino acid sequences of other exemplary anti-PD-1 antibody molecules 
               
               
                   
               
             
            
               
                 Nivolumab 
               
            
           
           
               
               
               
            
               
                 SEQ ID NO: 535 
                 Heavy 
                 QVQLVESGGGVVQPGRSLRLDCKASGITFSNSGMHWVRQAPG 
               
               
                   
                 chain 
                 KGLEWVAVIWYDGSKRYYADSVKGRFTISRDNSKNTLFLQMNSL 
               
               
                   
                   
                 RAEDTAVYYCATNDDYWGQGTLVTVSSASTKGPSVFPLAPCSR 
               
               
                   
                   
                 STSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS 
               
               
                   
                   
                 GLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGP 
               
               
                   
                   
                 PCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQ 
               
               
                   
                   
                 EDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQ 
               
               
                   
                   
                 DWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQ 
               
               
                   
                   
                 EEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD 
               
               
                   
                   
                 SDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLS 
               
               
                   
                   
                 LSLGK 
               
               
                   
               
               
                 SEQ ID NO: 536 
                 Light 
                 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAP 
               
               
                   
                 chain 
                 RLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQ 
               
               
                   
                   
                 QSSNWPRTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVV 
               
               
                   
                   
                 CLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLS 
               
               
                   
                   
                 STLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 
               
               
                   
               
            
           
           
               
            
               
                 Pembrolizumab 
               
            
           
           
               
               
               
            
               
                 SEQ ID NO: 537 
                 Heavy 
                 QVQLVQSGVEVKKPGASVKVSCKASGYTFTNYYMYWVRQAPG 
               
               
                   
                 chain 
                 QGLEWMGGINPSNGGTNFNEKFKNRVTLTTDSSTTTAYMELKSL 
               
               
                   
                   
                 QFDDTAVYYCARRDYRFDMGFDYWGQGTTVTVSSASTKGPSV 
               
               
                   
                   
                 FPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHT 
               
               
                   
                   
                 FPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDK 
               
               
                   
                   
                 RVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVT 
               
               
                   
                   
                 CVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRV 
               
               
                   
                   
                 VSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREP 
               
               
                   
                   
                 QVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPEN 
               
               
                   
                   
                 NYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEAL 
               
               
                   
                   
                 HNHYTQKSLSLSLGK 
               
               
                   
               
               
                 SEQ ID NO: 538 
                 Light 
                 EIVLTQSPATLSLSPGERATLSCRASKGVSTSGYSYLHWYQQKP 
               
               
                   
                 chain 
                 GQAPRLLIYLASYLESGVPARFSGSGSGTDFTLTISSLEPEDFAV 
               
               
                   
                   
                 YYCQHSRDLPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTA 
               
               
                   
                   
                 SVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTY 
               
               
                   
                   
                 SLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 
               
               
                   
               
            
           
           
               
            
               
                 Pidilizumab 
               
            
           
           
               
               
               
            
               
                 SEQ ID NO: 539 
                 Heavy 
                 QVQLVQSGSELKKPGASVKISCKASGYTFTNYGMNWVRQAPGQ 
               
               
                   
                 chain 
                 GLQWMGWINTDSGESTYAEEFKGRFVFSLDTSVNTAYLQITSLT 
               
               
                   
                   
                 AEDTGMYFCVRVGYDALDYWGQGTLVTVSSASTKGPSVFPLAP 
               
               
                   
                   
                 SSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL 
               
               
                   
                   
                 QSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPK 
               
               
                   
                   
                 SCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVV 
               
               
                   
                   
                 VDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVL 
               
               
                   
                   
                 TVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT 
               
               
                   
                   
                 LPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTT 
               
               
                   
                   
                 PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT 
               
               
                   
                   
                 QKSLSLSPGK 
               
               
                   
               
               
                 SEQ ID NO: 540 
                 Light 
                 EIVLTQSPSSLSASVGDRVTITCSARSSVSYMHWFQQKPGKAPK 
               
               
                   
                 chain 
                 LWIYRTSNLASGVPSRFSGSGSGTSYCLTINSLQPEDFATYYCQ 
               
               
                   
                   
                 QRSSFPLTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVC 
               
               
                   
                   
                 LLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSS 
               
               
                   
                   
                 TLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 
               
               
                   
               
            
           
         
       
     
     PD-L1 Inhibitors 
     In certain embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-L1. In some embodiments, the antibody conjugate of the present invention is administered in combination with a PD-L1 inhibitor. In some embodiments, the PD-L1 inhibitor is selected from FAZ053 (Novartis), Atezolizumab (Genentech/Roche), Avelumab (Merck Serono and Pfizer), Durvalumab (Medlmmune/AstraZeneca), or BMS-936559 (Bristol-Myers Squibb). 
     Exemplary PD-L1 Inhibitors 
     In one embodiment, the PD-L1 inhibitor is an anti-PD-L1 antibody molecule. In one embodiment, the PD-L1 inhibitor is an anti-PD-L1 antibody molecule as disclosed in US 2016/0108123, published on Apr. 21, 2016, entitled “Antibody Molecules to PD-L1 and Uses Thereof,” incorporated by reference in its entirety. 
     In one embodiment, the anti-PD-L1 antibody molecule comprises at least one, two, three, four, five or six complementarity determining regions (CDRs) (or collectively all of the CDRs) from a heavy and light chain variable region comprising an amino acid sequence shown in Table 13 (e.g., from the heavy and light chain variable region sequences of BAP058-Clone O or BAP058-Clone N disclosed in Table 13), or encoded by a nucleotide sequence shown in Table 13. In some embodiments, the CDRs are according to the Kabat definition (e.g., as set out in Table 13). In some embodiments, the CDRs are according to the Chothia definition (e.g., as set out in Table 13). In some embodiments, the CDRs are according to the combined CDR definitions of both Kabat and Chothia (e.g., as set out in Table 13). In one embodiment, the combination of Kabat and Chothia CDR of VH CDR1 comprises the amino acid sequence GYTFTSYWMY (SEQ ID NO: 647). In one embodiment, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six or more changes, e.g., amino acid substitutions (e.g., conservative amino acid substitutions) or deletions, relative to an amino acid sequence shown in Table 13, or encoded by a nucleotide sequence shown in Table 13. 
     In one embodiment, the anti-PD-L1 antibody molecule comprises a heavy chain variable region (VH) comprising a VHCDR1 amino acid sequence of SEQ ID NO: 601, a VHCDR2 amino acid sequence of SEQ ID NO: 602, and a VHCDR3 amino acid sequence of SEQ ID NO: 603; and a light chain variable region (VL) comprising a VLCDR1 amino acid sequence of SEQ ID NO: 609, a VLCDR2 amino acid sequence of SEQ ID NO: 610, and a VLCDR3 amino acid sequence of SEQ ID NO: 611, each disclosed in Table 13. 
     In one embodiment, the anti-PD-L1 antibody molecule comprises a VH comprising a VHCDR1 encoded by the nucleotide sequence of SEQ ID NO: 628, a VHCDR2 encoded by the nucleotide sequence of SEQ ID NO: 629, and a VHCDR3 encoded by the nucleotide sequence of SEQ ID NO: 630; and a VL comprising a VLCDR1 encoded by the nucleotide sequence of SEQ ID NO: 633, a VLCDR2 encoded by the nucleotide sequence of SEQ ID NO: 634, and a VLCDR3 encoded by the nucleotide sequence of SEQ ID NO: 635, each disclosed in Table 13. 
     In one embodiment, the anti-PD-L1 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 606, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 606. In one embodiment, the anti-PD-L1 antibody molecule comprises a VL comprising the amino acid sequence of SEQ ID NO: 616, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 616. In one embodiment, the anti-PD-L1 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 620, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 620. In one embodiment, the anti-PD-L1 antibody molecule comprises a VL comprising the amino acid sequence of SEQ ID NO: 624, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 624. In one embodiment, the anti-PD-L1 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 606 and a VL comprising the amino acid sequence of SEQ ID NO: 616. In one embodiment, the anti-PD-L1 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 620 and a VL comprising the amino acid sequence of SEQ ID NO: 624. 
     In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 607, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 607. In one embodiment, the antibody molecule comprises a VL encoded by the nucleotide sequence of SEQ ID NO: 617, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 617. In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 621, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 621. 
     In one embodiment, the antibody molecule comprises a VL encoded by the nucleotide sequence of SEQ ID NO: 625, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 625. In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 607 and a VL encoded by the nucleotide sequence of SEQ ID NO: 617. In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 621 and a VL encoded by the nucleotide sequence of SEQ ID NO: 625. 
     In one embodiment, the anti-PD-L1 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 608, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 608. In one embodiment, the anti-PD-L1 antibody molecule comprises a light chain comprising the amino acid sequence of SEQ ID NO: 618, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 618. In one embodiment, the anti-PD-L1 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 622, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 622. In one embodiment, the anti-PD-L1 antibody molecule comprises a light chain comprising the amino acid sequence of SEQ ID NO: 626, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 626. In one embodiment, the anti-PD-L1 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 608 and a light chain comprising the amino acid sequence of SEQ ID NO: 618. In one embodiment, the anti-PD-L1 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 622 and a light chain comprising the amino acid sequence of SEQ ID NO: 626. 
     In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 615, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 615. In one embodiment, the antibody molecule comprises a light chain encoded by the nucleotide sequence of SEQ ID NO: 619, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 619. In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 623, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 623. In one embodiment, the antibody molecule comprises a light chain encoded by the nucleotide sequence of SEQ ID NO: 627, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 627. In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 615 and a light chain encoded by the nucleotide sequence of SEQ ID NO: 619. In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 623 and a light chain encoded by the nucleotide sequence of SEQ ID NO: 627. 
     The antibody molecules described herein can be made by vectors, host cells, and methods described in US 2016/0108123, incorporated by reference in its entirety. 
     
       
         
           
               
             
               
                 TABLE 13 
               
               
                   
               
               
                 Amino acid and nucleotide sequences of exemplary anti-PD-L1 antibody molecules 
               
               
                   
               
             
            
               
                 BAP058-Clone O HC 
               
            
           
           
               
               
               
            
               
                 SEQ ID NO: 601 
                 HCDR1 
                 SYWMY 
               
               
                 (Kabat) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 602 
                 HCDR2 
                 RIDPNSGSTKYNEKFKN 
               
               
                 (Kabat) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 603 
                 HCDR3 
                 DYRKGLYAMDY 
               
               
                 (Kabat) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 604 
                 HCDR1 
                 GYTFTSY 
               
               
                 (Chothia) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 605 
                 HCDR2 
                 DPNSGS 
               
               
                 (Chothia) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 603 
                 HCDR3 
                 DYRKGLYAMDY 
               
               
                 (Chothia) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 606 
                 VH 
                 EVQLVQSGAEVKKPGATVKISCKVSGYTFTSYWMYWV 
               
               
                   
                   
                 RQARGQRLEWIGRIDPNSGSTKYNEKFKNRFTISRDNS 
               
               
                   
                   
                 KNTLYLQMNSLRAEDTAVYYCARDYRKGLYAMDYWG 
               
               
                   
                   
                 QGTTVTVSS 
               
               
                   
               
               
                 SEQ ID NO: 607 
                 DNA VH 
                 GAAGTGCAGCTGGTGCAGTCAGGCGCCGAAGTGAA 
               
               
                   
                   
                 GAAACCCGGCGCTACCGTGAAGATTAGCTGTAAAGT 
               
               
                   
                   
                 CTCAGGCTACACCTTCACTAGCTACTGGATGTACTG 
               
               
                   
                   
                 GGTCCGACAGGCTAGAGGGCAAAGACTGGAGTGGA 
               
               
                   
                   
                 TCGGTAGAATCGACCCTAATAGCGGCTCTACTAAGTA 
               
               
                   
                   
                 TAACGAGAAGTTTAAGAATAGGTTCACTATTAGTAGG 
               
               
                   
                   
                 GATAACTCTAAGAACACCCTGTACCTGCAGATGAATA 
               
               
                   
                   
                 GCCTGAGAGCCGAGGACACCGCCGTCTACTACTGC 
               
               
                   
                   
                 GCTAGAGACTATAGAAAGGGCCTGTACGCTATGGAC 
               
               
                   
                   
                 TACTGGGGTCAAGGCACTACCGTGACCGTGTCTTCA 
               
               
                   
               
               
                 SEQ ID NO: 608 
                 Heavy 
                 EVQLVQSGAEVKKPGATVKISCKVSGYTFTSYWMYWV 
               
               
                   
                 chain 
                 RQARGQRLEWIGRIDPNSGSTKYNEKFKNRFTISRDNS 
               
               
                   
                   
                 KNTLYLQMNSLRAEDTAVYYCARDYRKGLYAMDYWG 
               
               
                   
                   
                 QGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLV 
               
               
                   
                   
                 KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSS 
               
               
                   
                   
                 VVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPP 
               
               
                   
                   
                 CPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVV 
               
               
                   
                   
                 VDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNST 
               
               
                   
                   
                 YRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTIS 
               
               
                   
                   
                 KAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYP 
               
               
                   
                   
                 SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTV 
               
               
                   
                   
                 DKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG 
               
               
                   
               
               
                 SEQ ID NO: 615 
                 DNA 
                 GAAGTGCAGCTGGTGCAGTCAGGCGCCGAAGTGAA 
               
               
                   
                 heavy 
                 GAAACCCGGCGCTACCGTGAAGATTAGCTGTAAAGT 
               
               
                   
                 chain 
                 CTCAGGCTACACCTTCACTAGCTACTGGATGTACTG 
               
               
                   
                   
                 GGTCCGACAGGCTAGAGGGCAAAGACTGGAGTGGA 
               
               
                   
                   
                 TCGGTAGAATCGACCCTAATAGCGGCTCTACTAAGTA 
               
               
                   
                   
                 TAACGAGAAGTTTAAGAATAGGTTCACTATTAGTAGG 
               
               
                   
                   
                 GATAACTCTAAGAACACCCTGTACCTGCAGATGAATA 
               
               
                   
                   
                 GCCTGAGAGCCGAGGACACCGCCGTCTACTACTGC 
               
               
                   
                   
                 GCTAGAGACTATAGAAAGGGCCTGTACGCTATGGAC 
               
               
                   
                   
                 TACTGGGGTCAAGGCACTACCGTGACCGTGTCTTCA 
               
               
                   
                   
                 GCTAGCACTAAGGGCCCGTCCGTGTTCCCCCTGGCA 
               
               
                   
                   
                 CCTTGTAGCCGGAGCACTAGCGAATCCACCGCTGCC 
               
               
                   
                   
                 CTCGGCTGCCTGGTCAAGGATTACTTCCCGGAGCCC 
               
               
                   
                   
                 GTGACCGTGTCCTGGAACAGCGGAGCCCTGACCTC 
               
               
                   
                   
                 CGGAGTGCACACCTTCCCCGCTGTGCTGCAGAGCTC 
               
               
                   
                   
                 CGGGCTGTACTCGCTGTCGTCGGTGGTCACGGTGC 
               
               
                   
                   
                 CTTCATCTAGCCTGGGTACCAAGACCTACACTTGCAA 
               
               
                   
                   
                 CGTGGACCACAAGCCTTCCAACACTAAGGTGGACAA 
               
               
                   
                   
                 GCGCGTCGAATCGAAGTACGGCCCACCGTGCCCGC 
               
               
                   
                   
                 CTTGTCCCGCGCCGGAGTTCCTCGGCGGTCCCTCG 
               
               
                   
                   
                 GTCTTTCTGTTCCCACCGAAGCCCAAGGACACTTTGA 
               
               
                   
                   
                 TGATTTCCCGCACCCCTGAAGTGACATGCGTGGTCG 
               
               
                   
                   
                 TGGACGTGTCACAGGAAGATCCGGAGGTGCAGTTCA 
               
               
                   
                   
                 ATTGGTACGTGGATGGCGTCGAGGTGCACAACGCCA 
               
               
                   
                   
                 AAACCAAGCCGAGGGAGGAGCAGTTCAACTCCACTT 
               
               
                   
                   
                 ACCGCGTCGTGTCCGTGCTGACGGTGCTGCATCAG 
               
               
                   
                   
                 GACTGGCTGAACGGGAAGGAGTACAAGTGCAAAGTG 
               
               
                   
                   
                 TCCAACAAGGGACTTCCTAGCTCAATCGAAAAGACC 
               
               
                   
                   
                 ATCTCGAAAGCCAAGGGACAGCCCCGGGAACCCCA 
               
               
                   
                   
                 AGTGTATACCCTGCCACCGAGCCAGGAAGAAATGAC 
               
               
                   
                   
                 TAAGAACCAAGTCTCATTGACTTGCCTTGTGAAGGGC 
               
               
                   
                   
                 TTCTACCCATCGGATATCGCCGTGGAATGGGAGTCC 
               
               
                   
                   
                 AACGGCCAGCCGGAAAACAACTACAAGACCACCCCT 
               
               
                   
                   
                 CCGGTGCTGGACTCAGACGGATCCTTCTTCCTCTAC 
               
               
                   
                   
                 TCGCGGCTGACCGTGGATAAGAGCAGATGGCAGGA 
               
               
                   
                   
                 GGGAAATGTGTTCAGCTGTTCTGTGATGCATGAAGC 
               
               
                   
                   
                 CCTGCACAACCACTACACTCAGAAGTCCCTGTCCCT 
               
               
                   
                   
                 CTCCCTGGGA 
               
               
                   
               
            
           
           
               
            
               
                 BAP058-Clone O LC 
               
            
           
           
               
               
               
            
               
                 SEQ ID NO: 609 
                 LCDR1 
                 KASQDVGTAVA 
               
               
                 (Kabat) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 610 
                 LCDR2 
                 WASTRHT 
               
               
                 (Kabat) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 611 
                 LCDR3 
                 QQYNSYPLT 
               
               
                 Kabat) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 612 
                 LCDR1 
                 SQDVGTA 
               
               
                 (Chothia) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 613 
                 LCDR2 
                 WAS 
               
               
                 (Chothia) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 614 
                 LCDR3 
                 YNSYPL 
               
               
                 (Chothia) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 616 
                 VL 
                 AIQLTQSPSSLSASVGDRVTITCKASQDVGTAVAWYLQ 
               
               
                   
                   
                 KPGQSPQLLIYWASTRHTGVPSRFSGSGSGTDFTFTIS 
               
               
                   
                   
                 SLEAEDAATYYCQQYNSYPLTFGQGTKVEIK 
               
               
                   
               
               
                 SEQ ID NO: 617 
                 DNA VL 
                 GCTATTCAGCTGACTCAGTCACCTAGTAGCCTGAGC 
               
               
                   
                   
                 GCTAGTGTGGGCGATAGAGTGACTATCACCTGTAAA 
               
               
                   
                   
                 GCCTCTCAGGACGTGGGCACCGCCGTGGCCTGGTA 
               
               
                   
                   
                 TCTGCAGAAGCCTGGTCAATCACCTCAGCTGCTGAT 
               
               
                   
                   
                 CTACTGGGCCTCTACTAGACACACCGGCGTGCCCTC 
               
               
                   
                   
                 TAGGTTTAGCGGTAGCGGTAGTGGCACCGACTTCAC 
               
               
                   
                   
                 CTTCACTATCTCTTCACTGGAAGCCGAGGACGCCGC 
               
               
                   
                   
                 TACCTACTACTGTCAGCAGTATAATAGCTACCCCCTG 
               
               
                   
                   
                 ACCTTCGGTCAAGGCACTAAGGTCGAGATTAAG 
               
               
                   
               
               
                 SEQ ID NO: 618 
                 Light 
                 AIQLTQSPSSLSASVGDRVTITCKASQDVGTAVAWYLQ 
               
               
                   
                 chain 
                 KPGQSPQLLIYWASTRHTGVPSRFSGSGSGTDFTFTIS 
               
               
                   
                   
                 SLEAEDAATYYCQQYNSYPLTFGQGTKVEIKRTVAAPS 
               
               
                   
                   
                 VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDN 
               
               
                   
                   
                 ALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHK 
               
               
                   
                   
                 VYACEVTHQGLSSPVTKSFNRGEC 
               
               
                   
               
               
                 SEQ ID NO: 619 
                 DNA light 
                 GCTATTCAGCTGACTCAGTCACCTAGTAGCCTGAGC 
               
               
                   
                 chain 
                 GCTAGTGTGGGCGATAGAGTGACTATCACCTGTAAA 
               
               
                   
                   
                 GCCTCTCAGGACGTGGGCACCGCCGTGGCCTGGTA 
               
               
                   
                   
                 TCTGCAGAAGCCTGGTCAATCACCTCAGCTGCTGAT 
               
               
                   
                   
                 CTACTGGGCCTCTACTAGACACACCGGCGTGCCCTC 
               
               
                   
                   
                 TAGGTTTAGCGGTAGCGGTAGTGGCACCGACTTCAC 
               
               
                   
                   
                 CTTCACTATCTCTTCACTGGAAGCCGAGGACGCCGC 
               
               
                   
                   
                 TACCTACTACTGTCAGCAGTATAATAGCTACCCCCTG 
               
               
                   
                   
                 ACCTTCGGTCAAGGCACTAAGGTCGAGATTAAGCGT 
               
               
                   
                   
                 ACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCC 
               
               
                   
                   
                 AGCGACGAGCAGCTGAAGAGCGGCACCGCCAGCGT 
               
               
                   
                   
                 GGTGTGCCTGCTGAACAACTTCTACCCCCGGGAGGC 
               
               
                   
                   
                 CAAGGTGCAGTGGAAGGTGGACAACGCCCTGCAGA 
               
               
                   
                   
                 GCGGCAACAGCCAGGAGAGCGTCACCGAGCAGGAC 
               
               
                   
                   
                 AGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTG 
               
               
                   
                   
                 ACCCTGAGCAAGGCCGACTACGAGAAGCATAAGGTG 
               
               
                   
                   
                 TACGCCTGCGAGGTGACCCACCAGGGCCTGTCCAG 
               
               
                   
                   
                 CCCCGTGACCAAGAGCTTCAACAGGGGCGAGTGC 
               
               
                   
               
            
           
           
               
            
               
                 BAP058-Clone N HC 
               
            
           
           
               
               
               
            
               
                 SEQ ID NO: 601 
                 HCDR1 
                 SYWMY 
               
               
                 (Kabat) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 602 
                 HCDR2 
                 RIDPNSGSTKYNEKFKN 
               
               
                 (Kabat) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 603 
                 HCDR3 
                 DYRKGLYAMDY 
               
               
                 (Kabat) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 604 
                 HCDR1 
                 GYTFTSY 
               
               
                 (Chothia) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 605 
                 HCDR2 
                 DPNSGS 
               
               
                 (Chothia) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 603 
                 HCDR3 
                 DYRKGLYAMDY 
               
               
                 (Chothia) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 620 
                 VH 
                 EVQLVQSGAEVKKPGATVKISCKVSGYTFTSYWMYWV 
               
               
                   
                   
                 RQATGQGLEWMGRIDPNSGSTKYNEKFKNRVTITADK 
               
               
                   
                   
                 STSTAYMELSSLRSEDTAVYYCARDYRKGLYAMDYWG 
               
               
                   
                   
                 QGTTVTVSS 
               
               
                   
               
               
                 SEQ ID NO: 621 
                 DNA VH 
                 GAAGTGCAGCTGGTGCAGTCAGGCGCCGAAGTGAA 
               
               
                   
                   
                 GAAACCCGGCGCTACCGTGAAGATTAGCTGTAAAGT 
               
               
                   
                   
                 CTCAGGCTACACCTTCACTAGCTACTGGATGTACTG 
               
               
                   
                   
                 GGTCCGACAGGCTACCGGTCAAGGCCTGGAGTGGA 
               
               
                   
                   
                 TGGGTAGAATCGACCCTAATAGCGGCTCTACTAAGT 
               
               
                   
                   
                 ATAACGAGAAGTTTAAGAATAGAGTGACTATCACCGC 
               
               
                   
                   
                 CGATAAGTCTACTAGCACCGCCTATATGGAACTGTCT 
               
               
                   
                   
                 AGCCTGAGATCAGAGGACACCGCCGTCTACTACTGC 
               
               
                   
                   
                 GCTAGAGACTATAGAAAGGGCCTGTACGCTATGGAC 
               
               
                   
                   
                 TACTGGGGTCAAGGCACTACCGTGACCGTGTCTTCA 
               
               
                   
               
               
                 SEQ ID NO: 622 
                 Heavy 
                 EVQLVQSGAEVKKPGATVKISCKVSGYTFTSYWMYWV 
               
               
                   
                 chain 
                 RQATGQGLEWMGRIDPNSGSTKYNEKFKNRVTITADK 
               
               
                   
                   
                 STSTAYMELSSLRSEDTAVYYCARDYRKGLYAMDYWG 
               
               
                   
                   
                 QGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLV 
               
               
                   
                   
                 KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSS 
               
               
                   
                   
                 VVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPP 
               
               
                   
                   
                 CPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVV 
               
               
                   
                   
                 VDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNST 
               
               
                   
                   
                 YRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTIS 
               
               
                   
                   
                 KAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYP 
               
               
                   
                   
                 SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTV 
               
               
                   
                   
                 DKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG 
               
               
                   
               
               
                 SEQ ID NO: 623 
                 DNA 
                 GAAGTGCAGCTGGTGCAGTCAGGCGCCGAAGTGAA 
               
               
                   
                 heavy 
                 GAAACCCGGCGCTACCGTGAAGATTAGCTGTAAAGT 
               
               
                   
                 chain 
                 CTCAGGCTACACCTTCACTAGCTACTGGATGTACTG 
               
               
                   
                   
                 GGTCCGACAGGCTACCGGTCAAGGCCTGGAGTGGA 
               
               
                   
                   
                 TGGGTAGAATCGACCCTAATAGCGGCTCTACTAAGT 
               
               
                   
                   
                 ATAACGAGAAGTTTAAGAATAGAGTGACTATCACCGC 
               
               
                   
                   
                 CGATAAGTCTACTAGCACCGCCTATATGGAACTGTCT 
               
               
                   
                   
                 AGCCTGAGATCAGAGGACACCGCCGTCTACTACTGC 
               
               
                   
                   
                 GCTAGAGACTATAGAAAGGGCCTGTACGCTATGGAC 
               
               
                   
                   
                 TACTGGGGTCAAGGCACTACCGTGACCGTGTCTTCA 
               
               
                   
                   
                 GCTAGCACTAAGGGCCCGTCCGTGTTCCCCCTGGCA 
               
               
                   
                   
                 CCTTGTAGCCGGAGCACTAGCGAATCCACCGCTGCC 
               
               
                   
                   
                 CTCGGCTGCCTGGTCAAGGATTACTTCCCGGAGCCC 
               
               
                   
                   
                 GTGACCGTGTCCTGGAACAGCGGAGCCCTGACCTC 
               
               
                   
                   
                 CGGAGTGCACACCTTCCCCGCTGTGCTGCAGAGCTC 
               
               
                   
                   
                 CGGGCTGTACTCGCTGTCGTCGGTGGTCACGGTGC 
               
               
                   
                   
                 CTTCATCTAGCCTGGGTACCAAGACCTACACTTGCAA 
               
               
                   
                   
                 CGTGGACCACAAGCCTTCCAACACTAAGGTGGACAA 
               
               
                   
                   
                 GCGCGTCGAATCGAAGTACGGCCCACCGTGCCCGC 
               
               
                   
                   
                 CTTGTCCCGCGCCGGAGTTCCTCGGCGGTCCCTCG 
               
               
                   
                   
                 GTCTTTCTGTTCCCACCGAAGCCCAAGGACACTTTGA 
               
               
                   
                   
                 TGATTTCCCGCACCCCTGAAGTGACATGCGTGGTCG 
               
               
                   
                   
                 TGGACGTGTCACAGGAAGATCCGGAGGTGCAGTTCA 
               
               
                   
                   
                 ATTGGTACGTGGATGGCGTCGAGGTGCACAACGCCA 
               
               
                   
                   
                 AAACCAAGCCGAGGGAGGAGCAGTTCAACTCCACTT 
               
               
                   
                   
                 ACCGCGTCGTGTCCGTGCTGACGGTGCTGCATCAG 
               
               
                   
                   
                 GACTGGCTGAACGGGAAGGAGTACAAGTGCAAAGTG 
               
               
                   
                   
                 TCCAACAAGGGACTTCCTAGCTCAATCGAAAAGACC 
               
               
                   
                   
                 ATCTCGAAAGCCAAGGGACAGCCCCGGGAACCCCA 
               
               
                   
                   
                 AGTGTATACCCTGCCACCGAGCCAGGAAGAAATGAC 
               
               
                   
                   
                 TAAGAACCAAGTCTCATTGACTTGCCTTGTGAAGGGC 
               
               
                   
                   
                 TTCTACCCATCGGATATCGCCGTGGAATGGGAGTCC 
               
               
                   
                   
                 AACGGCCAGCCGGAAAACAACTACAAGACCACCCCT 
               
               
                   
                   
                 CCGGTGCTGGACTCAGACGGATCCTTCTTCCTCTAC 
               
               
                   
                   
                 TCGCGGCTGACCGTGGATAAGAGCAGATGGCAGGA 
               
               
                   
                   
                 GGGAAATGTGTTCAGCTGTTCTGTGATGCATGAAGC 
               
               
                   
                   
                 CCTGCACAACCACTACACTCAGAAGTCCCTGTCCCT 
               
               
                   
                   
                 CTCCCTGGGA 
               
               
                   
               
            
           
           
               
            
               
                 BAP058-Clone N LC 
               
            
           
           
               
               
               
            
               
                 SEQ ID NO: 609 
                 LCDR1 
                 KASQDVGTAVA 
               
               
                 (Kabat) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 610 
                 LCDR2 
                 WASTRHT 
               
               
                 (Kabat) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 611 
                 LCDR3 
                 QQYNSYPLT 
               
               
                 (Kabat) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 612 
                 LCDR1 
                 SQDVGTA 
               
               
                 (Chothia) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 613 
                 LCDR2 
                 WAS 
               
               
                 (Chothia) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 614 
                 LCDR3 
                 YNSYPL 
               
               
                 (Chothia) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 624 
                 VL 
                 DVVMTQSPLSLPVTLGQPASISCKASQDVGTAVAWYQ 
               
               
                   
                   
                 QKPGQAPRLLIYWASTRHTGVPSRFSGSGSGTEFTLTI 
               
               
                   
                   
                 SSLQPDDFATYYCQQYNSYPLTFGQGTKVEIK 
               
               
                   
               
               
                 SEQ ID NO: 625 
                 DNA VL 
                 GACGTCGTGATGACTCAGTCACCCCTGAGCCTGCCC 
               
               
                   
                   
                 GTGACCCTGGGGCAGCCCGCCTCTATTAGCTGTAAA 
               
               
                   
                   
                 GCCTCTCAGGACGTGGGCACCGCCGTGGCCTGGTA 
               
               
                   
                   
                 TCAGCAGAAGCCAGGGCAAGCCCCTAGACTGCTGAT 
               
               
                   
                   
                 CTACTGGGCCTCTACTAGACACACCGGCGTGCCCTC 
               
               
                   
                   
                 TAGGTTTAGCGGTAGCGGTAGTGGCACCGAGTTCAC 
               
               
                   
                   
                 CCTGACTATCTCTTCACTGCAGCCCGACGACTTCGC 
               
               
                   
                   
                 TACCTACTACTGTCAGCAGTATAATAGCTACCCCCTG 
               
               
                   
                   
                 ACCTTCGGTCAAGGCACTAAGGTCGAGATTAAG 
               
               
                   
               
               
                 SEQ ID NO: 626 
                 Light 
                 DVVMTQSPLSLPVTLGQPASISCKASQDVGTAVAWYQ 
               
               
                   
                 chain 
                 QKPGQAPRLLIYWASTRHTGVPSRFSGSGSGTEFTLTI 
               
               
                   
                   
                 SSLQPDDFATYYCQQYNSYPLTFGQGTKVEIKRTVAAP 
               
               
                   
                   
                 SVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVD 
               
               
                   
                   
                 NALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKH 
               
               
                   
                   
                 KVYACEVTHQGLSSPVTKSFNRGEC 
               
               
                   
               
               
                 SEQ ID NO: 627 
                 DNA light 
                 GACGTCGTGATGACTCAGTCACCCCTGAGCCTGCCC 
               
               
                   
                 chain 
                 GTGACCCTGGGGCAGCCCGCCTCTATTAGCTGTAAA 
               
               
                   
                   
                 GCCTCTCAGGACGTGGGCACCGCCGTGGCCTGGTA 
               
               
                   
                   
                 TCAGCAGAAGCCAGGGCAAGCCCCTAGACTGCTGAT 
               
               
                   
                   
                 CTACTGGGCCTCTACTAGACACACCGGCGTGCCCTC 
               
               
                   
                   
                 TAGGTTTAGCGGTAGCGGTAGTGGCACCGAGTTCAC 
               
               
                   
                   
                 CCTGACTATCTCTTCACTGCAGCCCGACGACTTCGC 
               
               
                   
                   
                 TACCTACTACTGTCAGCAGTATAATAGCTACCCCCTG 
               
               
                   
                   
                 ACCTTCGGTCAAGGCACTAAGGTCGAGATTAAGCGT 
               
               
                   
                   
                 ACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCC 
               
               
                   
                   
                 AGCGACGAGCAGCTGAAGAGCGGCACCGCCAGCGT 
               
               
                   
                   
                 GGTGTGCCTGCTGAACAACTTCTACCCCCGGGAGGC 
               
               
                   
                   
                 CAAGGTGCAGTGGAAGGTGGACAACGCCCTGCAGA 
               
               
                   
                   
                 GCGGCAACAGCCAGGAGAGCGTCACCGAGCAGGAC 
               
               
                   
                   
                 AGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTG 
               
               
                   
                   
                 ACCCTGAGCAAGGCCGACTACGAGAAGCATAAGGTG 
               
               
                   
                   
                 TACGCCTGCGAGGTGACCCACCAGGGCCTGTCCAG 
               
               
                   
                   
                 CCCCGTGACCAAGAGCTTCAACAGGGGCGAGTGC 
               
               
                   
               
            
           
           
               
            
               
                 BAP058-Clone O HC 
               
            
           
           
               
               
               
            
               
                 SEQ ID NO: 628 
                 HCDR1 
                 agctactggatgtac 
               
               
                 (Kabat) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 629 
                 HCDR2 
                 agaatcgaccctaatagcggctctactaagtataacgagaagtttaagaat 
               
               
                 (Kabat) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 630 
                 HCDR3 
                 gactatagaaagggcctgtacgctatggactac 
               
               
                 (Kabat) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 631 
                 HCDR1 
                 ggctacaccttcactagctac 
               
               
                 (Chothia) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 632 
                 HCDR2 
                 gaccctaatagcggctct 
               
               
                 (Chothia) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 630 
                 HCDR3 
                 gactatagaaagggcctgtacgctatggactac 
               
               
                 (Chothia) 
                   
                   
               
               
                   
               
            
           
           
               
            
               
                 BAP058-Clone O LC 
               
            
           
           
               
               
               
            
               
                 SEQ ID NO: 633 
                 LCDR1 
                 aaagcctctcaggacgtgggcaccgccgtggcc 
               
               
                 (Kabat) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 634 
                 LCDR2 
                 tgggcctctactagacacacc 
               
               
                 (Kabat) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 635 
                 LCDR3 
                 cagcagtataatagctaccccctgacc 
               
               
                 (Kabat) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 636 
                 LCDR1 
                 tctcaggacgtgggcaccgcc 
               
               
                 (Chothia) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 637 
                 LCDR2 
                 tgggcctct 
               
               
                 (Chothia) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 638 
                 LCDR3 
                 tataatagctaccccctg 
               
               
                 (Chothia) 
                   
                   
               
               
                   
               
            
           
           
               
            
               
                 BAP058-Clone N HC 
               
            
           
           
               
               
               
            
               
                 SEQ ID NO: 628 
                 HCDR1 
                 agctactggatgtac 
               
               
                 (Kabat) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 629 
                 HCDR2 
                 agaatcgaccctaatagcggctctactaagtataacgagaagtttaagaat 
               
               
                 (Kabat) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 630 
                 HCDR3 
                 gactatagaaagggcctgtacgctatggactac 
               
               
                 (Kabat) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 631 
                 HCDR1 
                 ggctacaccttcactagctac 
               
               
                 (Chothia) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 632 
                 HCDR2 
                 gaccctaatagcggctct 
               
               
                 (Chothia) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 630 
                 HCDR3 
                 gactatagaaagggcctgtacgctatggactac 
               
               
                 (Chothia) 
                   
                   
               
               
                   
               
            
           
           
               
            
               
                 BAP058-Clone N LC 
               
            
           
           
               
               
               
            
               
                 SEQ ID NO: 633 
                 LCDR1 
                 aaagcctctcaggacgtgggcaccgccgtggcc 
               
               
                 (Kabat) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 634 
                 LCDR2 
                 tgggcctctactagacacacc 
               
               
                 (Kabat) 
                   
                   
               
               
                 SEQ ID NO: 635 
                 LCDR3 
                 cagcagtataatagctaccccctgacc 
               
               
                   
               
               
                 (Kabat) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 636 
                 LCDR1 
                 tctcaggacgtgggcaccgcc 
               
               
                 (Chothia) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 637 
                 LCDR2 
                 tgggcctct 
               
               
                 (Chothia) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 638 
                 LCDR3 
                 tataatagctaccccctg 
               
               
                 (Chothia) 
               
               
                   
               
            
           
         
       
     
     Other Exemplary PD-L1 Inhibitors 
     In some embodiments, the PD-L1 inhibitor is anti-PD-L1 antibody. In some embodiments, the anti-PD-L1 inhibitor is selected from YW243.55.S70, MPDL3280A, MEDI-4736, or MDX-1105MSB-0010718C (also referred to as A09-246-2) disclosed in, e.g., WO 2013/0179174, and having a sequence disclosed herein (or a sequence substantially identical or similar thereto, e.g., a sequence at least 85%, 90%, 95% identical or higher to the sequence specified). 
     In one embodiment, the PD-L1 inhibitor is MDX-1105. MDX-1105, also known as BMS-936559, is an anti-PD-L1 antibody described in PCT Publication No. WO 2007/005874. 
     In one embodiment, the PD-L1 inhibitor is YW243.55.S70. The YW243.55.S70 antibody is an anti-PD-L1 described in PCT Publication No. WO 2010/077634. 
     In one embodiment, the PD-L1 inhibitor is MDPL3280A (Genentech/Roche) also known as Atezolizumabm, RG7446, RO5541267, YW243.55.S70, or TECENTRIQ™. MDPL3280A is a human Fc optimized IgG1 monoclonal antibody that binds to PD-L1. MDPL3280A and other human monoclonal antibodies to PD-L1 are disclosed in U.S. Pat. No. 7,943,743 and U.S. Publication No.: 20120039906 incorporated by reference in its entirety. In one embodiment, the anti-PD-L1 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of Atezolizumab, e.g., as disclosed in Table 14. 
     In other embodiments, the PD-L2 inhibitor is AMP-224. AMP-224 is a PD-L2 Fc fusion soluble receptor that blocks the interaction between PD1 and B7-H1 (B7-DCIg; Amplimmune; e.g., disclosed in PCT Publication Nos. WO2010/027827 and WO2011/066342). 
     In one embodiment the PD-L1 inhibitor is an anti-PD-L1 antibody molecule. In one embodiment, the anti-PD-L1 antibody molecule is Avelumab (Merck Serono and Pfizer), also known as MSB0010718C. Avelumab and other anti-PD-L1 antibodies are disclosed in WO 2013/079174, incorporated by reference in its entirety. In one embodiment, the anti-PD-L1 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of Avelumab, e.g., as disclosed in Table 14. 
     In one embodiment, the anti-PD-L1 antibody molecule is Durvalumab (Medlmmune/AstraZeneca), also known as MEDI4736. Durvalumab and other anti-PD-L1 antibodies are disclosed in U.S. Pat. No. 8,779,108, incorporated by reference in its entirety. In one embodiment, the anti-PD-L1 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of Durvalumab, e.g., as disclosed in Table 14. 
     In one embodiment, the anti-PD-L1 antibody molecule is BMS-936559 (Bristol-Myers Squibb), also known as MDX-1105 or 12A4. BMS-936559 and other anti-PD-L1 antibodies are disclosed in U.S. Pat. No. 7,943,743 and WO 2015/081158, incorporated by reference in their entirety. In one embodiment, the anti-PD-L1 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of BMS-936559, e.g., as disclosed in Table 14. 
     Further known anti-PD-L1 antibodies include those described, e.g., in WO 2015/181342, WO 2014/100079, WO 2016/000619, WO 2014/022758, WO 2014/055897, WO 2015/061668, WO 2013/079174, WO 2012/145493, WO 2015/112805, WO 2015/109124, WO 2015/195163, U.S. Pat. Nos. 8,168,179, 8,552,154, 8,460,927, and 9,175,082, incorporated by reference in their entirety. 
     In one embodiment, the anti-PD-L1 antibody is an antibody that competes for binding with, and/or binds to the same epitope on PD-L1 as, one of the anti-PD-L1 antibodies described herein. 
     
       
         
           
               
             
               
                 TABLE 14 
               
               
                   
               
               
                 Amino acid sequences of other exemplary anti-PD-L1 antibody molecules 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
            
               
                 Atezolizumab 
               
            
           
           
               
               
               
            
               
                 SEQ ID NO: 
                 Heavy 
                 EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKG 
               
               
                 639 
                 chain 
                 LEWVAWISPYGGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAED 
               
               
                   
                   
                 TAVYYCARRHWPGGFDYWGQGTLVTVSSASTKGPSVFPLAPSSK 
               
               
                   
                   
                 STSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG 
               
               
                   
                   
                 LYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH 
               
               
                   
                   
                 TCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHED 
               
               
                   
                   
                 PEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLN 
               
               
                   
                   
                 GKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKN 
               
               
                   
                   
                 QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY 
               
               
                   
                   
                 SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 
               
               
                   
               
               
                 SEQ ID NO: 
                 Light 
                 DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPK 
               
               
                 640 
                 chain 
                 LLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYL 
               
               
                   
                   
                 YHPATFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNF 
               
               
                   
                   
                 YPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA 
               
               
                   
                   
                 DYEKHKVYACEVTHQGLSSPVTKSFNRGEC 
               
               
                   
               
            
           
           
               
            
               
                 Avelumab 
               
            
           
           
               
               
               
            
               
                 SEQ ID NO: 
                 Heavy 
                 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYIMMWVRQAPGKGL 
               
               
                 641 
                 chain 
                 EWVSSIYPSGGITFYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTA 
               
               
                   
                   
                 VYYCARIKLGTVTTVDYWGQGTLVTVSSASTKGPSVFPLAPSSKST 
               
               
                   
                   
                 SGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY 
               
               
                   
                   
                 SLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTC 
               
               
                   
                   
                 PPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPE 
               
               
                   
                   
                 VKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNG 
               
               
                   
                   
                 KEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQV 
               
               
                   
                   
                 SLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSK 
               
               
                   
                   
                 LTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 
               
               
                   
               
               
                 SEQ ID NO: 
                 Light 
                 QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKA 
               
               
                 642 
                 chain 
                 PKLMIYDVSNRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCS 
               
               
                   
                   
                 SYTSSSTRVFGTGTKVTVLGQPKANPTVTLFPPSSEELQANKATLV 
               
               
                   
                   
                 CLISDFYPGAVTVAWKADGSPVKAGVETTKPSKQSNNKYAASSYLS 
               
               
                   
                   
                 LTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS 
               
               
                   
               
            
           
           
               
            
               
                 Durvalumab 
               
            
           
           
               
               
               
            
               
                 SEQ ID NO: 
                 Heavy 
                 EVQLVESGGGLVQPGGSLRLSCAASGFTFSRYWMSWVRQAPGKG 
               
               
                 643 
                 chain 
                 LEWVANIKQDGSEKYYVDSVKGRFTISRDNAKNSLYLQMNSLRAED 
               
               
                   
                   
                 TAVYYCAREGGWFGELAFDYWGQGTLVTVSSASTKGPSVFPLAPS 
               
               
                   
                   
                 SKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS 
               
               
                   
                   
                 SGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDK 
               
               
                   
                   
                 THTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSH 
               
               
                   
                   
                 EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD 
               
               
                   
                   
                 WLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPSREEM 
               
               
                   
                   
                 TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSF 
               
               
                   
                   
                 FLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 
               
               
                   
               
               
                 SEQ ID NO: 
                 Light 
                 EIVLTQSPGTLSLSPGERATLSCRASQRVSSSYLAWYQQKPGQAP 
               
               
                 644 
                 chain 
                 RLLIYDASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQY 
               
               
                   
                   
                 GSLPVVTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLN 
               
               
                   
                   
                 NFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLS 
               
               
                   
                   
                 KADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 
               
               
                   
               
            
           
           
               
            
               
                 BMS-936559 
               
            
           
           
               
               
               
            
               
                 SEQ ID NO: 
                 VH 
                 QVQLVQSGAEVKKPGSSVKVSCKTSGDTFSTYAISWVRQAPGQGL 
               
               
                 645 
                   
                 EWMGGIIPIFGKAHYAQKFQGRVTITADESTSTAYMELSSLRSEDTA 
               
               
                   
                   
                 VYFCARKFHFVSGSPFGMDVWGQGTTVTVSS 
               
               
                   
               
               
                 SEQ ID NO: 
                 VL 
                 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRL 
               
               
                 646 
                   
                 LIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSN 
               
               
                   
                   
                 WPTFGQGTKVEIK 
               
               
                   
               
            
           
         
       
     
     LAG-3 Inhibitors 
     In certain embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of LAG-3. In some embodiments, the antibody conjugate of the present invention is administered in combination with a LAG-3 inhibitor. In some embodiments, the LAG-3 inhibitor is selected from LAG525 (Novartis), BMS-986016 (Bristol-Myers Squibb), or TSR-033 (Tesaro). 
     Exemplary LAG-3 Inhibitors 
     In one embodiment, the LAG-3 inhibitor is an anti-LAG-3 antibody molecule. In one embodiment, the LAG-3 inhibitor is an anti-LAG-3 antibody molecule as disclosed in US 2015/0259420, published on Sep. 17, 2015, entitled “Antibody Molecules to LAG-3 and Uses Thereof,” incorporated by reference in its entirety. 
     In one embodiment, the anti-LAG-3 antibody molecule comprises at least one, two, three, four, five or six complementarity determining regions (CDRs) (or collectively all of the CDRs) from a heavy and light chain variable region comprising an amino acid sequence shown in Table 15 (e.g., from the heavy and light chain variable region sequences of BAP050-Clone I or BAP050-Clone J disclosed in Table 15), or encoded by a nucleotide sequence shown in Table 15. In some embodiments, the CDRs are according to the Kabat definition (e.g., as set out in Table 15). In some embodiments, the CDRs are according to the Chothia definition (e.g., as set out in Table 15). In some embodiments, the CDRs are according to the combined CDR definitions of both Kabat and Chothia (e.g., as set out in Table 15). In one embodiment, the combination of Kabat and Chothia CDR of VH CDR1 comprises the amino acid sequence GFTLTNYGMN (SEQ ID NO: 766). In one embodiment, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six or more changes, e.g., amino acid substitutions (e.g., conservative amino acid substitutions) or deletions, relative to an amino acid sequence shown in Table 15, or encoded by a nucleotide sequence shown in Table 15. 
     In one embodiment, the anti-LAG-3 antibody molecule comprises a heavy chain variable region (VH) comprising a VHCDR1 amino acid sequence of SEQ ID NO: 701, a VHCDR2 amino acid sequence of SEQ ID NO: 702, and a VHCDR3 amino acid sequence of SEQ ID NO: 703; and a light chain variable region (VL) comprising a VLCDR1 amino acid sequence of SEQ ID NO: 710, a VLCDR2 amino acid sequence of SEQ ID NO: 711, and a VLCDR3 amino acid sequence of SEQ ID NO: 712, each disclosed in Table 15. 
     In one embodiment, the anti-LAG-3 antibody molecule comprises a VH comprising a VHCDR1 encoded by the nucleotide sequence of SEQ ID NO: 736 or 737, a VHCDR2 encoded by the nucleotide sequence of SEQ ID NO: 738 or 739, and a VHCDR3 encoded by the nucleotide sequence of SEQ ID NO: 740 or 741; and a VL comprising a VLCDR1 encoded by the nucleotide sequence of SEQ ID NO: 746 or 747, a VLCDR2 encoded by the nucleotide sequence of SEQ ID NO: 748 or 749, and a VLCDR3 encoded by the nucleotide sequence of SEQ ID NO: 750 or 751, each disclosed in Table 15. In one embodiment, the anti-LAG-3 antibody molecule comprises a VH comprising a VHCDR1 encoded by the nucleotide sequence of SEQ ID NO: 758 or 737, a VHCDR2 encoded by the nucleotide sequence of SEQ ID NO: 759 or 739, and a VHCDR3 encoded by the nucleotide sequence of SEQ ID NO: 760 or 741; and a VL comprising a VLCDR1 encoded by the nucleotide sequence of SEQ ID NO: 746 or 747, a VLCDR2 encoded by the nucleotide sequence of SEQ ID NO: 748 or 749, and a VLCDR3 encoded by the nucleotide sequence of SEQ ID NO: 750 or 751, each disclosed in Table 15. 
     In one embodiment, the anti-LAG-3 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 706, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 706. In one embodiment, the anti-LAG-3 antibody molecule comprises a VL comprising the amino acid sequence of SEQ ID NO: 718, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 718. In one embodiment, the anti-LAG-3 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 724, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 724. In one embodiment, the anti-LAG-3 antibody molecule comprises a VL comprising the amino acid sequence of SEQ ID NO: 730, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 730. In one embodiment, the anti-LAG-3 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 706 and a VL comprising the amino acid sequence of SEQ ID NO: 718. In one embodiment, the anti-LAG-3 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 724 and a VL comprising the amino acid sequence of SEQ ID NO: 730. 
     In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 707 or 708, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 707 or 708. In one embodiment, the antibody molecule comprises a VL encoded by the nucleotide sequence of SEQ ID NO: 719 or 720, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 719 or 720. In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 725 or 726, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 725 or 726. In one embodiment, the antibody molecule comprises a VL encoded by the nucleotide sequence of SEQ ID NO: 731 or 732, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 731 or 732. In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 707 or 708 and a VL encoded by the nucleotide sequence of SEQ ID NO: 719 or 720. In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 725 or 726 and a VL encoded by the nucleotide sequence of SEQ ID NO: 731 or 732. 
     In one embodiment, the anti-LAG-3 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 709, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 709. In one embodiment, the anti-LAG-3 antibody molecule comprises a light chain comprising the amino acid sequence of SEQ ID NO: 721, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 721. In one embodiment, the anti-LAG-3 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 727, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 727. In one embodiment, the anti-LAG-3 antibody molecule comprises a light chain comprising the amino acid sequence of SEQ ID NO: 733, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 733. In one embodiment, the anti-LAG-3 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 709 and a light chain comprising the amino acid sequence of SEQ ID NO: 721. In one embodiment, the anti-LAG-3 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 727 and a light chain comprising the amino acid sequence of SEQ ID NO: 733. 
     In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 716 or 717, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 716 or 717. In one embodiment, the antibody molecule comprises a light chain encoded by the nucleotide sequence of SEQ ID NO: 722 or 723, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 722 or 723. In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 728 or 729, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 728 or 729. In one embodiment, the antibody molecule comprises a light chain encoded by the nucleotide sequence of SEQ ID NO: 734 or 735, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 734 or 735. In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 716 or 717 and a light chain encoded by the nucleotide sequence of SEQ ID NO: 722 or 723. In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 728 or 729 and a light chain encoded by the nucleotide sequence of SEQ ID NO: 734 or 735. 
     The antibody molecules described herein can be made by vectors, host cells, and methods described in US 2015/0259420, incorporated by reference in its entirety. 
     
       
         
           
               
             
               
                 TABLE 15 
               
               
                   
               
               
                 Amino acid and nucleotide sequences of exemplary anti-LAG-3 antibody molecules 
               
               
                   
               
             
            
               
                 BAP050-Clone I HC 
               
            
           
           
               
               
               
            
               
                 SEQ ID NO: 701 
                 HCDR1 
                 NYGMN 
               
               
                 (Kabat) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 702 
                 HCDR2 
                 WINTDTGEPTYADDFKG 
               
               
                 (Kabat) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 703 
                 HCDR3 
                 NPPYYYGTNNAEAMDY 
               
               
                 (Kabat) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 704 
                 HCDR1 
                 GFTLTNY 
               
               
                 (Chothia) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 705 
                 HCDR2 
                 NTDTGE 
               
               
                 (Chothia) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 703 
                 HCDR3 
                 NPPYYYGTNNAEAMDY 
               
               
                 (Chothia) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO:706 
                 VH 
                 QVQLVQSGAEVKKPGASVKVSCKASGFTLTNYGMNWVRQ 
               
               
                   
                   
                 ARGQRLEWIGWINTDTGEPTYADDFKGRFVFSLDTSVSTA 
               
               
                   
                   
                 YLQISSLKAEDTAVYYCARNPPYYYGTNNAEAMDYWGQG 
               
               
                   
                   
                 TTVTVSS 
               
               
                   
               
               
                 SEQ ID NO: 707 
                 DNA VH 
                 CAAGTGCAGCTGGTGCAGTCGGGAGCCGAAGTGAAGAA 
               
               
                   
                   
                 GCCTGGAGCCTCGGTGAAGGTGTCGTGCAAGGCATCCG 
               
               
                   
                   
                 GATTCACCCTCACCAATTACGGGATGAACTGGGTCAGAC 
               
               
                   
                   
                 AGGCCCGGGGTCAACGGCTGGAGTGGATCGGATGGATT 
               
               
                   
                   
                 AACACCGACACCGGGGAGCCTACCTACGCGGACGATTT 
               
               
                   
                   
                 CAAGGGACGGTTCGTGTTCTCCCTCGACACCTCCGTGT 
               
               
                   
                   
                 CCACCGCCTACCTCCAAATCTCCTCACTGAAAGCGGAG 
               
               
                   
                   
                 GACACCGCCGTGTACTATTGCGCGAGGAACCCGCCCTA 
               
               
                   
                   
                 CTACTACGGAACCAACAACGCCGAAGCCATGGACTACT 
               
               
                   
                   
                 GGGGCCAGGGCACCACTGTGACTGTGTCCAGC 
               
               
                   
               
               
                 SEQ ID NO: 708 
                 DNA VH 
                 CAGGTGCAGCTGGTGCAGTCTGGCGCCGAAGTGAAGAA 
               
               
                   
                   
                 ACCTGGCGCCTCCGTGAAGGTGTCCTGCAAGGCCTCTG 
               
               
                   
                   
                 GCTTCACCCTGACCAACTACGGCATGAACTGGGTGCGA 
               
               
                   
                   
                 CAGGCCAGGGGCCAGCGGCTGGAATGGATCGGCTGGA 
               
               
                   
                   
                 TCAACACCGACACCGGCGAGCCTACCTACGCCGACGAC 
               
               
                   
                   
                 TTCAAGGGCAGATTCGTGTTCTCCCTGGACACCTCCGTG 
               
               
                   
                   
                 TCCACCGCCTACCTGCAGATCTCCAGCCTGAAGGCCGA 
               
               
                   
                   
                 GGATACCGCCGTGTACTACTGCGCCCGGAACCCCCCTT 
               
               
                   
                   
                 ACTACTACGGCACCAACAACGCCGAGGCCATGGACTAT 
               
               
                   
                   
                 TGGGGCCAGGGCACCACCGTGACCGTGTCCTCT 
               
               
                   
               
               
                 SEQ ID NO: 709 
                 Heavy 
                 QVQLVQSGAEVKKPGASVKVSCKASGFTLTNYGMNWVRQ 
               
               
                   
                 chain 
                 ARGQRLEWIGWINTDTGEPTYADDFKGRFVFSLDTSVSTA 
               
               
                   
                   
                 YLQISSLKAEDTAVYYCARNPPYYYGTNNAEAMDYWGQG 
               
               
                   
                   
                 TTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFP 
               
               
                   
                   
                 EPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSS 
               
               
                   
                   
                 SLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEF 
               
               
                   
                   
                 LGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQF 
               
               
                   
                   
                 NWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWL 
               
               
                   
                   
                 NGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQ 
               
               
                   
                   
                 EEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP 
               
               
                   
                   
                 PVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHN 
               
               
                   
                   
                 HYTQKSLSLSLG 
               
               
                   
               
               
                 SEQ ID NO: 716 
                 DNA 
                 CAAGTGCAGCTGGTGCAGTCGGGAGCCGAAGTGAAGAA 
               
               
                   
                 heavy 
                 GCCTGGAGCCTCGGTGAAGGTGTCGTGCAAGGCATCCG 
               
               
                   
                 chain 
                 GATTCACCCTCACCAATTACGGGATGAACTGGGTCAGAC 
               
               
                   
                   
                 AGGCCCGGGGTCAACGGCTGGAGTGGATCGGATGGATT 
               
               
                   
                   
                 AACACCGACACCGGGGAGCCTACCTACGCGGACGATTT 
               
               
                   
                   
                 CAAGGGACGGTTCGTGTTCTCCCTCGACACCTCCGTGT 
               
               
                   
                   
                 CCACCGCCTACCTCCAAATCTCCTCACTGAAAGCGGAG 
               
               
                   
                   
                 GACACCGCCGTGTACTATTGCGCGAGGAACCCGCCCTA 
               
               
                   
                   
                 CTACTACGGAACCAACAACGCCGAAGCCATGGACTACT 
               
               
                   
                   
                 GGGGCCAGGGCACCACTGTGACTGTGTCCAGCGCGTC 
               
               
                   
                   
                 CACTAAGGGCCCGTCCGTGTTCCCCCTGGCACCTTGTA 
               
               
                   
                   
                 GCCGGAGCACTAGCGAATCCACCGCTGCCCTCGGCTGC 
               
               
                   
                   
                 CTGGTCAAGGATTACTTCCCGGAGCCCGTGACCGTGTC 
               
               
                   
                   
                 CTGGAACAGCGGAGCCCTGACCTCCGGAGTGCACACCT 
               
               
                   
                   
                 TCCCCGCTGTGCTGCAGAGCTCCGGGCTGTACTCGCTG 
               
               
                   
                   
                 TCGTCGGTGGTCACGGTGCCTTCATCTAGCCTGGGTAC 
               
               
                   
                   
                 CAAGACCTACACTTGCAACGTGGACCACAAGCCTTCCAA 
               
               
                   
                   
                 CACTAAGGTGGACAAGCGCGTCGAATCGAAGTACGGCC 
               
               
                   
                   
                 CACCGTGCCCGCCTTGTCCCGCGCCGGAGTTCCTCGGC 
               
               
                   
                   
                 GGTCCCTCGGTCTTTCTGTTCCCACCGAAGCCCAAGGA 
               
               
                   
                   
                 CACTTTGATGATTTCCCGCACCCCTGAAGTGACATGCGT 
               
               
                   
                   
                 GGTCGTGGACGTGTCACAGGAAGATCCGGAGGTGCAGT 
               
               
                   
                   
                 TCAATTGGTACGTGGATGGCGTCGAGGTGCACAACGCC 
               
               
                   
                   
                 AAAACCAAGCCGAGGGAGGAGCAGTTCAACTCCACTTA 
               
               
                   
                   
                 CCGCGTCGTGTCCGTGCTGACGGTGCTGCATCAGGACT 
               
               
                   
                   
                 GGCTGAACGGGAAGGAGTACAAGTGCAAAGTGTCCAAC 
               
               
                   
                   
                 AAGGGACTTCCTAGCTCAATCGAAAAGACCATCTCGAAA 
               
               
                   
                   
                 GCCAAGGGACAGCCCCGGGAACCCCAAGTGTATACCCT 
               
               
                   
                   
                 GCCACCGAGCCAGGAAGAAATGACTAAGAACCAAGTCT 
               
               
                   
                   
                 CATTGACTTGCCTTGTGAAGGGCTTCTACCCATCGGATA 
               
               
                   
                   
                 TCGCCGTGGAATGGGAGTCCAACGGCCAGCCGGAAAAC 
               
               
                   
                   
                 AACTACAAGACCACCCCTCCGGTGCTGGACTCAGACGG 
               
               
                   
                   
                 ATCCTTCTTCCTCTACTCGCGGCTGACCGTGGATAAGAG 
               
               
                   
                   
                 CAGATGGCAGGAGGGAAATGTGTTCAGCTGTTCTGTGAT 
               
               
                   
                   
                 GCATGAAGCCCTGCACAACCACTACACTCAGAAGTCCCT 
               
               
                   
                   
                 GTCCCTCTCCCTGGGA 
               
               
                   
               
               
                 SEQ ID NO: 717 
                 DNA 
                 CAGGTGCAGCTGGTGCAGTCTGGCGCCGAAGTGAAGAA 
               
               
                   
                 heavy 
                 ACCTGGCGCCTCCGTGAAGGTGTCCTGCAAGGCCTCTG 
               
               
                   
                 chain 
                 GCTTCACCCTGACCAACTACGGCATGAACTGGGTGCGA 
               
               
                   
                   
                 CAGGCCAGGGGCCAGCGGCTGGAATGGATCGGCTGGA 
               
               
                   
                   
                 TCAACACCGACACCGGCGAGCCTACCTACGCCGACGAC 
               
               
                   
                   
                 TTCAAGGGCAGATTCGTGTTCTCCCTGGACACCTCCGTG 
               
               
                   
                   
                 TCCACCGCCTACCTGCAGATCTCCAGCCTGAAGGCCGA 
               
               
                   
                   
                 GGATACCGCCGTGTACTACTGCGCCCGGAACCCCCCTT 
               
               
                   
                   
                 ACTACTACGGCACCAACAACGCCGAGGCCATGGACTAT 
               
               
                   
                   
                 TGGGGCCAGGGCACCACCGTGACCGTGTCCTCTGCTTC 
               
               
                   
                   
                 TACCAAGGGGCCCAGCGTGTTCCCCCTGGCCCCCTGCT 
               
               
                   
                   
                 CCAGAAGCACCAGCGAGAGCACAGCCGCCCTGGGCTG 
               
               
                   
                   
                 CCTGGTGAAGGACTACTTCCCCGAGCCCGTGACCGTGT 
               
               
                   
                   
                 CCTGGAACAGCGGAGCCCTGACCAGCGGCGTGCACAC 
               
               
                   
                   
                 CTTCCCCGCCGTGCTGCAGAGCAGCGGCCTGTACAGCC 
               
               
                   
                   
                 TGAGCAGCGTGGTGACCGTGCCCAGCAGCAGCCTGGG 
               
               
                   
                   
                 CACCAAGACCTACACCTGTAACGTGGACCACAAGCCCA 
               
               
                   
                   
                 GCAACACCAAGGTGGACAAGAGGGTGGAGAGCAAGTAC 
               
               
                   
                   
                 GGCCCACCCTGCCCCCCCTGCCCAGCCCCCGAGTTCCT 
               
               
                   
                   
                 GGGCGGACCCAGCGTGTTCCTGTTCCCCCCCAAGCCCA 
               
               
                   
                   
                 AGGACACCCTGATGATCAGCAGAACCCCCGAGGTGACC 
               
               
                   
                   
                 TGTGTGGTGGTGGACGTGTCCCAGGAGGACCCCGAGGT 
               
               
                   
                   
                 CCAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCACA 
               
               
                   
                   
                 ACGCCAAGACCAAGCCCAGAGAGGAGCAGTTTAACAGC 
               
               
                   
                   
                 ACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCA 
               
               
                   
                   
                 GGACTGGCTGAACGGCAAAGAGTACAAGTGTAAGGTCT 
               
               
                   
                   
                 CCAACAAGGGCCTGCCAAGCAGCATCGAAAAGACCATC 
               
               
                   
                   
                 AGCAAGGCCAAGGGCCAGCCTAGAGAGCCCCAGGTCTA 
               
               
                   
                   
                 CACCCTGCCACCCAGCCAAGAGGAGATGACCAAGAACC 
               
               
                   
                   
                 AGGTGTCCCTGACCTGTCTGGTGAAGGGCTTCTACCCA 
               
               
                   
                   
                 AGCGACATCGCCGTGGAGTGGGAGAGCAACGGCCAGC 
               
               
                   
                   
                 CCGAGAACAACTACAAGACCACCCCCCCAGTGCTGGAC 
               
               
                   
                   
                 AGCGACGGCAGCTTCTTCCTGTACAGCAGGCTGACCGT 
               
               
                   
                   
                 GGACAAGTCCAGATGGCAGGAGGGCAACGTCTTTAGCT 
               
               
                   
                   
                 GCTCCGTGATGCACGAGGCCCTGCACAACCACTACACC 
               
               
                   
                   
                 CAGAAGAGCCTGAGCCTGTCCCTGGGC 
               
               
                   
               
            
           
           
               
            
               
                 BAP050-Clone I LC 
               
            
           
           
               
               
               
            
               
                 SEQ ID NO: 710 
                 LCDR1 
                 SSSQDISNYLN 
               
               
                 (Kabat) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 711 
                 LCDR2 
                 YTSTLHL 
               
               
                 (Kabat) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 712 
                 LCDR3 
                 QQYYNLPWT 
               
               
                 (Kabat) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 713 
                 LCDR1 
                 SQDISNY 
               
               
                 (Chothia) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 714 
                 LCDR2 
                 YTS 
               
               
                 (Chothia) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 715 
                 LCDR3 
                 YYNLPW 
               
               
                 (Chothia) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 718 
                 VL 
                 DIQMTQSPSSLSASVGDRVTITCSSSQDISNYLNWYLQKPG 
               
               
                   
                   
                 QSPQLLIYYTSTLHLGVPSRFSGSGSGTEFTLTISSLQPDDF 
               
               
                   
                   
                 ATYYCQQYYNLPWTFGQGTKVEIK 
               
               
                   
               
               
                 SEQ ID NO: 719 
                 DNA VL 
                 GATATTCAGATGACTCAGTCACCTAGTAGCCTGAGCGCT 
               
               
                   
                   
                 AGTGTGGGCGATAGAGTGACTATCACCTGTAGCTCTAGT 
               
               
                   
                   
                 CAGGATATCTCTAACTACCTGAACTGGTATCTGCAGAAG 
               
               
                   
                   
                 CCCGGTCAATCACCTCAGCTGCTGATCTACTACACTAGC 
               
               
                   
                   
                 ACCCTGCACCTGGGCGTGCCCTCTAGGTTTAGCGGTAG 
               
               
                   
                   
                 CGGTAGTGGCACCGAGTTCACCCTGACTATCTCTAGCCT 
               
               
                   
                   
                 GCAGCCCGACGACTTCGCTACCTACTACTGTCAGCAGTA 
               
               
                   
                   
                 CTATAACCTGCCCTGGACCTTCGGTCAAGGCACTAAGGT 
               
               
                   
                   
                 CGAGATTAAG 
               
               
                   
               
               
                 SEQ ID NO: 720 
                 DNA VL 
                 GACATCCAGATGACCCAGTCCCCCTCCAGCCTGTCTGC 
               
               
                   
                   
                 TTCCGTGGGCGACAGAGTGACCATCACCTGTTCCTCCA 
               
               
                   
                   
                 GCCAGGACATCTCCAACTACCTGAACTGGTATCTGCAGA 
               
               
                   
                   
                 AGCCCGGCCAGTCCCCTCAGCTGCTGATCTACTACACC 
               
               
                   
                   
                 TCCACCCTGCACCTGGGCGTGCCCTCCAGATTTTCCGG 
               
               
                   
                   
                 CTCTGGCTCTGGCACCGAGTTTACCCTGACCATCAGCTC 
               
               
                   
                   
                 CCTGCAGCCCGACGACTTCGCCACCTACTACTGCCAGC 
               
               
                   
                   
                 AGTACTACAACCTGCCCTGGACCTTCGGCCAGGGCACC 
               
               
                   
                   
                 AAGGTGGAAATCAAG 
               
               
                   
               
               
                 SEQ ID NO: 721 
                 Light 
                 DIQMTQSPSSLSASVGDRVTITCSSSQDISNYLNWYLQKPG 
               
               
                   
                 chain 
                 QSPQLLIYYTSTLHLGVPSRFSGSGSGTEFTLTISSLQPDDF 
               
               
                   
                   
                 ATYYCQQYYNLPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQ 
               
               
                   
                   
                 LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESV 
               
               
                   
                   
                 TEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSS 
               
               
                   
                   
                 PVTKSFNRGEC 
               
               
                   
               
               
                 SEQ ID NO: 722 
                 DNA 
                 GATATTCAGATGACTCAGTCACCTAGTAGCCTGAGCGCT 
               
               
                   
                 light 
                 AGTGTGGGCGATAGAGTGACTATCACCTGTAGCTCTAGT 
               
               
                   
                 chain 
                 CAGGATATCTCTAACTACCTGAACTGGTATCTGCAGAAG 
               
               
                   
                   
                 CCCGGTCAATCACCTCAGCTGCTGATCTACTACACTAGC 
               
               
                   
                   
                 ACCCTGCACCTGGGCGTGCCCTCTAGGTTTAGCGGTAG 
               
               
                   
                   
                 CGGTAGTGGCACCGAGTTCACCCTGACTATCTCTAGCCT 
               
               
                   
                   
                 GCAGCCCGACGACTTCGCTACCTACTACTGTCAGCAGTA 
               
               
                   
                   
                 CTATAACCTGCCCTGGACCTTCGGTCAAGGCACTAAGGT 
               
               
                   
                   
                 CGAGATTAAGCGTACGGTGGCCGCTCCCAGCGTGTTCA 
               
               
                   
                   
                 TCTTCCCCCCCAGCGACGAGCAGCTGAAGAGCGGCACC 
               
               
                   
                   
                 GCCAGCGTGGTGTGCCTGCTGAACAACTTCTACCCCCG 
               
               
                   
                   
                 GGAGGCCAAGGTGCAGTGGAAGGTGGACAACGCCCTG 
               
               
                   
                   
                 CAGAGCGGCAACAGCCAGGAGAGCGTCACCGAGCAGG 
               
               
                   
                   
                 ACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTG 
               
               
                   
                   
                 ACCCTGAGCAAGGCCGACTACGAGAAGCATAAGGTGTA 
               
               
                   
                   
                 CGCCTGCGAGGTGACCCACCAGGGCCTGTCCAGCCCC 
               
               
                   
                   
                 GTGACCAAGAGCTTCAACAGGGGCGAGTGC 
               
               
                   
               
               
                 SEQ ID NO: 723 
                 DNA 
                 GACATCCAGATGACCCAGTCCCCCTCCAGCCTGTCTGC 
               
               
                   
                 light 
                 TTCCGTGGGCGACAGAGTGACCATCACCTGTTCCTCCA 
               
               
                   
                 chain 
                 GCCAGGACATCTCCAACTACCTGAACTGGTATCTGCAGA 
               
               
                   
                   
                 AGCCCGGCCAGTCCCCTCAGCTGCTGATCTACTACACC 
               
               
                   
                   
                 TCCACCCTGCACCTGGGCGTGCCCTCCAGATTTTCCGG 
               
               
                   
                   
                 CTCTGGCTCTGGCACCGAGTTTACCCTGACCATCAGCTC 
               
               
                   
                   
                 CCTGCAGCCCGACGACTTCGCCACCTACTACTGCCAGC 
               
               
                   
                   
                 AGTACTACAACCTGCCCTGGACCTTCGGCCAGGGCACC 
               
               
                   
                   
                 AAGGTGGAAATCAAGCGTACGGTGGCCGCTCCCAGCGT 
               
               
                   
                   
                 GTTCATCTTCCCCCCAAGCGACGAGCAGCTGAAGAGCG 
               
               
                   
                   
                 GCACCGCCAGCGTGGTGTGTCTGCTGAACAACTTCTAC 
               
               
                   
                   
                 CCCAGGGAGGCCAAGGTGCAGTGGAAGGTGGACAACG 
               
               
                   
                   
                 CCCTGCAGAGCGGCAACAGCCAGGAGAGCGTCACCGA 
               
               
                   
                   
                 GCAGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCA 
               
               
                   
                   
                 CCCTGACCCTGAGCAAGGCCGACTACGAGAAGCACAAG 
               
               
                   
                   
                 GTGTACGCCTGTGAGGTGACCCACCAGGGCCTGTCCAG 
               
               
                   
                   
                 CCCCGTGACCAAGAGCTTCAACAGGGGCGAGTGC 
               
               
                   
               
            
           
           
               
            
               
                 BAP050-Clone J HC 
               
            
           
           
               
               
               
            
               
                 SEQ ID NO: 701 
                 HCDR1 
                 NYGMN 
               
               
                 (Kabat) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 702 
                 HCDR2 
                 WINTDTGEPTYADDFKG 
               
               
                 (Kabat) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 703 
                 HCDR3 
                 NPPYYYGTNNAEAMDY 
               
               
                 (Kabat) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 704 
                 HCDR1 
                 GFTLTNY 
               
               
                 (Chothia) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 705 
                 HCDR2 
                 NTDTGE 
               
               
                 (Chothia) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 703 
                 HCDR3 
                 NPPYYYGTNNAEAMDY 
               
               
                 (Chothia) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 724 
                 VH 
                 QVQLVQSGAEVKKPGASVKVSCKASGFTLTNYGMNWVRQ 
               
               
                   
                   
                 APGQGLEWMGWINTDTGEPTYADDFKGRFVFSLDTSVST 
               
               
                   
                   
                 AYLQISSLKAEDTAVYYCARNPPYYYGTNNAEAMDYWGQ 
               
               
                   
                   
                 GTTVTVSS 
               
               
                   
               
               
                 SEQ ID NO: 725 
                 DNA VH 
                 CAGGTGCAGCTGGTGCAGTCAGGCGCCGAAGTGAAGAA 
               
               
                   
                   
                 ACCCGGCGCTAGTGTGAAAGTCAGCTGTAAAGCTAGTG 
               
               
                   
                   
                 GCTTCACCCTGACTAACTACGGGATGAACTGGGTCCGC 
               
               
                   
                   
                 CAGGCCCCAGGTCAAGGCCTCGAGTGGATGGGCTGGAT 
               
               
                   
                   
                 TAACACCGACACCGGCGAGCCTACCTACGCCGACGACT 
               
               
                   
                   
                 TTAAGGGCAGATTCGTGTTTAGCCTGGACACTAGTGTGT 
               
               
                   
                   
                 CTACCGCCTACCTGCAGATCTCTAGCCTGAAGGCCGAG 
               
               
                   
                   
                 GACACCGCCGTCTACTACTGCGCTAGAAACCCCCCCTA 
               
               
                   
                   
                 CTACTACGGCACTAACAACGCCGAGGCTATGGACTACT 
               
               
                   
                   
                 GGGGTCAAGGCACTACCGTGACCGTGTCTAGC 
               
               
                   
               
               
                 SEQ ID NO: 726 
                 DNA VH 
                 CAGGTGCAGCTGGTGCAGTCTGGCGCCGAAGTGAAGAA 
               
               
                   
                   
                 ACCTGGCGCCTCCGTGAAGGTGTCCTGCAAGGCCTCTG 
               
               
                   
                   
                 GCTTCACCCTGACCAACTACGGCATGAACTGGGTGCGA 
               
               
                   
                   
                 CAGGCCCCTGGACAGGGCCTGGAATGGATGGGCTGGA 
               
               
                   
                   
                 TCAACACCGACACCGGCGAGCCTACCTACGCCGACGAC 
               
               
                   
                   
                 TTCAAGGGCAGATTCGTGTTCTCCCTGGACACCTCCGTG 
               
               
                   
                   
                 TCCACCGCCTACCTGCAGATCTCCAGCCTGAAGGCCGA 
               
               
                   
                   
                 GGATACCGCCGTGTACTACTGCGCCCGGAACCCCCCTT 
               
               
                   
                   
                 ACTACTACGGCACCAACAACGCCGAGGCCATGGACTAT 
               
               
                   
                   
                 TGGGGCCAGGGCACCACCGTGACCGTGTCCTCT 
               
               
                   
               
               
                 SEQ ID NO: 727 
                 Heavy 
                 QVQLVQSGAEVKKPGASVKVSCKASGFTLTNYGMNWVRQ 
               
               
                   
                 chain 
                 APGQGLEWMGWINTDTGEPTYADDFKGRFVFSLDTSVST 
               
               
                   
                   
                 AYLQISSLKAEDTAVYYCARNPPYYYGTNNAEAMDYWGQ 
               
               
                   
                   
                 GTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYF 
               
               
                   
                   
                 PEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPS 
               
               
                   
                   
                 SSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPE 
               
               
                   
                   
                 FLGGPSVFLFPPKPKDTLMSRTPEVTCVVVDVSQEDPEVQ 
               
               
                   
                   
                 FNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDW 
               
               
                   
                   
                 LNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPS 
               
               
                   
                   
                 QEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTT 
               
               
                   
                   
                 PPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALH 
               
               
                   
                   
                 NHYTQKSLSLSLG 
               
               
                   
               
               
                 SEQ ID NO: 728 
                 DNA 
                 CAGGTGCAGCTGGTGCAGTCAGGCGCCGAAGTGAAGAA 
               
               
                   
                 heavy 
                 ACCCGGCGCTAGTGTGAAAGTCAGCTGTAAAGCTAGTG 
               
               
                   
                 chain 
                 GCTTCACCCTGACTAACTACGGGATGAACTGGGTCCGC 
               
               
                   
                   
                 CAGGCCCCAGGTCAAGGCCTCGAGTGGATGGGCTGGAT 
               
               
                   
                   
                 TAACACCGACACCGGCGAGCCTACCTACGCCGACGACT 
               
               
                   
                   
                 TTAAGGGCAGATTCGTGTTTAGCCTGGACACTAGTGTGT 
               
               
                   
                   
                 CTACCGCCTACCTGCAGATCTCTAGCCTGAAGGCCGAG 
               
               
                   
                   
                 GACACCGCCGTCTACTACTGCGCTAGAAACCCCCCCTA 
               
               
                   
                   
                 CTACTACGGCACTAACAACGCCGAGGCTATGGACTACT 
               
               
                   
                   
                 GGGGTCAAGGCACTACCGTGACCGTGTCTAGCGCTAGC 
               
               
                   
                   
                 ACTAAGGGCCCGTCCGTGTTCCCCCTGGCACCTTGTAG 
               
               
                   
                   
                 CCGGAGCACTAGCGAATCCACCGCTGCCCTCGGCTGCC 
               
               
                   
                   
                 TGGTCAAGGATTACTTCCCGGAGCCCGTGACCGTGTCC 
               
               
                   
                   
                 TGGAACAGCGGAGCCCTGACCTCCGGAGTGCACACCTT 
               
               
                   
                   
                 CCCCGCTGTGCTGCAGAGCTCCGGGCTGTACTCGCTGT 
               
               
                   
                   
                 CGTCGGTGGTCACGGTGCCTTCATCTAGCCTGGGTACC 
               
               
                   
                   
                 AAGACCTACACTTGCAACGTGGACCACAAGCCTTCCAAC 
               
               
                   
                   
                 ACTAAGGTGGACAAGCGCGTCGAATCGAAGTACGGCCC 
               
               
                   
                   
                 ACCGTGCCCGCCTTGTCCCGCGCCGGAGTTCCTCGGCG 
               
               
                   
                   
                 GTCCCTCGGTCTTTCTGTTCCCACCGAAGCCCAAGGACA 
               
               
                   
                   
                 CTTTGATGATTTCCCGCACCCCTGAAGTGACATGCGTGG 
               
               
                   
                   
                 TCGTGGACGTGTCACAGGAAGATCCGGAGGTGCAGTTC 
               
               
                   
                   
                 AATTGGTACGTGGATGGCGTCGAGGTGCACAACGCCAA 
               
               
                   
                   
                 AACCAAGCCGAGGGAGGAGCAGTTCAACTCCACTTACC 
               
               
                   
                   
                 GCGTCGTGTCCGTGCTGACGGTGCTGCATCAGGACTGG 
               
               
                   
                   
                 CTGAACGGGAAGGAGTACAAGTGCAAAGTGTCCAACAA 
               
               
                   
                   
                 GGGACTTCCTAGCTCAATCGAAAAGACCATCTCGAAAGC 
               
               
                   
                   
                 CAAGGGACAGCCCCGGGAACCCCAAGTGTATACCCTGC 
               
               
                   
                   
                 CACCGAGCCAGGAAGAAATGACTAAGAACCAAGTCTCAT 
               
               
                   
                   
                 TGACTTGCCTTGTGAAGGGCTTCTACCCATCGGATATCG 
               
               
                   
                   
                 CCGTGGAATGGGAGTCCAACGGCCAGCCGGAAAACAAC 
               
               
                   
                   
                 TACAAGACCACCCCTCCGGTGCTGGACTCAGACGGATC 
               
               
                   
                   
                 CTTCTTCCTCTACTCGCGGCTGACCGTGGATAAGAGCAG 
               
               
                   
                   
                 ATGGCAGGAGGGAAATGTGTTCAGCTGTTCTGTGATGCA 
               
               
                   
                   
                 TGAAGCCCTGCACAACCACTACACTCAGAAGTCCCTGTC 
               
               
                   
                   
                 CCTCTCCCTGGGA 
               
               
                   
               
               
                 SEQ ID NO: 729 
                 DNA 
                 CAGGTGCAGCTGGTGCAGTCTGGCGCCGAAGTGAAGAA 
               
               
                   
                 heavy 
                 ACCTGGCGCCTCCGTGAAGGTGTCCTGCAAGGCCTCTG 
               
               
                   
                 chain 
                 GCTTCACCCTGACCAACTACGGCATGAACTGGGTGCGA 
               
               
                   
                   
                 CAGGCCCCTGGACAGGGCCTGGAATGGATGGGCTGGA 
               
               
                   
                   
                 TCAACACCGACACCGGCGAGCCTACCTACGCCGACGAC 
               
               
                   
                   
                 TTCAAGGGCAGATTCGTGTTCTCCCTGGACACCTCCGTG 
               
               
                   
                   
                 TCCACCGCCTACCTGCAGATCTCCAGCCTGAAGGCCGA 
               
               
                   
                   
                 GGATACCGCCGTGTACTACTGCGCCCGGAACCCCCCTT 
               
               
                   
                   
                 ACTACTACGGCACCAACAACGCCGAGGCCATGGACTAT 
               
               
                   
                   
                 TGGGGCCAGGGCACCACCGTGACCGTGTCCTCTGCTTC 
               
               
                   
                   
                 TACCAAGGGGCCCAGCGTGTTCCCCCTGGCCCCCTGCT 
               
               
                   
                   
                 CCAGAAGCACCAGCGAGAGCACAGCCGCCCTGGGCTG 
               
               
                   
                   
                 CCTGGTGAAGGACTACTTCCCCGAGCCCGTGACCGTGT 
               
               
                   
                   
                 CCTGGAACAGCGGAGCCCTGACCAGCGGCGTGCACAC 
               
               
                   
                   
                 CTTCCCCGCCGTGCTGCAGAGCAGCGGCCTGTACAGCC 
               
               
                   
                   
                 TGAGCAGCGTGGTGACCGTGCCCAGCAGCAGCCTGGG 
               
               
                   
                   
                 CACCAAGACCTACACCTGTAACGTGGACCACAAGCCCA 
               
               
                   
                   
                 GCAACACCAAGGTGGACAAGAGGGTGGAGAGCAAGTAC 
               
               
                   
                   
                 GGCCCACCCTGCCCCCCCTGCCCAGCCCCCGAGTTCCT 
               
               
                   
                   
                 GGGCGGACCCAGCGTGTTCCTGTTCCCCCCCAAGCCCA 
               
               
                   
                   
                 AGGACACCCTGATGATCAGCAGAACCCCCGAGGTGACC 
               
               
                   
                   
                 TGTGTGGTGGTGGACGTGTCCCAGGAGGACCCCGAGGT 
               
               
                   
                   
                 CCAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCACA 
               
               
                   
                   
                 ACGCCAAGACCAAGCCCAGAGAGGAGCAGTTTAACAGC 
               
               
                   
                   
                 ACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCA 
               
               
                   
                   
                 GGACTGGCTGAACGGCAAAGAGTACAAGTGTAAGGTCT 
               
               
                   
                   
                 CCAACAAGGGCCTGCCAAGCAGCATCGAAAAGACCATC 
               
               
                   
                   
                 AGCAAGGCCAAGGGCCAGCCTAGAGAGCCCCAGGTCTA 
               
               
                   
                   
                 CACCCTGCCACCCAGCCAAGAGGAGATGACCAAGAACC 
               
               
                   
                   
                 AGGTGTCCCTGACCTGTCTGGTGAAGGGCTTCTACCCA 
               
               
                   
                   
                 AGCGACATCGCCGTGGAGTGGGAGAGCAACGGCCAGC 
               
               
                   
                   
                 CCGAGAACAACTACAAGACCACCCCCCCAGTGCTGGAC 
               
               
                   
                   
                 AGCGACGGCAGCTTCTTCCTGTACAGCAGGCTGACCGT 
               
               
                   
                   
                 GGACAAGTCCAGATGGCAGGAGGGCAACGTCTTTAGCT 
               
               
                   
                   
                 GCTCCGTGATGCACGAGGCCCTGCACAACCACTACACC 
               
               
                   
                   
                 CAGAAGAGCCTGAGCCTGTCCCTGGGC 
               
               
                   
               
            
           
           
               
            
               
                 BAP050-Clone J LC 
               
            
           
           
               
               
               
            
               
                 SEQ ID NO: 710 
                 LCDR1 
                 SSSQDISNYLN 
               
               
                 (Kabat) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 711 
                 LCDR2 
                 YTSTLHL 
               
               
                 (Kabat) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 712 
                 LCDR3 
                 QQYYNLPWT 
               
               
                 (Kabat) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 713 
                 LCDR1 
                 SQDISNY 
               
               
                 (Chothia) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 714 
                 LCDR2 
                 YTS 
               
               
                 (Chothia) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 715 
                 LCDR3 
                 YYNLPW 
               
               
                 (Chothia) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 730 
                 VL 
                 DIQMTQSPSSLSASVGDRVTITCSSSQDISNYLNWYQQKP 
               
               
                   
                   
                 GKAPKLLIYYTSTLHLGIPPRFSGSGYGTDFTLTINNIESEDA 
               
               
                   
                   
                 AYYFCQQYYNLPWTFGQGTKVEIK 
               
               
                   
               
               
                 SEQ ID NO: 731 
                 DNA VL 
                 GATATTCAGATGACTCAGTCACCTAGTAGCCTGAGCGCT 
               
               
                   
                   
                 AGTGTGGGCGATAGAGTGACTATCACCTGTAGCTCTAGT 
               
               
                   
                   
                 CAGGATATCTCTAACTACCTGAACTGGTATCAGCAGAAG 
               
               
                   
                   
                 CCCGGTAAAGCCCCTAAGCTGCTGATCTACTACACTAGC 
               
               
                   
                   
                 ACCCTGCACCTGGGAATCCCCCCTAGGTTTAGCGGTAG 
               
               
                   
                   
                 CGGCTACGGCACCGACTTCACCCTGACTATTAACAATAT 
               
               
                   
                   
                 CGAGTCAGAGGACGCCGCCTACTACTTCTGTCAGCAGT 
               
               
                   
                   
                 ACTATAACCTGCCCTGGACCTTCGGTCAAGGCACTAAGG 
               
               
                   
                   
                 TCGAGATTAAG 
               
               
                   
               
               
                 SEQ ID NO: 732 
                 DNA VL 
                 GACATCCAGATGACCCAGTCCCCCTCCAGCCTGTCTGC 
               
               
                   
                   
                 TTCCGTGGGCGACAGAGTGACCATCACCTGTTCCTCCA 
               
               
                   
                   
                 GCCAGGACATCTCCAACTACCTGAACTGGTATCAGCAGA 
               
               
                   
                   
                 AGCCCGGCAAGGCCCCCAAGCTGCTGATCTACTACACC 
               
               
                   
                   
                 TCCACCCTGCACCTGGGCATCCCCCCTAGATTCTCCGG 
               
               
                   
                   
                 CTCTGGCTACGGCACCGACTTCACCCTGACCATCAACAA 
               
               
                   
                   
                 CATCGAGTCCGAGGACGCCGCCTACTACTTCTGCCAGC 
               
               
                   
                   
                 AGTACTACAACCTGCCCTGGACCTTCGGCCAGGGCACC 
               
               
                   
                   
                 AAGGTGGAAATCAAG 
               
               
                   
               
               
                 SEQ ID NO: 733 
                 Light 
                 DIQMTQSPSSLSASVGDRVTITCSSSQDISNYLNWYQQKP 
               
               
                   
                 chain 
                 GKAPKLLIYYTSTLHLGIPPRFSGSGYGTDFTLTINNIESEDA 
               
               
                   
                   
                 AYYFCQQYYNLPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQ 
               
               
                   
                   
                 LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESV 
               
               
                   
                   
                 TEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSS 
               
               
                   
                   
                 PVTKSFNRGEC 
               
               
                   
               
               
                 SEQ ID NO: 734 
                 DNA 
                 GATATTCAGATGACTCAGTCACCTAGTAGCCTGAGCGCT 
               
               
                   
                 light 
                 AGTGTGGGCGATAGAGTGACTATCACCTGTAGCTCTAGT 
               
               
                   
                 chain 
                 CAGGATATCTCTAACTACCTGAACTGGTATCAGCAGAAG 
               
               
                   
                   
                 CCCGGTAAAGCCCCTAAGCTGCTGATCTACTACACTAGC 
               
               
                   
                   
                 ACCCTGCACCTGGGAATCCCCCCTAGGTTTAGCGGTAG 
               
               
                   
                   
                 CGGCTACGGCACCGACTTCACCCTGACTATTAACAATAT 
               
               
                   
                   
                 CGAGTCAGAGGACGCCGCCTACTACTTCTGTCAGCAGT 
               
               
                   
                   
                 ACTATAACCTGCCCTGGACCTTCGGTCAAGGCACTAAGG 
               
               
                   
                   
                 TCGAGATTAAGCGTACGGTGGCCGCTCCCAGCGTGTTC 
               
               
                   
                   
                 ATCTTCCCCCCCAGCGACGAGCAGCTGAAGAGCGGCAC 
               
               
                   
                   
                 CGCCAGCGTGGTGTGCCTGCTGAACAACTTCTACCCCC 
               
               
                   
                   
                 GGGAGGCCAAGGTGCAGTGGAAGGTGGACAACGCCCT 
               
               
                   
                   
                 GCAGAGCGGCAACAGCCAGGAGAGCGTCACCGAGCAG 
               
               
                   
                   
                 GACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCT 
               
               
                   
                   
                 GACCCTGAGCAAGGCCGACTACGAGAAGCATAAGGTGT 
               
               
                   
                   
                 ACGCCTGCGAGGTGACCCACCAGGGCCTGTCCAGCCC 
               
               
                   
                   
                 CGTGACCAAGAGCTTCAACAGGGGCGAGTGC 
               
               
                   
               
               
                 SEQ ID NO: 735 
                 DNA 
                 GACATCCAGATGACCCAGTCCCCCTCCAGCCTGTCTGC 
               
               
                   
                 light 
                 TTCCGTGGGCGACAGAGTGACCATCACCTGTTCCTCCA 
               
               
                   
                 chain 
                 GCCAGGACATCTCCAACTACCTGAACTGGTATCAGCAGA 
               
               
                   
                   
                 AGCCCGGCAAGGCCCCCAAGCTGCTGATCTACTACACC 
               
               
                   
                   
                 TCCACCCTGCACCTGGGCATCCCCCCTAGATTCTCCGG 
               
               
                   
                   
                 CTCTGGCTACGGCACCGACTTCACCCTGACCATCAACAA 
               
               
                   
                   
                 CATCGAGTCCGAGGACGCCGCCTACTACTTCTGCCAGC 
               
               
                   
                   
                 AGTACTACAACCTGCCCTGGACCTTCGGCCAGGGCACC 
               
               
                   
                   
                 AAGGTGGAAATCAAGCGTACGGTGGCCGCTCCCAGCGT 
               
               
                   
                   
                 GTTCATCTTCCCCCCAAGCGACGAGCAGCTGAAGAGCG 
               
               
                   
                   
                 GCACCGCCAGCGTGGTGTGTCTGCTGAACAACTTCTAC 
               
               
                   
                   
                 CCCAGGGAGGCCAAGGTGCAGTGGAAGGTGGACAACG 
               
               
                   
                   
                 CCCTGCAGAGCGGCAACAGCCAGGAGAGCGTCACCGA 
               
               
                   
                   
                 GCAGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCA 
               
               
                   
                   
                 CCCTGACCCTGAGCAAGGCCGACTACGAGAAGCACAAG 
               
               
                   
                   
                 GTGTACGCCTGTGAGGTGACCCACCAGGGCCTGTCCAG 
               
               
                   
                   
                 CCCCGTGACCAAGAGCTTCAACAGGGGCGAGTGC 
               
               
                   
               
            
           
           
               
            
               
                 BAP050-Clone I HC 
               
            
           
           
               
               
               
            
               
                 SEQ ID NO: 736 
                 HCDR1 
                 AATTACGGGATGAAC 
               
               
                 (Kabat) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 737 
                 HCDR1 
                 AACTACGGCATGAAC 
               
               
                 (Kabat) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 738 
                 HCDR2 
                 TGGATTAACACCGACACCGGGGAGCCTACCTACGCGGA 
               
               
                 (Kabat) 
                   
                 CGATTTCAAGGGA 
               
               
                   
               
               
                 SEQ ID NO: 739 
                 HCDR2 
                 TGGATCAACACCGACACCGGCGAGCCTACCTACGCCGA 
               
               
                 (Kabat) 
                   
                 CGACTTCAAGGGC 
               
               
                   
               
               
                 SEQ ID NO: 740 
                 HCDR3 
                 AACCCGCCCTACTACTACGGAACCAACAACGCCGAAGC 
               
               
                 (Kabat) 
                   
                 CATGGACTAC 
               
               
                   
               
               
                 SEQ ID NO: 741 
                 HCDR3 
                 AACCCCCCTTACTACTACGGCACCAACAACGCCGAGGC 
               
               
                 (Kabat) 
                   
                   
               
               
                   
               
               
                 CATGGACTAT 
                   
                   
               
               
                 SEQ ID NO: 742 
                 HCDR1 
                 GGATTCACCCTCACCAATTAC 
               
               
                 (Chothia) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 743 
                 HCDR1 
                 GGCTTCACCCTGACCAACTAC 
               
               
                 (Chothia) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 744 
                 HCDR2 
                 AACACCGACACCGGGGAG 
               
               
                 (Chothia) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 745 
                 HCDR2 
                 AACACCGACACCGGCGAG 
               
               
                 (Chothia) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 740 
                 HCDR3 
                 AACCCGCCCTACTACTACGGAACCAACAACGCCGAAGC 
               
               
                 (Chothia) 
                   
                 CATGGACTAC 
               
               
                   
               
               
                 SEQ ID NO: 741 
                 HCDR3 
                 AACCCCCCTTACTACTACGGCACCAACAACGCCGAGGC 
               
               
                 (Chothia) 
                   
                 CATGGACTAT 
               
               
                   
               
            
           
           
               
            
               
                 BAP050-Clone I LC 
               
            
           
           
               
               
               
            
               
                 SEQ ID NO: 746 
                 LCDR1 
                 AGCTCTAGTCAGGATATCTCTAACTACCTGAAC 
               
               
                 (Kabat) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 747 
                 LCDR1 
                 TCCTCCAGCCAGGACATCTCCAACTACCTGAAC 
               
               
                 (Kabat) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 748 
                 LCDR2 
                 TACACTAGCACCCTGCACCTG 
               
               
                 (Kabat) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 749 
                 LCDR2 
                 TACACCTCCACCCTGCACCTG 
               
               
                 (Kabat) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 750 
                 LCDR3 
                 CAGCAGTACTATAACCTGCCCTGGACC 
               
               
                 (Kabat) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 751 
                 LCDR3 
                 CAGCAGTACTACAACCTGCCCTGGACC 
               
               
                 (Kabat) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 752 
                 LCDR1 
                 AGTCAGGATATCTCTAACTAC 
               
               
                 (Chothia) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 753 
                 LCDR1 
                 AGCCAGGACATCTCCAACTAC 
               
               
                 (Chothia) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 754 
                 LCDR2 
                 TACACTAGC 
               
               
                 (Chothia) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 755 
                 LCDR2 
                 TACACCTCC 
               
               
                 (Chothia) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 756 
                 LCDR3 
                 TACTATAACCTGCCCTGG 
               
               
                 (Chothia) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 757 
                 LCDR3 
                 TACTACAACCTGCCCTGG 
               
               
                 (Chothia) 
                   
                   
               
               
                   
               
               
                 BAP050-Clone J HC 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 758 
                 HCDR1 
                 AACTACGGGATGAAC 
               
               
                 (Kabat) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 737 
                 HCDR1 
                 AACTACGGCATGAAC 
               
               
                 (Kabat) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 759 
                 HCDR2 
                 TGGATTAACACCGACACCGGCGAGCCTACCTACGCCGA 
               
               
                 (Kabat) 
                   
                 CGACTTTAAGGGC 
               
               
                   
               
               
                 SEQ ID NO: 739 
                 HCDR2 
                 TGGATCAACACCGACACCGGCGAGCCTACCTACGCCGA 
               
               
                 (Kabat) 
                   
                 CGACTTCAAGGGC 
               
               
                   
               
               
                 SEQ ID NO: 760 
                 HCDR3 
                 AACCCCCCCTACTACTACGGCACTAACAACGCCGAGGC 
               
               
                 (Kabat) 
                   
                 TATGGACTAC 
               
               
                   
               
               
                 SEQ ID NO: 741 
                 HCDR3 
                 AACCCCCCTTACTACTACGGCACCAACAACGCCGAGGC 
               
               
                 (Kabat) 
                   
                 CATGGACTAT 
               
               
                   
               
               
                 SEQ ID NO: 761 
                 HCDR1 
                 GGCTTCACCCTGACTAACTAC 
               
               
                 (Chothia) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 743 
                 HCDR1 
                 GGCTTCACCCTGACCAACTAC 
               
               
                 (Chothia) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 744 
                 HCDR2 
                 AACACCGACACCGGGGAG 
               
               
                 (Chothia) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 745 
                 HCDR2 
                 AACACCGACACCGGCGAG 
               
               
                 (Chothia) 
                   
                   
               
               
                   
               
               
                 SEQ ID NO: 760 
                 HCDR3 
                 AACCCCCCCTACTACTACGGCACTAACAACGCCGAGGC 
               
               
                 (Chothia) 
                   
                 TATGGACTAC 
               
               
                   
               
               
                 SEQ ID NO: 741 
                 HCDR3 
                 AACCCCCCTTACTACTACGGCACCAACAACGCCGAGGC 
               
               
                 (Chothia) 
                   
                 CATGGACTAT 
               
               
                   
               
            
           
           
               
            
               
                 BAP050-Clone J LC 
               
            
           
           
               
               
               
            
               
                 SEQ ID NO: 746 
                 LCDR1 
                 AGCTCTAGTCAGGATATCTCTAACTACCTGAAC 
               
               
                 (Kabat) 
                   
                   
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 SEQ 
                 ID NO: 747 
                 LCDR1 
                 TCCTCCAGCCAGGACATCTCCAACTACCTGAAC 
               
               
                 (Kabat) 
                   
                   
                   
               
               
                   
               
               
                 SEQ 
                 ID NO: 748 
                 LCDR2 
                 TACACTAGCACCCTGCACCTG 
               
               
                 (Kabat) 
                   
                   
                   
               
               
                   
               
               
                 SEQ 
                 ID NO: 749 
                 LCDR2 
                 TACACCTCCACCCTGCACCTG 
               
               
                 (Kabat) 
                   
                   
                   
               
               
                   
               
               
                 SEQ 
                 ID NO: 750 
                 LCDR3 
                 CAGCAGTACTATAACCTGCCCTGGACC 
               
               
                 (Kabat) 
                   
                   
                   
               
               
                   
               
               
                 SEQ 
                 ID NO: 751 
                 LCDR3 
                 CAGCAGTACTACAACCTGCCCTGGACC 
               
               
                 (Kabat) 
                   
                   
                   
               
               
                   
               
               
                 SEQ 
                 ID NO: 752 
                 LCDR1 
                 AGTCAGGATATCTCTAACTAC 
               
               
                 (Chothia) 
                   
                   
                   
               
               
                   
               
               
                 SEQ 
                 ID NO: 753 
                 LCDR1 
                 AGCCAGGACATCTCCAACTAC 
               
               
                 (Chothia) 
                   
                   
                   
               
               
                   
               
               
                 SEQ 
                 ID NO: 754 
                 LCDR2 
                 TACACTAGC 
               
               
                 (Chothia) 
                   
                   
                   
               
               
                   
               
               
                 SEQ 
                 ID NO: 755 
                 LCDR2 
                 TACACCTCC 
               
               
                 (Chothia) 
                   
                   
                   
               
               
                   
               
               
                 SEQ 
                 ID NO: 756 
                 LCDR3 
                 TACTATAACCTGCCCTGG 
               
               
                 (Chothia) 
                   
                   
                   
               
               
                   
               
               
                 SEQ 
                 ID NO: 757 
                 LCDR3 
                 TACTACAACCTGCCCTGG 
               
               
                 (Chothia) 
               
               
                   
               
            
           
         
       
     
     Other Exemplary LAG-3 Inhibitors 
     In one embodiment, the LAG-3 inhibitor is an anti-LAG-3 antibody molecule. In one embodiment, the LAG-3 inhibitor is BMS-986016 (Bristol-Myers Squibb), also known as BMS986016. BMS-986016 and other anti-LAG-3 antibodies are disclosed in WO 2015/116539 and U.S. Pat. No. 9,505,839, incorporated by reference in their entirety. In one embodiment, the anti-LAG-3 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of BMS-986016, e.g., as disclosed in Table 16. 
     In one embodiment, the anti-LAG-3 antibody molecule is TSR-033 (Tesaro). In one embodiment, the anti-LAG-3 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of TSR-033. 
     In one embodiment, the anti-LAG-3 antibody molecule is IMP731 or GSK2831781 (GSK and Prima BioMed). IMP731 and other anti-LAG-3 antibodies are disclosed in WO 2008/132601 and U.S. Pat. No. 9,244,059, incorporated by reference in their entirety. In one embodiment, the anti-LAG-3 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of IMP731, e.g., as disclosed in Table 16. 
     In one embodiment, the anti-LAG-3 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of GSK2831781. 
     In one embodiment, the anti-LAG-3 antibody molecule is IMP761 (Prima BioMed). In one embodiment, the anti-LAG-3 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of IMP761. 
     Further known anti-LAG-3 antibodies include those described, e.g., in WO 2008/132601, WO 2010/019570, WO 2014/140180, WO 2015/116539, WO 2015/200119, WO 2016/028672, U.S. Pat. Nos. 9,244,059, 9,505,839, incorporated by reference in their entirety. 
     In one embodiment, the anti-LAG-3 antibody is an antibody that competes for binding with, and/or binds to the same epitope on LAG-3 as, one of the anti-LAG-3 antibodies described herein. 
     In one embodiment, the anti-LAG-3 inhibitor is a soluble LAG-3 protein, e.g., IMP321 (Prima BioMed), e.g., as disclosed in WO 2009/044273, incorporated by reference in its entirety. 
     
       
         
           
               
             
               
                 TABLE 16 
               
               
                   
               
               
                 Amino acid sequences of other exemplary  
               
               
                 anti-LAG-3 antibody molecules 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
            
               
                 BMS-986016 
               
            
           
           
               
               
               
            
               
                 SEQ  
                 Heavy 
                 QVQLQQWGAGLLKPSETLSLTCAVYGGSFSDYYWNW 
               
               
                 ID 
                 chain 
                 IRQPPGKGLEWIGEINHRGSTNSNPSLKSRVTLSLD 
               
               
                 NO: 
                   
                 TSKNQFSLKLRSVTAADTAVYYCAFGYSDYEYNWFD 
               
               
                 762 
                   
                 PWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAA 
               
               
                   
                   
                 LGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS 
               
               
                   
                   
                 GLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDK 
               
               
                   
                   
                 RVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLM 
               
               
                   
                   
                 ISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAK 
               
               
                   
                   
                 TKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVS 
               
               
                   
                   
                 NKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTK 
               
               
                   
                   
                 NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPP 
               
               
                   
                   
                 VLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEAL 
               
               
                   
                   
                 HNHYTQKSLSLSLGK 
               
               
                   
               
               
                 SEQ   
                 Light 
                 EIVLTQSPATLSLSPGERATLSCRASQSISSYLAWY 
               
               
                 ID 
                 chain 
                 QQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFT 
               
               
                 NO: 
                   
                 LTISSLEPEDFAVYYCQQRSNWPLTFGQGTNLEIKR 
               
               
                 763 
                   
                 TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREA 
               
               
                   
                   
                 KVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT 
               
               
                   
                   
                 LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 
               
               
                   
               
            
           
           
               
            
               
                 IMP731 
               
            
           
           
               
               
               
            
               
                 SEQ   
                 Heavy 
                 QVQLKESGPGLVAPSQSLSITCTVSGFSLTAYGVNW 
               
               
                 ID 
                 chain 
                 VRQPPGKGLEWLGMIWDDGSTDYNSALKSRLSISKD 
               
               
                 NO: 
                   
                 NSKSQVFLKMNSLQTDDTARYYCAREGDVAFDYWGQ 
               
               
                 764 
                   
                 GTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL 
               
               
                   
                   
                 VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS 
               
               
                   
                   
                 LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEP 
               
               
                   
                   
                 KSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMI 
               
               
                   
                   
                 SRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKT 
               
               
                   
                   
                 KPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN 
               
               
                   
                   
                 KALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKN 
               
               
                   
                   
                 QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPV 
               
               
                   
                   
                 LDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH 
               
               
                   
                   
                 NHYTQKSLSLSPGK 
               
               
                   
               
               
                 SEQ   
                 Light 
                 DIVMTQSPSSLAVSVGQKVTMSCKSSQSLLNGSNQK 
               
               
                 ID 
                 chain 
                 NYLAWYQQKPGQSPKLLVYFASTRDSGVPDRFIGSG 
               
               
                 NO: 
                   
                 SGTDFTLTISSVQAEDLADYFCLQHFGTPPTFGGGT 
               
               
                 765 
                   
                 KLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNN 
               
               
                   
                   
                 FYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS 
               
               
                   
                   
                 LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN 
               
               
                   
                   
                 RGEC 
               
               
                   
               
            
           
         
       
     
     TIM-3 Inhibitors 
     In certain embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of TIM-3. In some embodiments, the antibody conjugate of the present invention is administered in combination with a TIM-3 inhibitor. In some embodiments, the TIM-3 inhibitor is MGB453 (Novartis) or TSR-022 (Tesaro). 
     Exemplary TIM-3 Inhibitors 
     In one embodiment, the TIM-3 inhibitor is an anti-TIM-3 antibody molecule. In one embodiment, the TIM-3 inhibitor is an anti-TIM-3 antibody molecule as disclosed in US 2015/0218274, published on Aug. 6, 2015, entitled “Antibody Molecules to TIM-3 and Uses Thereof,” incorporated by reference in its entirety. 
     In one embodiment, the anti-TIM-3 antibody molecule comprises at least one, two, three, four, five or six complementarity determining regions (CDRs) (or collectively all of the CDRs) from a heavy and light chain variable region comprising an amino acid sequence shown in Table 17 (e.g., from the heavy and light chain variable region sequences of ABTIM3-hum11 or ABTIM3-hum03 disclosed in Table 17), or encoded by a nucleotide sequence shown in Table 17. In some embodiments, the CDRs are according to the Kabat definition (e.g., as set out in Table 17). In some embodiments, the CDRs are according to the Chothia definition (e.g., as set out in Table 17). In one embodiment, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six or more changes, e.g., amino acid substitutions (e.g., conservative amino acid substitutions) or deletions, relative to an amino acid sequence shown in Table 17, or encoded by a nucleotide sequence shown in Table 17. 
     In one embodiment, the anti-TIM-3 antibody molecule comprises a heavy chain variable region (VH) comprising a VHCDR1 amino acid sequence of SEQ ID NO: 801, a VHCDR2 amino acid sequence of SEQ ID NO: 802, and a VHCDR3 amino acid sequence of SEQ ID NO: 803; and a light chain variable region (VL) comprising a VLCDR1 amino acid sequence of SEQ ID NO: 810, a VLCDR2 amino acid sequence of SEQ ID NO: 811, and a VLCDR3 amino acid sequence of SEQ ID NO: 812, each disclosed in Table 17. In one embodiment, the anti-TIM-3 antibody molecule comprises a heavy chain variable region (VH) comprising a VHCDR1 amino acid sequence of SEQ ID NO: 801, a VHCDR2 amino acid sequence of SEQ ID NO: 820, and a VHCDR3 amino acid sequence of SEQ ID NO: 803; and a light chain variable region (VL) comprising a VLCDR1 amino acid sequence of SEQ ID NO: 810, a VLCDR2 amino acid sequence of SEQ ID NO: 811, and a VLCDR3 amino acid sequence of SEQ ID NO: 812, each disclosed in Table 17. 
     In one embodiment, the anti-TIM-3 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 806, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 806. In one embodiment, the anti-TIM-3 antibody molecule comprises a VL comprising the amino acid sequence of SEQ ID NO: 816, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 816. In one embodiment, the anti-TIM-3 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 822, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 822. In one embodiment, the anti-TIM-3 antibody molecule comprises a VL comprising the amino acid sequence of SEQ ID NO: 826, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 826. In one embodiment, the anti-TIM-3 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 806 and a VL comprising the amino acid sequence of SEQ ID NO: 816. In one embodiment, the anti-TIM-3 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 822 and a VL comprising the amino acid sequence of SEQ ID NO: 826. 
     In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 807, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 807. In one embodiment, the antibody molecule comprises a VL encoded by the nucleotide sequence of SEQ ID NO: 817, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 817. In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 823, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 823. In one embodiment, the antibody molecule comprises a VL encoded by the nucleotide sequence of SEQ ID NO: 827, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 827. In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 807 and a VL encoded by the nucleotide sequence of SEQ ID NO: 817. In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 823 and a VL encoded by the nucleotide sequence of SEQ ID NO: 827. 
     In one embodiment, the anti-TIM-3 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 808, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 808. In one embodiment, the anti-TIM-3 antibody molecule comprises a light chain comprising the amino acid sequence of SEQ ID NO: 818, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 818. In one embodiment, the anti-TIM-3 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 824, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 824. In one embodiment, the anti-TIM-3 antibody molecule comprises a light chain comprising the amino acid sequence of SEQ ID NO: 828, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 828. In one embodiment, the anti-TIM-3 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 808 and a light chain comprising the amino acid sequence of SEQ ID NO: 818. In one embodiment, the anti-TIM-3 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 824 and a light chain comprising the amino acid sequence of SEQ ID NO: 828. 
     In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 809, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 809. In one embodiment, the antibody molecule comprises a light chain encoded by the nucleotide sequence of SEQ ID NO: 819, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 819. In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 825, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 825. In one embodiment, the antibody molecule comprises a light chain encoded by the nucleotide sequence of SEQ ID NO: 829, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 829. In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 809 and a light chain encoded by the nucleotide sequence of SEQ ID NO: 819. In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 825 and a light chain encoded by the nucleotide sequence of SEQ ID NO: 829. 
     The antibody molecules described herein can be made by vectors, host cells, and methods described in US 2015/0218274, incorporated by reference in its entirety. 
     
       
         
           
               
             
               
                 TABLE 17 
               
               
                   
               
               
                 Amino acid and nucleotide sequences of  
               
               
                 exemplary anti-TIM-3 antibody molecules 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
            
               
                 
                   ABTIM3-hum11 
                 
               
            
           
           
               
               
               
            
               
                 SEQ ID   
                 HCDR1 
                 SYNMH 
               
               
                 NO: 801 
                   
                   
               
               
                 (Kabat) 
                   
                   
               
               
                   
               
               
                 SEQ ID  
                 HCDR2 
                 DIYPGNGDTSYNQKFKG 
               
               
                 NO: 802 
                   
                   
               
               
                 (Kabat) 
                   
                   
               
               
                   
               
               
                 SEQ ID  
                 HCDR3 
                 VGGAFPMDY 
               
               
                 NO: 803 
                   
                   
               
               
                 (Kabat) 
                   
                   
               
               
                   
               
               
                 SEQ ID  
                 HCDR1 
                 GYTFTSY 
               
            
           
           
               
            
               
                 NO: 804 
               
            
           
           
               
               
               
            
               
                 (Chothia) 
                   
                   
               
               
                   
               
               
                 SEQ ID  
                 HCDR2 
                 YPGNGD 
               
               
                 NO: 805 
                   
                   
               
               
                 (Chothia) 
                   
                   
               
               
                   
               
               
                 SEQ ID  
                 HCDR3 
                 VGGAFPMDY 
               
               
                 NO: 803 
                   
                   
               
               
                 (Chothia) 
                   
                   
               
               
                   
               
               
                 SEQ ID  
                 VH 
                 QVQLVQSGAEVKKPGSSVKVSCKASGYTFTS 
               
               
                 NO: 806 
                   
                 YNMHWVRQAPGQGLEWMGDIYPGNGDTSYNQ 
               
               
                   
                   
                 KFKGRVTITADKSTSTVYMELSSLRSEDTAV 
               
               
                   
                   
                 YYCARVGGAFPMDYWGQGTTVTVSS 
               
               
                   
               
               
                 SEQ ID  
                 DNA VH 
                 CAGGTGCAGCTGGTGCAGTCAGGCGCCGAAG 
               
               
                 NO: 807 
                   
                 TGAAGAAACCCGGCTCTAGCGTGAAAGTTTC 
               
               
                   
                   
                 TTGTAAAGCTAGTGGCTACACCTTCACTAGC 
               
               
                   
                   
                 TATAATATGCACTGGGTTCGCCAGGCCCCAG 
               
               
                   
                   
                 GGCAAGGCCTCGAGTGGATGGGCGATATCTA 
               
               
                   
                   
                 CCCCGGGAACGGCGACACTAGTTATAATCAG 
               
               
                   
                   
                 AAGTTTAAGGGTAGAGTCACTATCACCGCCG 
               
               
                   
                   
                 ATAAGTCTACTAGCACCGTCTATATGGAACT 
               
               
                   
                   
                 GAGTTCCCTGAGGTCTGAGGACACCGCCGTC 
               
               
                   
                   
                 TACTACTGCGCTAGAGTGGGCGGAGCCTTCC 
               
               
                   
                   
                 CTATGGACTACTGGGGTCAAGGCACTACCGT 
               
               
                   
                   
                 GACCGTGTCTAGC 
               
               
                   
               
               
                 SEQ ID  
                 Heavy 
                 QVQLVQSGAEVKKPGSSVKVSCKASGYTFTS 
               
               
                 NO: 808 
                 chain 
                 YNMHWVRQAPGQGLEWMGDIYPGNGDTSYNQ 
               
               
                   
                   
                 KFKGRVTITADKSTSTVYMELSSLRSEDTAV 
               
               
                   
                   
                 YYCARVGGAFPMDYWGQGTTVTVSSASTKGP 
               
               
                   
                   
                 SVFPLAPCSRSTSESTAALGCLVKDYFPEPV 
               
               
                   
                   
                 TVSWNSGALTSGVHTFPAVLQSSGLYSLSSV 
               
               
                   
                   
                 VTVPSSSLGTKTYTCNVDHKPSNTKVDKRVE 
               
               
                   
                   
                 SKYGPPCPPCPAPEFLGGPSVFLFPPKPKDT 
               
               
                   
                   
                 LMISRTPEVTCVVVDVSQEDPEVQFNWYVDG 
               
               
                   
                   
                 VEVHNAKTKPREEQFNSTYRVVSVLTVLHQD 
               
               
                   
                   
                 WLNGKEYKCKVSNKGLPSSIEKTISKAKGQP 
               
               
                   
                   
                 REPQVYTLPPSQEEMTKNQVSLTCLVKGFYP 
               
               
                   
                   
                 SDIAVEWESNGQPENNYKTTPPVLDSDGSFF 
               
               
                   
                   
                 LYSRLTVDKSRWQEGNVFSCSVMHEALHNHY 
               
               
                   
                   
                 TQKSLSLSLG 
               
               
                   
               
               
                 SEQ ID  
                 DNA 
                 CAGGTGCAGCTGGTGCAGTCAGGCGCCGAAG 
               
               
                 NO: 809 
                 heavy 
                 TGAAGAAACCCGGCTCTAGCGTGAAAGTTTC 
               
               
                   
                 chain 
                 TTGTAAAGCTAGTGGCTACACCTTCACTAGC 
               
               
                   
                   
                 TATAATATGCACTGGGTTCGCCAGGCCCCAG 
               
               
                   
                   
                 GGCAAGGCCTCGAGTGGATGGGCGATATCTA 
               
               
                   
                   
                 CCCCGGGAACGGCGACACTAGTTATAATCAG 
               
               
                   
                   
                 AAGTTTAAGGGTAGAGTCACTATCACCGCCG 
               
               
                   
                   
                 ATAAGTCTACTAGCACCGTCTATATGGAACT 
               
               
                   
                   
                 GAGTTCCCTGAGGTCTGAGGACACCGCCGTC 
               
               
                   
                   
                 TACTACTGCGCTAGAGTGGGCGGAGCCTTCC 
               
               
                   
                   
                 CTATGGACTACTGGGGTCAAGGCACTACCGT 
               
               
                   
                   
                 GACCGTGTCTAGCGCTAGCACTAAGGGCCCG 
               
               
                   
                   
                 TCCGTGTTCCCCCTGGCACCTTGTAGCCGGA 
               
               
                   
                   
                 GCACTAGCGAATCCACCGCTGCCCTCGGCTG 
               
               
                   
                   
                 CCTGGTCAAGGATTACTTCCCGGAGCCCGTG 
               
               
                   
                   
                 ACCGTGTCCTGGAACAGCGGAGCCCTGACCT 
               
               
                   
                   
                 CCGGAGTGCACACCTTCCCCGCTGTGCTGCA 
               
               
                   
                   
                 GAGCTCCGGGCTGTACTCGCTGTCGTCGGTG 
               
               
                   
                   
                 GTCACGGTGCCTTCATCTAGCCTGGGTACCA 
               
               
                   
                   
                 AGACCTACACTTGCAACGTGGACCACAAGCC 
               
               
                   
                   
                 TTCCAACACTAAGGTGGACAAGCGCGTCGAA 
               
               
                   
                   
                 TCGAAGTACGGCCCACCGTGCCCGCCTTGTC 
               
               
                   
                   
                 CCGCGCCGGAGTTCCTCGGCGGTCCCTCGGT 
               
               
                   
                   
                 CTTTCTGTTCCCACCGAAGCCCAAGGACACT 
               
               
                   
                   
                 TTGATGATTTCCCGCACCCCTGAAGTGACAT 
               
               
                   
                   
                 GCGTGGTCGTGGACGTGTCACAGGAAGATCC 
               
               
                   
                   
                 GGAGGTGCAGTTCAATTGGTACGTGGATGGC 
               
               
                   
                   
                 GTCGAGGTGCACAACGCCAAAACCAAGCCGA 
               
               
                   
                   
                 GGGAGGAGCAGTTCAACTCCACTTACCGCGT 
               
               
                   
                   
                 CGTGTCCGTGCTGACGGTGCTGCATCAGGAC 
               
               
                   
                   
                 TGGCTGAACGGGAAGGAGTACAAGTGCAAAG 
               
               
                   
                   
                 TGTCCAACAAGGGACTTCCTAGCTCAATCGA 
               
               
                   
                   
                 AAAGACCATCTCGAAAGCCAAGGGACAGCCC 
               
               
                   
                   
                 CGGGAACCCCAAGTGTATACCCTGCCACCGA 
               
               
                   
                   
                 GCCAGGAAGAAATGACTAAGAACCAAGTCTC 
               
               
                   
                   
                 ATTGACTTGCCTTGTGAAGGGCTTCTACCCA 
               
               
                   
                   
                 TCGGATATCGCCGTGGAATGGGAGTCCAACG 
               
               
                   
                   
                 GCCAGCCGGAAAACAACTACAAGACCACCCC 
               
               
                   
                   
                 TCCGGTGCTGGACTCAGACGGATCCTTCTTC 
               
               
                   
                   
                 CTCTACTCGCGGCTGACCGTGGATAAGAGCA 
               
               
                   
                   
                 GATGGCAGGAGGGAAATGTGTTCAGCTGTTC 
               
               
                   
                   
                 TGTGATGCATGAAGCCCTGCACAACCACTAC 
               
               
                   
                   
                 ACTCAGAAGTCCCTGTCCCTCTCCCTGGGA 
               
               
                   
               
               
                 SEQ ID  
                 LCDR1 
                 RASESVEYYGTSLMQ 
               
               
                 NO: 810 
                   
                   
               
               
                 (Kabat) 
                   
                   
               
               
                   
               
               
                 SEQ ID  
                 LCDR2 
                 AASNVES 
               
               
                 NO: 811 
                   
                   
               
               
                 (Kabat) 
                   
                   
               
               
                   
               
               
                 SEQ ID  
                 LCDR3 
                 QQSRKDPST 
               
               
                 NO: 812 
                   
                   
               
               
                 (Kabat) 
                   
                   
               
               
                   
               
               
                 SEQ ID  
                 LCDR1 
                 SESVEYYGTSL 
               
               
                 NO: 813 
                   
                   
               
               
                 (Chothia) 
                   
                   
               
               
                   
               
               
                 SEQ ID  
                 LCDR2 
                 AAS 
               
               
                 NO: 814 
                   
                   
               
               
                 (Chothia) 
                   
                   
               
               
                   
               
               
                 SEQ ID  
                 LCDR3 
                 SRKDPS 
               
               
                 NO: 815 
                   
                   
               
               
                 (Chothia) 
                   
                   
               
               
                   
               
               
                 SEQ ID  
                 VL 
                 AIQLTQSPSSLSASVGDRVTITCRASESVEYY 
               
               
                 NO: 816 
                   
                 GTSLMQWYQQKPGKAPKLLIYAASNVESGVPS 
               
               
                   
                   
                 RFSGSGSGTDFTLTISSLQPEDFATYFCQQSR 
               
               
                   
                   
                 KDPSTFGGGTKV 
               
               
                   
               
               
                 SEQ ID  
                 DNA VL 
                 EIKGCTATTCAGCTGACTCAGTCACCTAGTAG 
               
               
                 NO: 817 
                   
                 CCTGAGCGCTAGTGTGGGCGATAGAGTGACTA 
               
               
                   
                   
                 TCACCTGTAGAGCTAGTGAATCAGTCGAGTAC 
               
               
                   
                   
                 TACGGCACTAGCCTGATGCAGTGGTATCAGCA 
               
               
                   
                   
                 GAAGCCCGGGAAAGCCCCTAAGCTGCTGATCT 
               
               
                   
                   
                 ACGCCGCCTCTAACGTGGAATCAGGCGTGCCC 
               
               
                   
                   
                 TCTAGGTTTAGCGGTAGCGGTAGTGGCACCGA 
               
               
                   
                   
                 CTTCACCCTGACTATCTCTAGCCTGCAGCCCG 
               
               
                   
                   
                 AGGACTTCGCTACCTACTTCTGTCAGCAGTCT 
               
               
                   
                   
                 AGGAAGGACCCTAGCACCTTCGGCGGAGGCAC 
               
               
                   
                   
                 TAAG 
               
               
                   
               
               
                 SEQ ID  
                 Light 
                 GTCGAGATTAAGAIQLTQSPSSLSASVGDRVT 
               
               
                 NO: 818 
                 chain 
                 ITCRASESVEYYGTSLMQWYQQKPGKAPKLLI 
               
               
                   
                   
                 YAASNVESGVPSRFSGSGSGTDFTLTISSLQP 
               
               
                   
                   
                 EDFATYFCQQSRKDPSTFGGGTKVEIKRTVAA 
               
               
                   
                   
                 PSVFIFPPSDEQLKSGTASVVCLLNNFYPREA 
               
               
                   
                   
                 KVQWKVDNALQSGNSQESVTEQDSKDSTYSLS 
               
               
                   
                   
                 STLTLSKADYEKHKVYACEVTHQG 
               
               
                   
               
               
                 SEQ ID  
                 DNA 
                 LSSPVTKSFNRGECGCTATTCAGCTGACTCAG 
               
               
                 NO: 819 
                 light 
                 TCACCTAGTAGCCTGAGCGCTAGTGTGGGCGA 
               
               
                   
                 chain 
                 TAGAGTGACTATCACCTGTAGAGCTAGTGAAT 
               
               
                   
                   
                 CAGTCGAGTACTACGGCACTAGCCTGATGCAG 
               
               
                   
                   
                 TGGTATCAGCAGAAGCCCGGGAAAGCCCCTAA 
               
               
                   
                   
                 GCTGCTGATCTACGCCGCCTGCCCTCTAGGTT 
               
               
                   
                   
                 TAGCGGTAGCGGTAGTGGCACCGACTAACGTG 
               
               
                   
                   
                 GAATCAGGCGTCTTCACCCTGACTATCTCTAG 
               
               
                   
                   
                 CCTGCAGCCCGAGGACTTCGCTACCTACTTCT 
               
               
                   
                   
                 GTCAGCAGTCTAGGAAGGACCCTAGCACCTTC 
               
               
                   
                   
                 GGCGGAGGCACTAAGGTCGAGATTAAGCGTAC 
               
               
                   
                   
                 GGTGGCCGCTCCCAGCGTGTTCATCTTCCCCC 
               
               
                   
                   
                 CCAGCGACGAGCAGCTGAAGAGCGGCACCGCC 
               
               
                   
                   
                 AGCGTGGTGTGCCTGCTGAACAACTTCTACCC 
               
               
                   
                   
                 CCGGGAGGCCAAGGTGCAGTGGAAGGTGGACA 
               
               
                   
                   
                 ACGCCCTGCAGAGCGGCAACAGCCAGGAGAGC 
               
               
                   
                   
                 GTCACCGAGCAGGACAGCAAGGACTCCACCTA 
               
               
                   
                   
                 CAGCCTGAGCAGCACCCTGACCCTGAGCAAGG 
               
               
                   
                   
                 CCGACTACGAGAAGCATAAGGTGTACGCCTGC 
               
               
                   
                   
                 GAGGTGACCCACCAGGGCCTGTCCAGCCCCGT 
               
               
                   
                   
                 GACCAAGAGCTTCAACAGGGGCGAGTGC 
               
               
                   
               
            
           
           
               
            
               
                 
                   ABTIM3-hum03 
                 
               
            
           
           
               
               
               
            
               
                 SEQ ID  
                 HCDR1 
                 SYNMH 
               
               
                 NO: 801 
                   
                   
               
               
                 (Kabat) 
                   
                   
               
               
                   
               
               
                 SEQ ID  
                 HCDR2 
                 DIYPGQGDTSYNQKFKG 
               
               
                 NO: 820 
                   
                   
               
               
                 (Kabat) 
                   
                   
               
               
                   
               
               
                 SEQ ID  
                 HCDR3 
                 VGGAFPMDY 
               
               
                 NO: 803 
                   
                   
               
               
                 (Kabat) 
                   
                   
               
               
                   
               
               
                 SEQ ID  
                 HCDR1 
                 GYTFTSY 
               
               
                 NO: 804 
                   
                   
               
               
                 (Chothia) 
                   
                   
               
               
                   
               
               
                 SEQ ID  
                 HCDR2 
                 YPGQGD 
               
               
                 NO: 821 
                   
                   
               
               
                 (Chothia) 
                   
                   
               
               
                   
               
               
                 SEQ ID  
                 HCDR3 
                 VGGAFPMDY 
               
               
                 NO: 803 
                   
                   
               
               
                 (Chothia) 
                   
                   
               
               
                   
               
               
                 SEQ ID  
                 VH 
                 QVQLVQSGAEVKKPGASVKVSCKASGYTFTSY 
               
               
                 NO: 822 
                   
                 NMHWVRQAPGQGLEWIGDIYPGQGDTSYNQKF 
               
               
                   
                   
                 KGRATMTADKSTSTVYMELSSLRSEDTAVYYC 
               
               
                   
                   
                 ARVGGAFPMDYWGQGTLVTVSS 
               
               
                   
               
               
                 SEQ ID  
                 DNA VH 
                 CAGGTGCAGCTGGTGCAGTCAGGCGCCGAAGT 
               
               
                 NO: 823 
                   
                 GAAGAAACCCGGCGCTAGTGTGAAAGTTAGCT 
               
               
                   
                   
                 GTAAAGCTAGTGGCTATACTTTCACTTCTTAT 
               
               
                   
                   
                 AATATGCACTGGGTCCGCCAGGCCCCAGGTCA 
               
               
                   
                   
                 AGGCCTCGAGTGGATCGGCGATATCTACCCCG 
               
               
                   
                   
                 GTCAAGGCGACACTTCCTATAATCAGAAGTTT 
               
               
                   
                   
                 AAGGGTAGAGCTACTATGACCGCCGATAAGTC 
               
               
                   
                   
                 TACTTCTACCGTCTATATGGAACTGAGTTCCC 
               
               
                   
                   
                 TGAGGTCTGAGGACACCGCCGTCTACTACTGC 
               
               
                   
                   
                 GCTAGAGTGGGCGGAGCCTTCCCAATGGACTA 
               
               
                   
                   
                 CTGGGGTCAAGGCACCCTGGTCACCGTGTCTA 
               
               
                   
                   
                 GC 
               
               
                   
               
               
                 SEQ ID  
                 Heavy 
                 QVQLVQSGAEVKKPGASVKVSCKASGYTFTSY 
               
               
                 NO: 824 
                 chain 
                 NMHWVRQAPGQGLEWIGDIYPGQGDTSYNQKF 
               
               
                   
                   
                 KGRATMTADKSTSTVYMELSSLRSEDTAVYYC 
               
               
                   
                   
                 ARVGGAFPMDYWGQGTLVTVSSASTKGPSVFP 
               
               
                   
                   
                 LAPCSRSTSESTAALGCLVKDYFPEPVTVSWN 
               
               
                   
                   
                 SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSS 
               
               
                   
                   
                 SLGTKTYTCNVDHKPSNTKVDKRVESKYGPPC 
               
               
                   
                   
                 PPCPAPEFLGGPSVFLFPPKPKDTLMISRTPE 
               
               
                   
                   
                 VTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTK 
               
               
                   
                   
                 PREEQFNSTYRVVSVLTVLHQDWLNGKEYKCK 
               
               
                   
                   
                 VSNKGLPSSIEKTISKAKGQPREPQVYTLPPS 
               
               
                   
                   
                 QEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQ 
               
               
                   
                   
                 PENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQ 
               
               
                   
                   
                 EGNVFSCSVMHEALHNHYTQKSLSLSLG 
               
               
                   
               
               
                 SEQ ID  
                 DNA 
                 CAGGTGCAGCTGGTGCAGTCAGGCGCCGAAGT 
               
               
                 NO: 825 
                 heavy 
                 GAAGAAACCCGGCGCTAGTGTGAAAGTTAGCT 
               
               
                   
                 chain 
                 GTAAAGCTAGTGGCTATACTTTCACTTCTTAT 
               
               
                   
                   
                 AATATGCACTGGGTCCGCCAGGCCCCAGGTCA 
               
               
                   
                   
                 AGGCCTCGAGTGGATCGGCGATATCTACCCCG 
               
               
                   
                   
                 GTCAAGGCGACACTTCCTATAATCAGAAGTTT 
               
               
                   
                   
                 AAGGGTAGAGCTACTATGACCGCCGATAAGTC 
               
               
                   
                   
                 TACTTCTACCGTCTATATGGAACTGAGTTCCC 
               
               
                   
                   
                 TGAGGTCTGAGGACACCGCCGTCTACTACTGC 
               
               
                   
                   
                 GCTAGAGTGGGCGGAGCCTTCCCAATGGACTA 
               
               
                   
                   
                 CTGGGGTCAAGGCACCCTGGTCACCGTGTCTA 
               
               
                   
                   
                 GCGCTAGCTACTAAGGGCCCGCCGTGTTCCCC 
               
               
                   
                   
                 CTGGCACCTTGTAGCCGGAGCACTAGCGAATC 
               
               
                   
                   
                 CACCGCTGCCCTCGGCTGCCTGGTCAAGGATT 
               
               
                   
                   
                 ACTTCCCGGAGCCCGTGACCGTGTCCTGGAAC 
               
               
                   
                   
                 AGCGGAGCCCTGACCTCCGGAGTGCACACCTT 
               
               
                   
                   
                 CCCCGCTGTGCTGCAGAGCTCCGGGCTGTACT 
               
               
                   
                   
                 CGCTGTCGTCGGTGGTCACGGTGCCTTCATCT 
               
               
                   
                   
                 AGCCTGGGTACCAAGACCTACACTTGCAACGT 
               
               
                   
                   
                 GGACCACAAGCCTTCCAACACTAAGGTGGACA 
               
               
                   
                   
                 AGCGCGTCGAATCGAAGTACGGCCCACCGTGC 
               
               
                   
                   
                 CCGCCTTGTCCCGCGCCGGAGTTCCTCGGCGG 
               
               
                   
                   
                 TCCCTCGGTCTTTCTGTTCCCACCGAAGCCCA 
               
               
                   
                   
                 AGGACACTTTGATGATTTCCCGCACCCCTGAA 
               
               
                   
                   
                 GTGACATGCGTGGTCGTGGACGTGTCACAGGA 
               
               
                   
                   
                 AGATCCGGAGGTGCAGTTCAATTGGTACGTGG 
               
               
                   
                   
                 ATGGCGTCGAGGTGCACAACGCCAAAACCAAG 
               
               
                   
                   
                 CCGAGGGAGGAGCAGTTCAACTCCACTTACCG 
               
               
                   
                   
                 CGTCGTGTCCGTGCTGACGGTGCTGCATCAGG 
               
               
                   
                   
                 ACTGGCTGAACGGGAAGGAGTACAAGTGCAAA 
               
               
                   
                   
                 GTGTCCAACAAGGGACTTCCTAGCTCAATCGA 
               
               
                   
                   
                 AAAGACCATCTCGAAAGCCAAGGGACAGCCCC 
               
               
                   
                   
                 GGGAACCCCAAGTGTATACCCTGCCACCGAGC 
               
               
                   
                   
                 CAGGAAGAAATGACTAAGAACCAAGTCTCATT 
               
               
                   
                   
                 GACTTGCCTTGTGAAGGGCTTCTACCCATCGG 
               
               
                   
                   
                 ATATCGCCGTGGAATGGGAGTCCAACGGCCAG 
               
               
                   
                   
                 CCGGAAAACAACTACAAGACCACCCCTCCGGT 
               
               
                   
                   
                 GCTGGACTCAGACGGATCCTTCTTCCTCTACT 
               
               
                   
                   
                 CGCGGCTGACCGTGGATAAGAGCAGATGGCAG 
               
               
                   
                   
                 GAGGGAAATGTGTTCAGCTGTTCTGTGATGCA 
               
               
                   
                   
                 TGAAGCCCTGCACAACCACTACACTCAGAAGT 
               
               
                   
                   
                 CCCTGTCCCTCTCCCTGGGA 
               
               
                   
               
               
                 SEQ ID  
                 LCDR1 
                 RASESVEYYGTSLMQ 
               
               
                 NO: 810 
                   
                   
               
               
                 (Kabat) 
                   
                   
               
               
                   
               
               
                 SEQ ID  
                 LCDR2 
                 AASNVES 
               
               
                 NO: 811 
                   
                   
               
               
                 (Kabat) 
                   
                   
               
               
                   
               
               
                 SEQ ID  
                 LCDR3 
                 QQSRKDPST 
               
               
                 NO: 812 
                   
                   
               
               
                 (Kabat) 
                   
                   
               
               
                   
               
               
                 SEQ ID  
                 LCDR1 
                 SESVEYYGTSL 
               
               
                 NO: 813 
                   
                   
               
               
                 (Chothia) 
                   
                   
               
               
                   
               
               
                 SEQ ID  
                 LCDR2 
                 AAS 
               
               
                 NO: 814 
                   
                   
               
               
                 (Chothia) 
                   
                   
               
               
                   
               
               
                 SEQ ID  
                 LCDR3 
                 SRKDPS 
               
               
                 NO: 815 
                   
                   
               
               
                 (Chothia) 
                   
                   
               
               
                   
               
               
                 SEQ ID  
                 VL 
                 DIVLTQSPDSLAVSLGERATINCRASESVEYY 
               
               
                 NO: 826 
                   
                 GTSLMQWYQQKPGQPPKLLIYAASNVESGVPD 
               
               
                   
                   
                 RFSGSGSGTDFTLTISSLQAEDVAVYYCQQSR 
               
               
                   
                   
                 KDPSTFGGGTKVEIK 
               
               
                   
               
               
                 SEQ ID  
                 DNA VL 
                 GATATCGTCCTGACTCAGTCACCCGATAGCCT 
               
               
                 NO: 827 
                   
                 GGCCGTCAGCCTGGGCGAGCGGGCTACTATTA 
               
               
                   
                   
                 ACTGTAGAGCTAGTGAATCAGTCGAGTACTAC 
               
               
                   
                   
                 GGCACTAGCCTGATGCAGTGGTATCAGCAGAA 
               
               
                   
                   
                 GCCCGGTCAACCCCCTAAGCTGCTGATCTACG 
               
               
                   
                   
                 CCGCCTCTAACGTGGAATCAGGCGTGCCCGAT 
               
               
                   
                   
                 AGGTTTAGCGGTAGCGGTAGTGGCACCGACTT 
               
               
                   
                   
                 CACCCTGACTATTAGTAGCCTGCAGGCCGAGG 
               
               
                   
                   
                 ACGTGGCCGTCTACTACTGTCAGCAGTCTAGG 
               
               
                   
                   
                 AAGGACCCTAGCACCTTCGGCGGAGGCACTAA 
               
               
                   
                   
                 GGTCGAGATTAAG 
               
               
                   
               
               
                 SEQ ID  
                 Light 
                 DIVLTQSPDSLAVSLGERATINCRASESVEYY 
               
               
                 NO: 828 
                 chain 
                 MQWYQQKPGQPPKLLIYAASNVESGVPDRFSG 
               
               
                   
                   
                 GTSLSGSGTDFTLTISSLQAEDVAVYYCQQSR 
               
               
                   
                   
                 KDPSTFGGGTKVEIKRTVAAPSVFIFPPSDEQ 
               
               
                   
                   
                 LKSGTASVVCLLNNFYPREAKVQWKVDNALQS 
               
               
                   
                   
                 GNSQESVTEQDSKDSTYSLSSTLTLSKADYEK 
               
               
                   
                   
                 HKVYACEVTHQGLSSPVTKSFNRGEC 
               
               
                   
               
               
                 SEQ ID  
                 DNA 
                 GATATCGTCCTGACTCAGTCACCCGATAGCCT 
               
               
                 NO: 829 
                 light 
                 GGCCGTCAGCCTGGGCGAGCGGGCTACTATTA 
               
               
                   
                 chain 
                 ACTGTAGAGCTAGTGAATCAGTCGAGTACTAC 
               
               
                   
                   
                 GGCACTAGCCTGATGCAGTGGTATCAGCAGAA 
               
               
                   
                   
                 GCCCGGTCAACCCCCTAAGCTGCTGATCTACG 
               
               
                   
                   
                 CCGCCTCTAACGTGGAATCAGGCGTGCCCGAT 
               
               
                   
                   
                 AGGTTTAGCGGTAGCGGTAGTGGCACCGACTT 
               
               
                   
                   
                 CACCCTGACTATTAGTAGCCTGCAGGCCGAGG 
               
               
                   
                   
                 ACGTGGCCGTCTACTACTGTCAGCAGTCTAGG 
               
               
                   
                   
                 AAGGACCCTAGCACCTTCGGCGGAGGCACTAA 
               
               
                   
                   
                 GGTCGAGATTAAGCGTACGGTGGCCGCTCCCA 
               
               
                   
                   
                 GCGTGTTCATCTTCCCCCCCAGCGACGAGCAG 
               
               
                   
                   
                 CTGAAGAGCGGCACCGCCAGCGTGGTGTGCCT 
               
               
                   
                   
                 GCTGAACAACTTCTACCCCCGGGAGGCCAAGG 
               
               
                   
                   
                 TGCAGTGGAAGGTGGACAACGCCCTGCAGAGC 
               
               
                   
                   
                 GGCAACAGCCAGGAGAGCGTCACCGAGCAGGA 
               
               
                   
                   
                 CAGCAAGGACTCCACCTACAGCCTGAGCAGCA 
               
               
                   
                   
                 CCCTGACCCTGAGCAAGGCCGACTACGAGAAG 
               
               
                   
                   
                 CATAAGGTGTACGCCTGCGAGGTGACCCACCA 
               
               
                   
                   
                 GGGCCTGTCCAGCCCCGTGACCAAGAGCTTCA 
               
               
                   
                   
                 ACAGGGGCGAGTGC 
               
               
                   
               
            
           
         
       
     
     Other Exemplary TIM-3 Inhibitors 
     In one embodiment, the anti-TIM-3 antibody molecule is TSR-022 (AnaptysBio/Tesaro). In one embodiment, the anti-TIM-3 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of TSR-022. In one embodiment, the anti-TIM-3 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of APE5137 or APE5121, e.g., as disclosed in Table 18. APE5137, APE5121, and other anti-TIM-3 antibodies are disclosed in WO 2016/161270, incorporated by reference in its entirety. 
     In one embodiment, the anti-TIM-3 antibody molecule is the antibody clone F 38 -2E2. In one embodiment, the anti-TIM-3 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of F 38 -2E2. 
     Further known anti-TIM-3 antibodies include those described, e.g., in WO 2016/111947, WO 2016/071448, WO 2016/144803, U.S. Pat. Nos. 8,552,156, 8,841,418, and 9,163,087, incorporated by reference in their entirety. 
     In one embodiment, the anti-TIM-3 antibody is an antibody that competes for binding with, and/or binds to the same epitope on TIM-3 as, one of the anti-TIM-3 antibodies described herein. 
     
       
         
           
               
             
               
                 TABLE 18 
               
               
                   
               
               
                 Amino acid sequences of other exemplary  
               
               
                 anti-TIM-3 antibody molecules 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
            
               
                 
                   APE5137 
                 
               
            
           
           
               
               
               
            
               
                 SEQ   
                 VH 
                 EVQLLESGGGLVQPGGSLRLSCAAASGFTFSSYDMSWVRQAP 
               
               
                 ID 
                   
                 GKGLDWVSTISGGGTYTYYQDSVKGRFTISRDNSKNTLYLQM 
               
               
                 NO: 
                   
                 NSLRAEDTAVYYCASMDYWGQGTTVTVSSA 
               
               
                 830 
                   
                   
               
               
                   
               
               
                 SEQ   
                 VL 
                 DIQMTQSPSSLSASVGDRVTITCRASQSIRRYLNWYHQKPGK 
               
               
                 ID 
                   
                 APKLLIYGASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFA 
               
               
                 NO: 
                   
                 VYYCQQSHSAPLTFGGGTKVEIKR 
               
               
                 831 
                   
                   
               
               
                   
               
            
           
           
               
            
               
                 
                   APE5121 
                 
               
            
           
           
               
               
               
            
               
                 SEQ   
                 VH 
                 EVQVLESGGGLVQPGGSLRLYCVASGFTFSGSYAMSWVRQAP 
               
               
                 ID 
                   
                 GKGLEWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQM 
               
               
                 NO: 
                   
                 NSLRAEDTAVYYCAKKYYVGPADYWGQGTLVTVSSG 
               
               
                 832 
                   
                   
               
               
                   
               
               
                 SEQ   
                 VL 
                 DIVMTQSPDSLAVSLGERATINCKSSQSVLYSSNNKNYLAWY 
               
               
                 ID 
                   
                 QHGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQA 
               
               
                 NO: 
                   
                 EDVAVYYCQQYYSSPLTFGGGTKIEVK 
               
               
                 833 
               
               
                   
               
            
           
         
       
     
     Cytokines 
     In yet another embodiment, the present invention provides a method of treating cancer by administering to a subject in need thereof antibody conjugate of the present invention in combination with one or more cytokines, including but not limited to, interferon, IL-2, IL-15, IL-7, or IL21. In certain embodiments, antibody conjugate is administered in combination with an IL-15/IL-15Ra complex. In some embodiments, the IL-15/IL-15Ra complex is selected from NIZ985 (Novartis), ATL-803 (Altor) or CYP0150 (Cytune). 
     Exemplary IL-15/IL-15Ra Complexes 
     In one embodiment, the cytokine is IL-15 complexed with a soluble form of IL-15 receptor alpha (IL-15Ra). The IL-15/IL-15Ra complex may comprise IL-15 covalently or noncovalently bound to a soluble form of IL-15Ra. In a particular embodiment, the human IL-15 is noncovalently bonded to a soluble form of IL-15Ra. In a particular embodiment, the human IL-15 of the composition comprises an amino acid sequence of SEQ ID NO: 922 in Table 21 or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 922, and the soluble form of human IL-15Ra comprises an amino acid sequence of SEQ ID NO:923 in Table 19, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 923, as described in WO 2014/066527, incorporated by reference in its entirety. The molecules described herein can be made by vectors, host cells, and methods described in WO 2007084342, incorporated by reference in its entirety. 
     
       
         
           
               
             
               
                 TABLE 19 
               
               
                   
               
               
                 Amino acid and nucleotide sequences  
               
               
                 of exemplary IL-15/IL-15Ra complexes 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
            
               
                 
                   NIZ985 
                 
               
            
           
           
               
               
               
            
               
                 SEQ ID NO: 
                 Human  
                 NWVNVISDLKKIEDLIQSMHIDATLYT 
               
               
                 922 
                 IL-15 
                 ESDVHPSCKVTAMKCFLLELQVISLES 
               
               
                   
                   
                 GDASIHDTVENLIILANNSLSSNGNVT 
               
               
                   
                   
                 ESGCKECEELEEKNIKEFLQSFVHIVQ 
               
               
                   
                   
                 MFINTS 
               
               
                   
               
               
                 SEQ ID NO: 
                 Human 
                 ITCPPPMSVEHADIWVKSYSLYSRERY 
               
               
                 923 
                 Soluble  
                 ICNSGFKRKAGTSSLTECVLNKATNVA 
               
               
                   
                 IL-15Ra 
                 HWTTPSLKCIRDPALVHQRPAPPSTVT 
               
               
                   
                   
                 TAGVTPQPESLSPSGKEPAASSPSSNN 
               
               
                   
                   
                 PTAATTAAIVPGSQLMPSKSSTGTTEI 
               
               
                   
                   
                 SSHESSHGTPSQTTAKNWELTASASHQ 
               
               
                   
                   
                 PPGVYPQG 
               
               
                   
               
            
           
         
       
     
     Other Exemplary IL-15/IL-15Ra Complexes 
     In one embodiment, the IL-15/IL-15Ra complex is ALT-803, an IL-15/IL-15Ra Fc fusion protein (IL-15N72D:IL-15RaSu/Fc soluble complex). ALT-803 is described in WO 2008/143794, incorporated by reference in its entirety. In one embodiment, the IL-15/IL-15Ra Fc fusion protein comprises the sequences as disclosed in Table 20. 
     In one embodiment, the IL-15/IL-15Ra complex comprises IL-15 fused to the sushi domain of IL-15Ra (CYP0150, Cytune). The sushi domain of IL-15Ra refers to a domain beginning at the first cysteine residue after the signal peptide of IL-15Ra, and ending at the fourth cysteine residue after said signal peptide. The complex of IL-15 fused to the sushi domain of IL-15Ra is described in WO 2007/04606 and WO 2012/175222, incorporated by reference in their entirety. In one embodiment, the IL-15/IL-15Ra sushi domain fusion comprises the sequences as disclosed in Table 20. 
     
       
         
           
               
             
               
                 TABLE 20 
               
               
                   
               
               
                 Amino acid sequences of other exemplary IL-15/IL-15Ra complexes 
               
               
                   
               
             
            
               
                 
                   ALT-803 
                 
               
            
           
           
               
               
               
            
               
                 SEQ ID 
                 IL-15N72D 
                 NWVNVISDLKKIEDLIQSMHIDATLYTESDVHPSCKVTAMKCF 
               
               
                 NO: 924 
                   
                 LLELQVISLESGDASIHDTVENLIILANDSLSSNGNVTESGCKE 
               
               
                   
                   
                 CEELEEKNIKEFLQSFVHIVQMFINTS 
               
               
                   
               
               
                 SEQ ID 
                 IL-15RaSu/ 
                 ITCPPPMSVEHADIWVKSYSLYSRERYICNSGFKRKAGTSSLT 
               
               
                 NO: 925 
                 Fc 
                 ECVLNKATNVAHWTTPSLKCIREPKSCDKTHTCPPCPAPELL 
               
               
                   
                   
                 GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNW 
               
               
                   
                   
                 YVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKE 
               
               
                   
                   
                 YKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKN 
               
               
                   
                   
                 QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS 
               
               
                   
                   
                 FFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLS 
               
               
                   
                   
                 PGK 
               
               
                   
               
            
           
           
               
            
               
                 IL-15 / IL-15Ra sushi domain fusion (CYP0150) 
               
            
           
           
               
               
               
            
               
                 SEQ ID 
                 Human 
                 IL-15 NWVNVISDLKKIEDLIQSMHIDATLYTESDVHPSCKVT 
               
               
                 NO: 926 
                   
                 AMKCFLLELQVISLESGDASIHDTVENLIILANNSLSSNGNVTE 
               
               
                   
                   
                 SGCKECEELEXKNIKEFLQSFVHIVQMFINTS 
               
               
                   
                   
                 Where X is E or K 
               
               
                   
               
               
                 SEQ ID 
                 Human IL- 
                 ITCPPPMSVEHADIWVKSYSLYSRERYICNSGFKRKAGTSSLT 
               
               
                 NO: 927 
                 15Ra sushi 
                 ECVLNKATNVAHWTTPSLKCIRDPALVHQRPAPP 
               
               
                   
                 and hinge 
                   
               
               
                   
                 domains 
               
               
                   
               
            
           
         
       
     
     In yet another embodiment, the present invention provides a method of treating cancer by administering to a subject in need thereof antibody conjugate of the present invention in combination with one or more agonists of toll like receptors (TLRs, e.g., TLR7, TLR8, TLR9). In some embodiments, the antibody conjugate of the present invention can be used in combination with a TLR7 agonist or a TLR7 agonist conjugate. 
     In another embodiment, the present invention provides a method of treating cancer by administering to a subject in need thereof antibody conjugate of the present invention in combination with one or more angiogenesis inhibitors, e.g., Bevacizumab (Avastin®), axitinib (Inlyta®); Brivanib alaninate (BMS-582664, (S)—((R)-1-(4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan-2-yl)2-aminopropanoate); Sorafenib (Nexavar®); Pazopanib (Votrient®); Sunitinib malate (Sutent®); Cediranib (AZD2171, CAS 288383-20-1); Vargatef (BIBF1120, CAS 928326-83-4); Foretinib (GSK1363089); Telatinib (BAY57-9352, CAS 332012-40-5); Apatinib (YN968D1, CAS 811803-05-1); Imatinib (Gleevec®); Ponatinib (AP24534, CAS 943319-70-8); Tivozanib (AV951, CAS 475108-18-0); Regorafenib (BAY73-4506, CAS 755037-03-7); Vatalanib dihydrochloride (PTK787, CAS 212141-51-0); Brivanib (BMS-540215, CAS 649735-46-6); Vandetanib (Caprelsa® or AZD6474); Motesanib diphosphate (AMG706, CAS 857876-30-3, N-(2,3-dihydro-3,3-dimethyl-1H-indol-6-yl)-2-[(4-pyridinylmethyl)amino]-3-pyridinecarboxamide, described in PCT Publication No. WO 02/066470); Dovitinib dilactic acid (TK1258, CAS 852433-84-2); Linfanib (ABT869, CAS 796967-16-3); Cabozantinib (XL184, CAS 849217-68-1); Lestaurtinib (CAS 111358-88-4); N-[5-[[[5-(1,1-Dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide (BMS38703, CAS 345627-80-7); (3R,4R)-4-Amino-1-((4-((3-methoxyphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)methyl)piperidin-3-ol (BMS690514); N-(3,4-Dichloro-2-fluorophenyl)-6-methoxy-7-[[(3aα,5β,6aα)-octahydro-2-methylcyclopenta[c]pyrrol-5-yl]methoxy]-4-quinazolinamine (XL647, CAS 781613-23-8); 4-Methyl-3-[[1-methyl-6-(3-pyridinyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]amino]-N-[3-(trifluoromethyl)phenyl]-benzamide (BHG712, CAS 940310-85-0); or Aflibercept (Eylea®). 
     In another embodiment, the present invention provides a method of treating cancer by administering to a subject in need thereof antibody conjugate of the present invention in combination with one or more heat shock protein inhibitors, e.g., Tanespimycin (17-allylamino-17-demethoxygeldanamycin, also known as KOS-953 and 17-AAG, available from SIGMA, and described in U.S. Pat. No. 4,261,989); Retaspimycin (IP1504), Ganetespib (STA-9090); [6-Chloro-9-(4-methoxy-3,5-dimethylpyridin-2-ylmethyl)-9H-purin-2-yl]amine (BIIB021 or CNF2024, CAS 848695-25-0); trans-4-[[2-(Aminocarbonyl)-5-[4,5,6,7-tetrahydro-6,6-dimethyl-4-oxo-3-(trifluoromethyl)-1H-indazol-1-yl]phenyl]amino]cyclohexyl glycine ester (SNX5422 or PF04929113, CAS 908115-27-5); 5-[2,4-Dihydroxy-5-(1-methylethyl)phenyl]-N-ethyl-4-[4-(4-morpholinylmethyl)phenyl]-3-Isoxazolecarboxamide (AUY922, CAS 747412-49-3); or 17-Dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG). 
     In another embodiment, the present invention provides a method of treating cancer by administering to a subject in need thereof antibody conjugate of the present invention in combination with one or more HDAC inhibitors or other epigenetic modifiers. Exemplary HDAC inhibitors include, but not limited to, Voninostat (Zolinza®); Romidepsin (Istodax®); Treichostatin A (TSA); Oxamflatin; Vorinostat (Zolinza®, Suberoylanilide hydroxamic acid); Pyroxamide (syberoyl-3-aminopyridineamide hydroxamic acid); Trapoxin A (RF-1023A); Trapoxin B (RF-10238); Cyclo[(αS,2S)-α-amino-η-oxo-2-oxiraneoctanoyl-O-methyl-D-tyrosyl-L-isoleucyl-L-prolyl] (Cyl-1); Cyclo[(αS,2S)-α-amino-η-oxo-2-oxiraneoctanoyl-O-methyl-D-tyrosyl-L-isoleucyl-(2S)-2-piperidinecarbonyl] (Cyl-2); Cyclic[L-alanyl-D-alanyl-(2S)-η-oxo-L-α-aminooxiraneoctanoyl-D-prolyl] (HC-toxin); Cyclo[(αS,2S)-α-amino-η-oxo-2-oxiraneoctanoyl-D-phenylalanyl-L-leucyl-(2S)-2-piperidinecarbonyl] (WF-3161); Chlamydocin ((S)-Cyclic(2-methylalanyl-L-phenylalanyl-D-prolyl-η-oxo-L-α-aminooxiraneoctanoyl); Apicidin (Cyclo(8-oxo-L-2-aminodecanoyl-1-methoxy-L-tryptophyl-L-isoleucyl-D-2-piperidinecarbonyl); Romidepsin (Istodax®, FR-901228); 4-Phenylbutyrate; Spiruchostatin A; Mylproin (Valproic acid); Entinostat (MS-275, N-(2-Aminophenyl)-4-[N-(pyridine-3-yl-methoxycarbonyl)-amino-methyl]-benzamide); Depudecin (4,5:8,9-dianhydro-1,2,6,7,11-pentadeoxy-D-threo-D-ido-Undeca-1,6-dienitol); 4-(Acetylamino)-N-(2-aminophenyl)-benzamide (also known as CI-994); N1-(2-Aminophenyl)-N8-phenyl-octanediamide (also known as BML-210); 4-(Dimethylamino)-N-(7-(hydroxyamino)-7-oxoheptyl)benzamide (also known as M344); (E)-3-(4-(((2-(1H-indol-3-yl)ethyl)(2-hydroxyethyl)amino)-methyl)phenyl)-N-hydroxyacrylamide; Panobinostat (Farydak®); Mocetinostat, and Belinostat (also known as PXD101, Beleodaq®, or (2E)-N-Hydroxy-3-[3-(phenylsulfamoyl)phenyl]prop-2-enamide), or chidamide (also known as CS055 or HBI-8000, (E)-N-(2-amino-5-fluorophenyl)-4-((3-(pyridin-3-yl)acrylamido)methyl)benzamide). Other epigenetic modifiers include but not limited to inhibitors of EZH2 (enhancer of zeste homolog 2), EED (embryonic ectoderm development), or LSD1 (lysine-specific histone demethylase 1A or KDM1A). 
     In yet another embodiment, the present invention provides a method of treating cancer by administering to a subject in need thereof antibody conjugate of the present invention in combination with one or more inhibitors of indoleamine-pyrrole 2,3-dioxygenase (IDO), for example, Indoximod (also known as NLG-8189), α-Cyclohexyl-5H-imidazo[5,1-a]isoindole-5-ethanol (also known as NLG919), or (4E)-4-[(3-Chloro-4-fluoroanilino)-nitrosomethylidene]-1,2,5-oxadiazol-3-amine (also known as INCB024360). 
     In yet another embodiment, the present invention provides a method of treating cancer by administering to a subject in need thereof antibody conjugate of the present invention in combination with one or more agents that control or treat cytokine release syndrome (CRS). Therapies for CRS include but not are limited to, IL-6 inhibitor or IL-6 receptor (IL-6R) inhibitors (e.g., tocilizumab or siltuximab), bazedoxifene, sgp130 blockers, vasoactive medications, corticosteroids, immunosuppressive agents, histamine H 2  receptor antagonists, anti-pyretics, analgesics (e.g., acetaminophen), and mechanical ventilation. Exemplary therapies for CRS are described in International Application WO2014011984, which is hereby incorporated by reference. 
     Tocilizumab is a humanized, immunoglobulin G1kappa anti-human IL-6R monoclonal antibody. Tocilizumab blocks binding of IL-6 to soluble and membrane bound IL-6 receptors (IL-6Rs) and thus inhibitos classical and trans-IL-6 signaling. In embodiments, tocilizumab is administered at a dose of about 4-12 mg/kg, e.g., about 4-8 mg/kg for adults and about 8-12 mg/kg for pediatric subjects, e.g., administered over the course of 1 hour. 
     In some embodiments, the CRS therapeutic is an inhibitor of IL-6 signalling, e.g., an inhibitor of IL-6 or IL-6 receptor. In one embodiment, the inhibitor is an anti-IL-6 antibody, e.g., an anti-IL-6 chimeric monoclonal antibody such as siltuximab. In other embodiments, the inhibitor comprises a soluble gp130 (sgp130) or a fragment thereof that is capable of blocking IL-6 signalling. In some embodiments, the sgp130 or fragment thereof is fused to a heterologous domain, e.g., an Fc domain, e.g., is a gp130-Fc fusion protein such as FE301. In embodiments, the inhibitor of IL-6 signalling comprises an antibody, e.g., an antibody to the IL-6 receptor, such as sarilumab, olokizumab (CDP6038), elsilimomab, sirukumab (CNTO 136), ALD518/BMS-945429, ARGX-109, or FM101. In some embodiments, the inhibitor of IL-6 signalling comprises a small molecule such as CPSI-2364. 
     Exemplary vasoactive medications include but are not limited to angiotensin-11, endothelin-1, alpha adrenergic agonists, rostanoids, phosphodiesterase inhibitors, endothelin antagonists, inotropes (e.g., adrenaline, dobutamine, isoprenaline, ephedrine), vasopressors (e.g., noradrenaline, vasopressin, metaraminol, vasopressin, methylene blue), inodilators (e.g., milrinone, levosimendan), and dopamine. 
     Exemplary vasopressors include but are not limited to norepinephrine, dopamine, phenylephrine, epinephrine, and vasopressin. In some embodiments, a high-dose vasopressor includes one or more of the following: norpepinephrine monotherapy at ≥20 ug/min, dopamine monotherapy at ≥10 ug/kg/min, phenylephrine monotherapy at ≥200 ug/min, and/or epinephrine monotherapy at ≥10 ug/min. In some embodiments, if the subject is on vasopressin, a high-dose vasopressor includes vasopressin+norepinephrine equivalent of ≥10 ug/min, where the norepinephrine equivalent dose=[norepinephrine (ug/min)]+[dopamine (ug/kg/min)/2]+[epinephrine (ug/min)]+[phenylephrine (ug/min)/10]. In some embodiments, if the subject is on combination vasopressors (not vasopressin), a high-dose vasopressor includes norepinephrine equivalent of ≥20 ug/min, where the norepinephrine equivalent dose=[norepinephrine (ug/min)]+[dopamine (ug/kg/min)/2]+[epinephrine (ug/min)]+[phenylephrine (ug/min)/10]. See e.g., Id. 
     In some embodiments, a low-dose vasopressor is a vasopressor administered at a dose less than one or more of the doses listed above for high-dose vasopressors. 
     Exemplary corticosteroids include but are not limited to dexamethasone, hydrocortisone, and methylprednisolone. In embodiments, a dose of dexamethasone of 0.5 mg/kg is used. In embodiments, a maximum dose of dexamethasone of 10 mg/dose is used. In embodiments, a dose of methylprednisolone of 2 mg/kg/day is used. 
     Exemplary immunosuppressive agents include but are not limited to an inhibitor of TNFα or an inhibitor of IL-1. In embodiments, an inhibitor of TNFα comprises an anti-TNFα antibody, e.g., monoclonal antibody, e.g., infliximab. In embodiments, an inhibitor of TNFα comprises a soluble TNFα receptor (e.g., etanercept). In embodiments, an IL-1 or IL-1R inhibitor comprises anakinra. 
     Exemplary histamine H 2  receptor antagonists include but are not limited to cimetidine (Tagamet®), ranitidine (Zantac®), famotidine (Pepcid®) and nizatidine (Axid®). 
     Exemplary anti-pyretic and analgesic includes but is not limited to acetaminophen (Tylenol®), ibuprofen, and aspirin. 
     In some embodiments, the present invention provides a method of treating cancer by administering to a subject in need thereof antibody conjugate of the present invention in combination with two or more of any of the above described inhibitors, activators, immunomodulators, agonists, or modifiers. For example, the antibody conjugate of the present invention can be used in combination with one or more checkpoint inhibitors and/or one or more immune activators. 
     In addition to the above therapeutic regimes, the patient may be subjected to surgical removal of cancer cells and/or radiation therapy. 
     Pharmaceutical Compositions 
     To prepare pharmaceutical or sterile compositions including one or more antibody conjugates described herein, provided antibody conjugate can be mixed with a pharmaceutically acceptable carrier or excipient. 
     Formulations of therapeutic and diagnostic agents can be prepared by mixing with physiologically acceptable carriers, excipients, or stabilizers in the form of, e.g., lyophilized powders, slurries, aqueous solutions, lotions, or suspensions (see, e.g., Hardman et al., Goodman and Gilman&#39;s The Pharmacological Basis of Therapeutics, McGraw-Hill, New York, N.Y., 2001; Gennaro, Remington: The Science and Practice of Pharmacy, Lippincott, Williams, and Wilkins, New York, N.Y., 2000; Avis, et al. (eds.), Pharmaceutical Dosage Forms: Parenteral Medications, Marcel Dekker, NY, 1993; Lieberman, et al. (eds.), Pharmaceutical Dosage Forms: Tablets, Marcel Dekker, NY, 1990; Lieberman, et al. (eds.) Pharmaceutical Dosage Forms: Disperse Systems, Marcel Dekker, NY, 1990; Weiner and Kotkoskie, Excipient Toxicity and Safety, Marcel Dekker, Inc., New York, N.Y., 2000). 
     In some embodiments, the pharmaceutical composition comprising the antibody conjugate of the present invention is a lyophilisate preparation. In certain embodiments a pharmaceutical composition comprising the antibody conjugate is a lyophilisate in a vial containing an antibody conjugate, histidine, sucrose, and polysorbate 20. In certain embodiments the pharmaceutical composition comprising the antibody conjugate is a lyophilisate in a vial containing an antibody conjugate, sodium succinate, and polysorbate 20. In certain embodiments the pharmaceutical composition comprising the antibody conjugate is a lyophilisate in a vial containing an antibody conjugate, trehalose, citrate, and polysorbate 8. The lyophilisate can be reconstituted, e.g., with water, saline, for injection. In a specific embodiment, the solution comprises the antibody conjugate, histidine, sucrose, and polysorbate 20 at a pH of about 5.0. In another specific embodiment the solution comprises the antibody conjugate, sodium succinate, and polysorbate 20. In another specific embodiment, the solution comprises the antibody conjugate, trehalose dehydrate, citrate dehydrate, citric acid, and polysorbate 8 at a pH of about 6.6. For intravenous administration, the obtained solution will usually be further diluted into a carrier solution. 
     Selecting an administration regimen for a therapeutic depends on several factors, including the serum or tissue turnover rate of the entity, the level of symptoms, the immunogenicity of the entity, and the accessibility of the target cells in the biological matrix. In certain embodiments, an administration regimen maximizes the amount of therapeutic delivered to the patient consistent with an acceptable level of side effects. Accordingly, the amount of biologic delivered depends in part on the particular entity and the severity of the condition being treated. Guidance in selecting appropriate doses of antibodies, cytokines, and small molecules are available (see, e.g., Wawrzynczak, Antibody Therapy, Bios Scientific Pub. Ltd, Oxfordshire, U K, 1996; Kresina (ed.), Monoclonal Antibodies, Cytokines and Arthritis, Marcel Dekker, New York, N.Y., 1991; Bach (ed.), Monoclonal Antibodies and Peptide Therapy in Autoimmune Diseases, Marcel Dekker, New York, N.Y., 1993; Baert et al., New Engl. J. Med. 348:601-608, 2003; Milgrom et al., New Engl. J. Med. 341:1966-1973, 1999; Slamon et al., New Engl. J. Med. 344:783-792, 2001; Beniaminovitz et al., New Engl. J. Med. 342:613-619, 2000; Ghosh et al., New Engl. J. Med. 348:24-32, 2003; Lipsky et al., New Engl. J. Med. 343:1594-1602, 2000). 
     Determination of the appropriate dose is made by the clinician, e.g., using parameters or factors known or suspected in the art to affect treatment or predicted to affect treatment. Generally, the dose begins with an amount somewhat less than the optimum dose and it is increased by small increments thereafter until the desired or optimum effect is achieved relative to any negative side effects. Important diagnostic measures include those of symptoms of, e.g., the inflammation or level of inflammatory cytokines produced. 
     Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient. The selected dosage level will depend upon a variety of pharmacokinetic factors including the activity of the particular compositions of the present invention employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compositions employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors known in the medical arts. 
     Compositions comprising the antibody conjugate of the invention can be provided by continuous infusion, or by doses at intervals of, e.g., one day, one week, or 1-7 times per week, once every other week, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, or once very eight weeks. Doses may be provided intravenously, subcutaneously, topically, orally, nasally, rectally, intramuscular, intracerebrally, or by inhalation. A specific dose protocol is one involving the maximal dose or dose frequency that avoids significant undesirable side effects. 
     For the antibody conjugates of the invention, the dosage administered to a patient may be 0.0001 mg/kg to 100 mg/kg of the patient&#39;s body weight. The dosage may be between 0.001 mg/kg and 50 mg/kg, 0.005 mg/kg and 20 mg/kg, 0.01 mg/kg and 20 mg/kg, 0.02 mg/kg and 10 mg/kg, 0.05 and 5 mg/kg, 0.1 mg/kg and 10 mg/kg, 0.1 mg/kg and 8 mg/kg, 0.1 mg/kg and 5 mg/kg, 0.1 mg/kg and 2 mg/kg, 0.1 mg/kg and 1 mg/kg of the patient&#39;s body weight. The dosage of the antibody conjugate may be calculated using the patient&#39;s weight in kilograms (kg) multiplied by the dose to be administered in mg/kg. 
     Doses of the antibody conjugates the invention may be repeated and the administrations may be separated by less than 1 day, at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, 4 months, 5 months, or at least 6 months. In some embodiments, an antibody conjugate of the invention is administered twice weekly, once weekly, once every two weeks, once every three weeks, once every four weeks, or less frequently. In a specific embodiment, doses of the antibody conjugates of the invention are repeated every 2 weeks. 
     An effective amount for a particular patient may vary depending on factors such as the condition being treated, the overall health of the patient, the method, route and dose of administration and the severity of side effects (see, e.g., Maynard et al., A Handbook of SOPs for Good Clinical Practice, Interpharm Press, Boca Raton, Fla., 1996; Dent, Good Laboratory and Good Clinical Practice, Urch Publ., London, U K, 2001). 
     The route of administration may be by, e.g., topical or cutaneous application, injection or infusion by subcutaneous, intravenous, intraperitoneal, intracerebral, intramuscular, intraocular, intraarterial, intracerebrospinal, intralesional administration, or by sustained release systems or an implant (see, e.g., Sidman et al., Biopolymers 22:547-556, 1983; Langer et al., J. Biomed. Mater. Res. 15:167-277, 1981; Langer, Chem. Tech. 12:98-105, 1982; Epstein et al., Proc. Natl. Acad. Sci. USA 82:3688-3692, 1985; Hwang et al., Proc. Natl. Acad. Sci. USA 77:4030-4034, 1980; U.S. Pat. Nos. 6,350,466 and 6,316,024). Where necessary, the composition may also include a solubilizing agent or a local anesthetic such as lidocaine to ease pain at the site of the injection, or both. In addition, pulmonary administration can also be employed, e.g., by use of an inhaler or nebulizer, and formulation with an aerosolizing agent. See, e.g., U.S. Pat. Nos. 6,019,968, 5,985,320, 5,985,309, 5,934,272, 5,874,064, 5,855,913, 5,290,540, and 4,880,078; and PCT Publication Nos. WO 92/19244, WO 97/32572, WO 97/44013, WO 98/31346, and WO 99/66903, each of which is incorporated herein by reference their entirety. 
     Examples of such additional ingredients are well-known in the art. 
     Methods for co-administration or treatment with a second therapeutic agent, e.g., a cytokine, steroid, chemotherapeutic agent, antibiotic, or radiation, are known in the art (see, e.g., Hardman et al., (eds.) (2001) Goodman and Gilman&#39;s The Pharmacological Basis of Therapeutics, 10.sup.th ed., McGraw-Hill, New York, N.Y.; Poole and Peterson (eds.) (2001) Pharmacotherapeutics for Advanced Practice:A Practical Approach, Lippincott, Williams &amp; Wilkins, Phila., Pa.; Chabner and Longo (eds.) (2001) Cancer Chemotherapy and Biotherapy, Lippincott, Williams &amp; Wilkins, Phila., Pa.). An effective amount of therapeutic may decrease the symptoms by at least 10%; by at least 20%; at least about 30%; at least 40%, or at least 50%. 
     Additional therapies (e.g., prophylactic or therapeutic agents), which can be administered in combination with the antibody conjugates of the invention may be administered less than 5 minutes apart, less than 30 minutes apart, 1 hour apart, at about 1 hour apart, at about 1 to about 2 hours apart, at about 2 hours to about 3 hours apart, at about 3 hours to about 4 hours apart, at about 4 hours to about 5 hours apart, at about 5 hours to about 6 hours apart, at about 6 hours to about 7 hours apart, at about 7 hours to about 8 hours apart, at about 8 hours to about 9 hours apart, at about 9 hours to about 10 hours apart, at about 10 hours to about 11 hours apart, at about 11 hours to about 12 hours apart, at about 12 hours to 18 hours apart, 18 hours to 24 hours apart, 24 hours to 36 hours apart, 36 hours to 48 hours apart, 48 hours to 52 hours apart, 52 hours to 60 hours apart, 60 hours to 72 hours apart, 72 hours to 84 hours apart, 84 hours to 96 hours apart, or 96 hours to 120 hours apart from the antibody conjugates of the invention. The two or more therapies may be administered within one same patient visit. 
     In certain embodiments, the antibody conjugates of the invention can be formulated to ensure proper distribution in vivo. Exemplary targeting moieties include folate or biotin (see, e.g., U.S. Pat. No. 5,416,016 to Low et al.); mannosides (Umezawa et al., (1988) Biochem. Biophys. Res. Commun. 153:1038); antibodies (Bloeman et al., (1995) FEBS Lett. 357:140; Owais et al., (1995) Antimicrob. Agents Chemother. 39:180); surfactant Protein A receptor (Briscoe et al., (1995) Am. J. Physiol. 1233:134); p 120 (Schreier et al, (1994) J. Biol. Chem. 269:9090); see also K. Keinanen; M. L. Laukkanen (1994) FEBS Lett. 346:123; J. J. Killion; I. J. Fidler (1994) Immunomethods 4:273. 
     The invention provides protocols for the administration of pharmaceutical composition comprising antibody conjugates of the invention alone or in combination with other therapies to a subject in need thereof. The therapies (e.g., prophylactic or therapeutic agents) of the combination therapies of the present invention can be administered concomitantly or sequentially to a subject. The therapy (e.g., prophylactic or therapeutic agents) of the combination therapies of the present invention can also be cyclically administered. Cycling therapy involves the administration of a first therapy (e.g., a first prophylactic or therapeutic agent) for a period of time, followed by the administration of a second therapy (e.g., a second prophylactic or therapeutic agent) for a period of time and repeating this sequential administration, i.e., the cycle, in order to reduce the development of resistance to one of the therapies (e.g., agents) to avoid or reduce the side effects of one of the therapies (e.g., agents), and/or to improve, the efficacy of the therapies. 
     The therapies (e.g., prophylactic or therapeutic agents) of the combination therapies of the invention can be administered to a subject concurrently. 
     The term “concurrently” is not limited to the administration of therapies (e.g., prophylactic or therapeutic agents) at exactly the same time, but rather it is meant that a pharmaceutical composition comprising antibodies or fragments thereof the invention are administered to a subject in a sequence and within a time interval such that the antibodies or antibody conjugates of the invention can act together with the other therapy(ies) to provide an increased benefit than if they were administered otherwise. For example, each therapy may be administered to a subject at the same time or sequentially in any order at different points in time; however, if not administered at the same time, they should be administered sufficiently close in time so as to provide the desired therapeutic or prophylactic effect. Each therapy can be administered to a subject separately, in any appropriate form and by any suitable route. In various embodiments, the therapies (e.g., prophylactic or therapeutic agents) are administered to a subject less than 5 minutes apart, less than 15 minutes apart, less than 30 minutes apart, less than 1 hour apart, at about 1 hour apart, at about 1 hour to about 2 hours apart, at about 2 hours to about 3 hours apart, at about 3 hours to about 4 hours apart, at about 4 hours to about 5 hours apart, at about 5 hours to about 6 hours apart, at about 6 hours to about 7 hours apart, at about 7 hours to about 8 hours apart, at about 8 hours to about 9 hours apart, at about 9 hours to about 10 hours apart, at about 10 hours to about 11 hours apart, at about 11 hours to about 12 hours apart, 24 hours apart, 48 hours apart, 72 hours apart, or 1 week apart. In other embodiments, two or more therapies (e.g., prophylactic or therapeutic agents) are administered within the same patient visit. 
     Prophylactic or therapeutic agents of the combination therapies can be administered to a subject in the same pharmaceutical composition. Alternatively, the prophylactic or therapeutic agents of the combination therapies can be administered concurrently to a subject in separate pharmaceutical compositions. The prophylactic or therapeutic agents may be administered to a subject by the same or different routes of administration. 
     It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. 
     EXAMPLES 
     The invention is further described in the following examples, which are not intended to limit the scope of the invention described in the claims. 
     Example 1: Synthesis of Linker Intermediates 
     Example 1-1: Synthesis of 5,5,9,12,15,15-hexamethyl-8,13-dioxo-14-oxa-3,4-dithia-9,12-diazahexadecyl carbonochloridate (LI-1) 
     
       
         
         
             
             
         
       
     
     Step 1: Acetic acid (0.025 ml, 1.3 mmol) was added to a solution of 4-mercapto-4-methylpentanoic acid (250 mg, 1.69 mmol) and 2-(pyridin-2-yldisulfanyl)ethanol (380 mg, 2.02 mmol) in MeOH (15 mL) and the mixture was heated at 45° C. for 5 days and then concentrated and purified by ISCO using 15 g C18 column, eluted with 5-40% acetonitrile (ACN) in water with 0.05% TFA. The fractions containing the desired product were concentrated to give 4-((2-hydroxyethyl)disulfanyl)-4-methylpentanoic acid (220 mg, 58.1% yield). LCMS M+23=247.1, tr=0.768 min. 1H NMR (500 MHz, Chloroform-d) δ 3.86 (t, J=5.8 Hz, 1H), 2.84 (t, J=5.8 Hz, 2H), 2.49-2.37 (m, 2H), 2.00-1.86 (m, 2H), 1.29 (s, 6H). 
     Step 2: DIEA (0.082 ml, 0.47 mmol) and tert-butyl methyl(2-(methylamino)ethyl)carbamate (44 mg, 0.23 mmol) were added to a solution of 4-((2-hydroxyethyl)disulfanyl)-4-methylpentanoic acid (35 mg, 0.16 mmol) in dichloromethane (DCM) (5 ml), followed by the addition of N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (EDCl) (45 mg, 0.23 mmol). The mixture was stirred at room temperature for 16 hours, then quenched with water, extracted with DCM, dried, concentrated and purified by ISCO using 15 g C18 column, eluted with ACN-water containing 0.05% TFA to obtain tert-butyl (2-(4-((2-hydroxyethyl)disulfanyl)-N,4-dimethylpentanamido)ethyl)(methyl)carbamate (34 mg, 50% yield). LCMS M+1=395.2, tr=1.044 min.  1 H NMR (500 MHz, Chloroform-d) δ 3.84 (t, J=6.0 Hz, 2H), 3.49 (s, 2H), 3.35 (t, J=6.1 Hz, 2H), 3.03 (s, 2H), 2.94 (s, 1H), 2.89-2.78 (m, 5H), 2.38 (d, J=7.3 Hz, 2H), 2.01-1.90 (m, 2H), 1.83 (s, 3H), 1.44 (s, 9H), 1.30 (s, 6H). 
     Step 3: Pyridine (0.010 ml, 0.12 mmol) was added to a solution of tert-butyl (2-(4-((2-hydroxyethyl)disulfanyl)-N,4-dimethylpentanamido)ethyl)(methyl)carbamate (27 mg, 0.068 mmol) in DCM (4 ml) at 00° C. followed by addition of a 20% phosgene solution in toluene (0.3 ml). The reaction was stirred for 15 mins and then concentrated to give 5,5,9,12,15,15-hexamethyl-8,13-dioxo-14-oxa-3,4-dithia-9,12-diazahexadecyl carbonochloridate (LI-1) which was immediately used without purification. 
     Example 1-2: Synthesis of 18-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-5,5,9,12-tetramethyl-8,13-dioxo-16-oxa-3,4-dithia-9,12-diazaoctadecyl (4-nitrophenyl) carbonate (LI-2) 
     
       
         
         
             
             
         
       
     
     Step 1: Trifluoroacetic acid (TFA) (1 ml) was added to a flask containing tert-butyl (2-(4-((2-hydroxyethyl)disulfanyl)-N,4-dimethylpentanamido)ethyl)(methyl)carbamate (34 mg, 0.086 mmol) and the mixture was immediately concentrated to give 4-((2-hydroxyethyl)disulfanyl)-N,4-dimethyl-N-(2-(methylamino)ethyl)pentanamide as a TFA salt. LCMS M+1=295.3, tr=0.619 min. 
     Step 2: N,N-diisopropyl ethylamine (DIEA) (0.075 ml, 0.431 mmol) was added to a solution of 3-(2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethoxy)propanoic acid (Mal-PEG1-Acid) (18.4 mg, 0.086 mmol) in DMF (2 ml), followed by the addition of 3-[Bis(dimethylamino)methyliumyl]-3H-benzotriazol-1-oxide hexafluorophosphate (HBTU) (33 mg, 0.086 mmol). The mixture was stirred at room temperature for 5 mins and then added dropwise to a solution of 4-((2-hydroxyethyl)disulfanyl)-N,4-dimethyl-N-(2-(methylamino)ethyl)pentanamide TFA salt (35 mg, 0.086 mmol) in N,N-dimethyl formamide (DMF) (1 ml). The mixture was then stirred at room temperature for 2 hours and then purified by mass-triggered reverse phase HPLC using a C18 column, eluted with 10-40% acetonitrile-H 2 O containing 0.05% TFA. Fractions containing desired product were concentrated to obtain N-(2-(3-(2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethoxy)-N-methylpropanamido)ethyl)-4-((2-hydroxyethyl)disulfanyl)-N,4-dimethylpentanamide (40.1 mg, 90% yield). LCMS M+1=490.3 tr=0.841 min. 
     Step 3: To a solution of N-(2-(3-(2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethoxy)-N-methylpropanamido)ethyl)-4-((2-hydroxyethyl)disulfanyl)-N,4-dimethylpentanamide (40.1 mg, 0.082 mmol) obtained in step 2 in DCM (3 ml) was added bis(4-nitrophenyl) carbonate (125 mg, 0.409 mmol) and then DIEA (0.043 mL, 0.246 mmol). It was stirred at room temperature for 4 days and the reaction was complete to form the desired product. It was concentrated and the residue was dissolved in ACN and purified by ISCO using 50 g C18 column, eluted with 25-75% ACN in water with 0.035% TFA. Fractions containing the desired product were combined and lyophilized to give 18-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-5,5,9,12-tetramethyl-8,13-dioxo-16-oxa-3,4-dithia-9,12-diazaoctadecyl (4-nitrophenyl) carbonate (LI-2) (44 mg, 73% yield). LCMS M+1=655.2, tr=1.177 min. It is contaminated by a small amount of bis (4-nitrophenyl) carbonate and hydrolyzed alcohol by-product. 
     Example 1-3: Synthesis of 4-((S)-2-((S)-2-(3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propanamido)-3-methylbutanamido)-5-ureidopentanamido)benzyl (4-nitrophenyl) carbonate (LI-3) 
     
       
         
         
             
             
         
       
     
     Step 1: (S)-2-((S)-2-amino-3-methylbutanamido)-N-(4-(hydroxymethyl)phenyl)-5-ureidopentanamide (valcit-pab-OH) (100 mg, 0.264 mmol) (purchased from Levena Biopharma, San Diego) was added to 2,5-dioxopyrrolidin-1-yl 3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propanoate (77 mg, 0.29 mmol) in DMF (5 ml) at room temperature, followed by the addition of DIEA (70 mg, 0.54 mmol). The mixture was stirred at room temperature for 2 hrs, concentrated and then purified by ISCO using 50 g C18 aq column, eluted with 10-25% ACN-water with 0.05% TFA. Fractions containing (S)-2-((S)-2-(3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propanamido)-3-methylbutanamido)-N-(4-(hydroxymethyl)phenyl)-5-ureidopentanamide (MP-valcit-pab-OH) were combined and concentrated (79.8 mg, 0.150 mmol, 57.1% yield). LCMS M+1=531.3, tr=0.687 min. 
     Step 2: A solution of MP-valcit-pab-OH (33 mg, 0.062 mmol), bis(4-nitrophenyl) carbonate (189 mg, 0.622 mmol) and DIEA (0.033 mL, 0.19 mmol) in DMF-DCM (1:4, 5 ml) was stirred at room temperature for 1 week, then concentrated and purified by silica gel column, eluted with MeOH:DCM (2% to 10%). Fractions containing the desired compound were combined and concentrated to give 4-((S)-2-((S)-2-(3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propanamido)-3-methylbutanamido)-5-ureidopentanamido)benzyl (4-nitrophenyl) carbonate (LI-3) (20 mg, 0.029 mmol, 46% yield). LCMS M+1=696.3, tr=1.039 min. 
     Example 1-4: Synthesis of (S)-4-(2-(3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propanamido)-3-phenylpropanamido)benzyl (4-nitrophenyl) carbonate (LI-4) 
     
       
         
         
             
             
         
       
     
     Step 1: N-Hydroxybenzotriazole (HOBT) (509 mg, 3.77 mmol) and DMF (6 ml) was added to a solution of BocPhe-OH (500 mg, 1.89 mmol) and (4-aminophenyl)methanol (464 mg, 3.77 mmol) in DCM (30 ml), followed by the addition of diisopropylcarbodiimide (476 mg, 3.77 mmol). The mixture was stirred at room temperature for 16 hours, concentrated to remove DCM and then purified by silica gel column eluted with 10% MeOH in DCM to give tert-butyl (S)-(1-((4-(hydroxymethyl)phenyl)amino)-1-oxo-3-phenylpropan-2-yl)carbamate (1.12 g, 97% yield). LCMS M+1=275.2. tr=0.561 min. 1H NMR (500 MHz, Chloroform-d) δ 7.99 (s, 1H), 7.88 (d, J=7.1 Hz, 1H), 7.39-7.18 (m, 9H), 5.17 (s, 1H), 4.60 (s, 2H), 4.46 (s, 1H), 3.12 (d, J=6.9 Hz, 2H), 1.40 (s, 9H). 
     Step 2: TFA (5 ml) and DCM (1 ml) were added to tert-butyl (S)-(1-((4-(hydroxymethyl)phenyl)amino)-1-oxo-3-phenylpropan-2-yl)carbamate (1.12 g, 1.82 mmol) and the mixture was concentrated immediately. The solid was then dissolved in MeOH-DCM (5%) and extracted from 2M Na 2 CO 3  aqueous solution, dried and concentrated to obtain (S)-2-amino-N-(4-(hydroxymethyl)phenyl)-3-phenylpropanamide (Phe-pab-OH), which was used in the next step without further purification. LCMS M+1=271.3 tr=0.618 min. 
     Step 3: HOBT (200 mg, 1.48 mmol) was added to a solution of Phe-pab-OH (400 mg, 1.48 mmol) and 3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propanoic acid (250 mg, 1.480 mmol) in DCM-DMF (5:1, 24 ml), followed by the addition of diisopropylcarbodiimide (187 mg, 1.48 mmol). The mixture was stirred at room temperature for 16 hours, concentrated and purified by silica gel column, eluted with 5% MeOH in DCM. Fractions containing the desired product were combined and concentrated. The mixture was further purified by reverse phase ISCO using 50 g C18 aq column, eluted with 10-50% acetonitrile-H2O containing 0.05% TFA. Fractions containing the desired product were concentrated to obtain (S)-2-(3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propanamido)-N-(4-(hydroxymethyl)phenyl)-3-phenylpropanamide (MP-Phe-pab-OH) (0.214 g, 32.6% yield) as free base. LCMS M+1=422.2, tr=0.851 min. 1H NMR (500 MHz, Acetonitrile-d3) δ 8.40 (s, 1H), 7.45 (d, J=8.5 Hz, 2H), 7.25 (ddd, J=20.2, 7.7, 3.3 Hz, 7H), 6.80 (d, J=7.8 Hz, 1H), 6.70 (s, 2H), 4.62 (td, J=8.0, 6.2 Hz, 1H), 4.51 (s, 2H), 3.64 (t, J=7.0 Hz, 2H), 3.13 (dd, J=13.9, 6.2 Hz, 1H), 2.93 (dd, J=13.9, 8.1 Hz, 1H), 2.54-2.31 (m, 2H). 
     Step 4: A solution of (S)-2-(3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propanamido)-N-(4-(hydroxymethyl)phenyl)-3-phenylpropanamide (MP-Phe-pab-OH) (89.3 mg, 0.212 mmol), bis(4-nitrophenyl) carbonate (645 mg, 2.119 mmol) and DIEA (0.111 mL, 0.636 mmol) was stirred at room temperature for 2 days, then concentrated and purified by silica gel column, eluted with 2-6% MeOH:DCM. Fractions containing the desired product were collected and concentrated to give (S)-4-(2-(3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propanamido)-3-phenylpropanamido)benzyl (4-nitrophenyl) carbonate (LI-4) (116 mg, 89% yield). LCMS M+1=587.2, tr=1.268 min. 1H NMR (500 MHz, DMSO-d6) δ 10.21 (s, 1H), 8.46 (d, J=8.1 Hz, 1H), 8.40-8.23 (m, 2H), 7.68-7.56 (m, 4H), 7.45 (d, J=8.6 Hz, 2H), 7.30 (d, J=4.4 Hz, 4H), 7.01 (s, 2H), 5.28 (s, 2H), 4.68 (dt, J=8.7, 4.4 Hz, 1H), 3.63-3.48 (m, 2H), 3.36 (s, 4H), 3.05 (dd, J=13.7, 5.5 Hz, 1H), 2.92-2.83 (m, 2H), 2.44-2.34 (m, 2H). 
     Example 1-5: Synthesis of 4-((S)-2-((S)-2-(3-(2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethoxy)propanamido)-3-methylbutanamido)-5-ureidopentanamido)benzyl (4-nitrophenyl) carbonate (LI-5) 
     
       
         
         
             
             
         
       
     
     Step 1: DIEA (204 mg, 1.6 mmol) was added to a solution of Mal-PEG1-Acid (112 mg, 0.53 mmol) in DMF (10 ml), followed by the addition of 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (200 mg, 0.53 mmol). The mixture was stirred at room temperature for 5 mins and then was added to a solution of (S)-2-((S)-2-amino-3-methylbutanamido)-N-(4-(hydroxymethyl)phenyl)-5-ureidopentanamide (valcit-pab-OH) (purchased from Levena Biopharma, San Diego) (200 mg, 0.527 mmol) in DMF (5 ml). The mixture was stirred at room temperature for 1 h and then concentrated and purified by reverse phase ISCO using 50 g C18 column, eluted with 10-40% acetonitrile-H2O containing 0.05% TFA. Fractions containing the desired product were concentrated to obtain (S)-2-((S)-2-(3-(2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethoxy)propanamido)-3-methylbutanamido)-N-(4-(hydroxymethyl)phenyl)-5-ureidopentanamide (MPEG1-vc-pab-OH) (190 mg, 57% yield) as a free base. LCMS M+1=575.3, tr=0.658 min. 
     Step 2: A solution of (S)-2-((S)-2-(3-(2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethoxy)propanamido)-3-methylbutanamido)-N-(4-(hydroxymethyl)phenyl)-5-ureidopentanamide (MPEG1-valcit-pabOH) (57.5 mg, 0.100 mmol), bis(4-nitrophenyl) carbonate (130 mg, 1.0 mmol) and DIEA (0.056 mL, 0.32 mmol) was stirred at room temperature for 2 days. The mixture was then concentrated and purified by silica gel column, eluted with 2-6% MeOH:DCM and fractions containing the desired product were collected and concentrated to give 4-((S)-2-((S)-2-(3-(2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethoxy)propanamido)-3-methylbutanamido)-5-ureidopentanamido)benzyl (4-nitrophenyl) carbonate (LI-5) (59 mg, 80% yield). LCMS M+1=740.2, tr=1.02 min. 
     Example 1-6: Synthesis of tert-butyl (2S,4S)-2-(((chlorocarbonyl)oxy)methyl)-4-fluoropyrrolidine-1-carboxylate (LI-6) 
     
       
         
         
             
             
         
       
     
     To a dry flask was introduced potassium carbonate (257 mg, 1.7 equiv), followed by toluene (5 mL). Phosgene in toluene (2.4 mL, 15% in toluene, 3.0 equiv) was added under nitrogen at −35° C. To this vigorously stirred suspension was added dropwise a solution of (2S,4S)-tert-butyl 4-fluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylate (1.093 mmol, 1.0 equiv) in toluene (3.6 ml). Upon completion of the addition, the mixture was stirred at low temperature (˜−35° C. to 0° C.) for 30 mins. The cool bath was removed, and the mixture stirred for a further 1h at room temperature and then filtered by syringe filters with 0.45 micron pore. The volatiles were removed under vacuum with rotary evaporator and the resultant clear pare yellow oil was used directly without further purification. 
     Example 1-7: Synthesis of Ketone-Coenzyme A Analog (LI-7) 
     
       
         
         
             
             
         
       
     
     Coenzyme A trilithium salt (259 mg, Sigma, assay&gt;93%) was dissolved in 2.0 mL of 100 mM phosphate buffer (pH 7.5) containing 5 mM EDTA, followed by addition of 3-buten-2-one (29.0 μL, Aldrich, 99%). The reaction was carried out for 75 min at 20° C. Next, the reaction mixture was loaded onto a reverse phase RediSep Rf Gold® C18Aq column (Teledyne Isco), where the product eluted at 100% H 2 O. Product-containing fractions were combined and lyophilized, affording linker intermediate (LI-7) as crystalline solid. MS (ESI+) m/z 838.2 (M+1). H-NMR (400 MHz, D 2 O) δ 8.525 (s, 1H), 8.235 (s, 1H), 6.140 (d, 1H, J=7.2 Hz), 4.746 (m, 1H), 4.546 (bs, 1H), 4.195 (bs, 1H), 3.979 (s, 1H), 3.786 (dd, 1H, J=4.8, 9.6 Hz), 3.510 (dd, 1H, J=4.8, 9.6 Hz), 3.429 (t, 2H, J=6.6 Hz), 3.294S (t, 2H, J=6.6 Hz), 2.812 (t, 2H, J=6.8 Hz), 2.676 (t, 2H, J=6.8 Hz), 2.604 (t, 2H, J=6.8 Hz), 2.420 (t, 2H, J=6.6 Hz), 2.168 (s, 3H), 0.842 (s, 3H), 0.711 (s, 3H) (note: some peaks which overlap with D 2 O are not reported). 
     Example 1-8: Synthesis of 4-((tert-butoxycarbonyl)amino)butanoic anhydride (LI-8) 
     
       
         
         
             
             
         
       
     
     A solution of DCC (0.53 g, 2.56 mmol) in anhydrous dichloromethane (5 ml) was added via syringe to a solution of 4-((tert-butoxycarbonyl)amino)butanoic acid (1.0 g, 4.9 mmol) in anhydrous dichloromethane (30 ml). After 1 hr of stirring, precipitation of urea was filtered through a syringe filter and the solvent was removed under vacuum. 4-((tert-butoxycarbonyl)amino)butanoic anhydride (LI-8) (1 g, 105% yield) was obtained as a white solid and used without further purification. 
     Example 1-9: Synthesis of (((4-((S)-2-((S)-2-(3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propanamido)-3-methylbutanamido)-5-ureidopentanamido)benzyl)oxy)carbonyl)glycine (LI-9) 
     
       
         
         
             
             
         
       
     
     DIEA (25.8 mg, 0.2 mmol) was added to glycine (16.7 mg, 0.06 mmol) dissolved in 1 mL DMF and Linker intermediate (LI-3) (34.8 mg, 0.05 mmol) was added, followed by HOAT (8.2 mg, 0.06 mmol). The mixture was then stirred at rt overnight. After completion DMF was removed under reduced pressure, and the crude product was purified by reverse phase ISCO, eluted with 5-50% acetonitrile-H 2 O. Fractions containing the desired product were combined and lyophilized to obtain (((4-((S)-2-((S)-2-(3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propanamido)-3-methylbutanamido)-5-ureidopentanamido)benzyl)oxy)carbonyl)glycine (LI-9) (16.4 mg, 49% yield). LCMS M+1=632.3, tr=0.714 min. 
     Example 2: Synthesis of Cyclic Dinucleotide (CDN) Intermediates 
     Example 2-1: Synthesis of 2-(methylamino)ethyl (9-((2R,3R,3aR,5R,7aR,9R,10R,10aR,12R,14aR)-9-(6-amino-9H-purin-9-yl)-3,10-difluoro-5,12-dimercapto-5,12-dioxidooctahydro-2H,7H-difuro[3,2-d:3′,2′-j][1,3,7,9]tetraoxa[2,8]diphosphacyclododecin-2-yl)-9H-purin-6-yl)carbamate (CDNI-1) 
     Step 1: 
     
       
         
         
             
             
         
       
     
     To a solution of phosgene 15% in toluene (14.4 ml, 21.7 mmol) in anhydrous DCM (30 ml) at −78° C. was added a solution of tert-butyl (2-hydroxyethyl)(methyl)carbamate (1.76 g, 10.0 mmol) and pyridine (1.85 ml, 23.4 mmol) in DCM (10 ml). The mixture was stirred at −78° C. for 10 min, warmed to room temperature, stirred for an additional 20 mins and then concentrated and residual solvent was further removed under vacuum. Compound (T1-1) Et 3 N salt (300 mg, 0.334 mmol) was dissolved in pyridine (5 ml) and then added to the residue and the mixture was stirred at room temperature for 1 hour resulting in approximately 60% conversion with ˜30% diadduct. Water was added to the mixture, and the mixture was stirred for 10 mins and then concentrated. The residue was suspended in DMSO and purified by ISCO using 15.5 g C18 aq column, eluted with ACN-water 5-50%, aq phase containing 10 mM HOAc-Et 3 N. Fractions containing the monoadduct Et 3 N salt and were collected and concentrated. (131 mg) LCMS M+1=896.1, tr=0.770 min.  1 H NMR (500 MHz, Methanol-d 4 ) δ 8.96 (d, J=6.0 Hz, 1H), 8.64 (s, 1H), 8.57 (s, 1H), 8.42 (s, 1H), 8.18 (s, 1H), 6.44 (d, J=16.8 Hz, 1H), 6.36 (d, J=17.3 Hz, 1H), 5.46 (ddd, J=51.9, 15.5, 3.8 Hz, 2H), 5.24-4.99 (m, 2H), 4.64-4.50 (m, 2H), 4.47-4.30 (m, 4H), 4.00 (dt, J=10.3, 4.8 Hz, 2H), 3.64 (t, J=5.9 Hz, 2H), 3.58 (s, 2H), 3.18 (q, J=7.3 Hz, 22H), 3.01-2.83 (m, 7H), 1.46 (s, 8H), 1.41 (d, J=7.6 Hz, 10H), 1.29 (t, J=7.3 Hz, 35H).
         Note: Fractions containing the diadduct were collected and concentrated (218 mg). LCMS M+1=1097.1, tr=0.958 min). Monoadduct and starting compound (T1-1) were then obtained by treating the diadduct with NaOH. Specifically the diadduct was dissolved in ACN (10 ml) and then water (20 ml) was added, followed by 1.2 g NaOH. The mixture was stirred at 50° C. for 4h hours, neutralized with 10% HCl and then concentrated. The residue was purified by reverse phase ISCO C18 column, eluted with 10-40 acetonitrile-H 2 O containing 10 mM Et 3 N HOAc to give monoadduct (106 mg).       

     Step 2: 
     
       
         
         
             
             
         
       
     
     To a flask containing 4-methylbenzenethiol sodium salt (318 mg, 2.16 mmol) was added TFA (5 ml) and the mixture was stirred until near complete dissolution of the solid. This mixture was then added to a flask containing the monoadduct from Step 1 (237 mg, 0.216 mmol) and the mixture was stirred for 2 mins and then concentrated. LCMS showed full Boc deprotection, however approximately ⅓ of t-butylthio adduct remained. The residue was dissolved in DMSO and purified by ISCO using C18 aq column, eluted with 5-30% ACN-water containing 0.05% TFA. Fractions containing the desired product were collected and concentrated to give (CDNI-1) (107 mg, 39.2% yield) (LCMS M+1=796.1, tr=0.555 min). 1H NMR (500 MHz, DMSO-d6) b 10.34 (s, 1H), 8.83 (b, 7H), 8.09 (s, 1H), 6.41 (d, J=15.2 Hz, 1H), 6.30 (d, J=15.2 Hz, 1H), 5.70-5.51 (m, 1H), 5.44 (d, J=51.8 Hz, 1H), 5.03 (d, J=25.7 Hz, 2H), 4.49-4.33 (m, 4H), 4.27 (s, 2H), 3.90-3.55 (m, 2H), 3.10 (d, J=51.8 Hz, 1H), 2.91-2.57 (m, 2H)
         Note: Fractions containing the t-butylthio adduct (LCMS M+1=852.1, tr=0.792 min) were collected and after standing for 3 days the t-butylthio adduct converted to (CDNI-1) (37 mg, 0.029 mmol, 13% yield).       

     Example 2-1: Synthesis of 4-((S)-2-((S)-2-amino-3-methylbutanamido)-5-ureidopentanamido)benzyl (2-(((9-((2R,3R,3aR,5R,7aR,9R,10R,10aR,12R,14aR)-9-(6-amino-9H-purin-9-yl)-3,10-difluoro-5,12-dimercapto-5,12-dioxidooctahydro-2H,7H-difuro[3,2-d:3′,2′-j][1,3,7,9]tetraoxa[2,8]diphosphacyclododecin-2-yl)-9H-purin-6-yl)carbamoyl)oxy)ethyl)(methyl)carbamate (CDNI-2) 
     
       
         
         
             
             
         
       
     
     Step 1: 4-((S)-2-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-methylbutanamido)-5-ureidopentanamido)benzyl 2-(4-nitrophenyl)acetate (Fmoc-Val-Cit-PABC-PNP) (23.18 mg, 0.030 mmol) (purchased from Levena Biopharma, San Diego), DIEA (0.024 mL, 0.137 mmol) and 3-Hydroxytriazolo[4,5-b]pyridine (HOAT) (3.74 mg, 0.027 mmol) were added to a round bottom flask containing (CDNI-1) (25 mg, 0.027 mmol) in DMF (2 mL). The reaction was stirred at room temperature for 4 hours and then heated to 45° C. and stirred for an additional hour. The mixture was then concentrated and the residue purified by ISCO using 15.5 g C18 aq column, eluted with 5-60% ACN-water with 0.05% TFA. Fmoc-vc-pabc-(CDNI-2) (34.4 mg, 81% yield) was obtained. LCMS M/2+1=712.3, tr=1.007 min. 
     Step 2: Piperidine (0.200 ml) was added to a solution of Fmoc-vc-pabc-(CDNI-2) (34.4 mg, 0.022 mmol) TFA salt in DMF (5 mL) and the mixture was stirred at room temperature for 30 mins, and then concentrated. The residue was purified by reverse phase ISCO using C18 aq column, eluted with 5-35% acetonitrile-H 2 O containing 0.05% TFA. Fractions containing desired product were concentrated to (CDNI-2) (31.1 mg, 92% yield) as TFA salt. LCMS M+1=1201.2 tr=0.671 min. 
     Example 2-3: Synthesis of (CDNI-3) 
     
       
         
         
             
             
         
       
     
     Step 1: a) Et 3 N (1 ml) was added to Compound (T1-2) ammonium salt (400 mg, 0.552 mmol) in pyridine (30 ml) and the mixture was concentrated. The procedure was repeated twice to obtain the triethylammonium salt of Compound (T1-2). 
     b) A solution of tert-butyl (2-hydroxyethyl)(methyl)carbamate (290 mg, 1.66 mmol) in DCM (10 ml) with pyridine (0.313 mL, 3.86 mmol) was added to a solution of 15% phosgene solution in toluene (4.4 ml) in DCM (20 ml) at −78° C. and the mixture was stirred for 15 mins and then warmed to room temperature and concentrated to obtain 2-((tert-butoxycarbonyl) (methyl)amino)ethyl carbonochloridate. 
     Step 2: Compound (T1-2) Et 3 N salt was resuspended in anhydrous pyridine (30 ml) and then added to 2-((tert-butoxycarbonyl)(methyl)amino)ethyl carbonochloridate from step 1 b) and the mixture was stirred at room temperature for 30 mins. Water was then added and the mixture was concentrated. The residue was suspended in DMSO-water and then purified by reverse phase ISCO using C18 column, 15.5 g aq column, eluted with 2-40% acetonitrile-H 2 O containing 10 mM Et 3 N HOAc. The fractions containing the desired Boc protected monoadduct (387 mg, 57.7% yield) were collected and lyophilized. M+1=892.2. tr=0.770 min. 1H NMR (500 MHz, Methanol-d 4 ) δ 8.83 (s, 1H), 8.34 (s, 1H), 8.24 (s, 1H), 8.18 (s, 1H), 6.33 (dd, J=25.9, 6.9 Hz, 2H), 6.10 (s, 1H), 5.51 (s, 1H), 5.33 (s, 1H), 4.68 (s, 1H), 4.51-4.14 (m, 7H), 4.03 (d, J=9.5 Hz, 1H), 3.70-3.56 (m, 1H), 3.45 (s, 2H), 3.17 (d, J=7.3 Hz, 22H), 2.88 (s, 4H), 1.40 (s, 4H), 1.29 (t, J=7.3 Hz, 33H). 
     Step 3: TFA (5 mL) was added to a flask containing 4-methylbenzenethiol sodium salt (200 mg, 1.36 mmol) and the mixture was stirred until complete dissolution. The mixture was then added to another flask containing the Boc protected mono-adduct from step 2 (250 mg, 0.228 mmol) and after 1 min at room temperature the TFA was removed. The mixture was then dissolved in DMSO and purified by reverse phase ISCO using 15 g C18 aq column, eluted with 2-20% acetonitrile-H 2 O containing 0.05% TFA. The fractions containing desired product were concentrated to obtain the de-protected monoadduct (CDNI-3) as a TFA salt. LCMS M+1=792.0, tr=0.611 min.  1 H NMR (500 MHz, DMSO-d 6 ) δ 9.37 (d, J=41.6 Hz, 2H), 8.89 (s, 1H), 8.70 (s, 1H), 8.43 (s, 1H), 8.30 (s, 1H), 6.33 (d, J=7.8 Hz, 1H), 6.21 (d, J=8.2 Hz, 1H), 5.51-5.24 (m, 2H), 4.72-4.62 (m, 1H), 4.49 (s, 1H), 4.41 (s, 1H), 4.31 (s, 3H), 4.07 (s, 2H), 3.85 (s, 1H), 3.43 (s, 1H), 3.23 (s, 1H), 2.67 (s, 2H).
         Note: Fractions containing the t-butylthio adduct were collected and after standing for 3 days the t-butylthio adduct converted to (CDNI-3)       

     Example 2-4: Synthesis of (CDNI-4) 
     
       
         
         
             
             
         
       
     
     
       
         
         
             
             
         
       
     
     Step 1: Di-t-butyl dicarbonate (4.26 g, 19.5 mmol) was added dropwise over 10 minutes to a mixture of 4-(methylamino)butyric acid hydrochloride (2.0 g, 13.0 mmol) in MeOH (25 mL) and Et 3 N (7.26 mL, 52.1 mmol). The reaction mixture was stirred at room temperature for 22 hrs and then concentrated. The residue was dissolved in EtOAc (100 mL), and washed with an ice-cold 0.1 N HCl solution (20.0 mL). The organic layer was then washed with water to neutral pH, and then washed with sat. NaCl. The EtOAc layer was dried over Na 2 SO 4  and concentrated to give 4-((tert-butoxycarbonyl)(methyl)amino)butanoic acid (2.08 g, 70%). 1H NMR (500 MHz, Chloroform-d) δ 3.28 (t, J=6.9 Hz, 2H), 2.84 (s, 3H), 2.35 (t, J=7.2 Hz, 2H), 1.84 (p, J=7.1 Hz, 2H), 1.45 (s, 9H). 
     Step 2: A solution of dicyclohexylcarbodiimide (704 mg, 3.41 mmol) in 10 ml of anhydrous DCM was added drop wise under N 2  to a flask containing 4-((tert-butoxycarbonyl)(methyl)amino)butanoic acid (1.43 g, 6.56 mmol) in anhydrous DCM (20 ml). The mixture was stirred for 2 hrs and then concentrated to about 15 mL, filtered and the solvent removed under vacuum. The crude was filtered through 0.45 micron filter twice to yield 4-((tert-butoxycarbonyl)(methyl)amino)butanoic anhydride as a clear pale yellow oil (1.36 g, 99% yield).  1 H NMR (500 MHz, Chloroform-d) δ 3.28 (t, J=6.9 Hz, 2H), 2.84 (s, 3H), 2.46 (t, J=7.3 Hz, 2H), 1.87 (p, J=7.2 Hz, 2H), 1.45 (s, 9H). 
     Step 3: 4-((tert-butoxycarbonyl)(methyl)amino)butanoic anhydride (152.0 mg, 0.366 mmol) in DMF (1.6 mL) was added to Compound (T1-2) (63.1 mg, 0.091 mmol) in pyridine (0.8 mL). The reaction mixture was stirred at room temperature for 3 days and then the solvent was removed. The residue was purified by reverse phase ISCO using C18 column, 50 g aq column, eluted with 5-50% MeCN/water (containing 10 mM Et 3 N HOAc). Fractions containing desired boc protected monoadduct were collected and lyophilized (45.3 mg, 56% yield). LCMS M+1=890.20, tr=0.787 min. 
     Step 4: TFA (2 mL) was added to a flask containing 4-methylbenzenethiol sodium salt and the mixture was stirred until complete dissolution and then added to another flask containing the boc protected monoadduct from step 3. TFA was immediately removed and the mixture was then dissolved in DMSO and purified by reverse phase ISCO C18 column, 15 g C18 aq column, eluted with 2-20% acetonitrile-H 2 O containing 0.05% TFA. Fractions containing desired product were concentrated to obtain (CDNI-4) (35.0 mg, 89% yield) as TFA salt. LCMS M+1=790.2, tr=0.220 min. 
     Example 2-5: Synthesis of (CDNI-5) 
     
       
         
         
             
             
         
       
     
     
       
         
         
             
             
         
       
     
     Step 1: a) Compound (T1-2) (20 mg, 0.028 mmol) ammonium salt was dissolved in 5 ml pyridine and 0.06 ml Et 3 N was then added. The mixture was concentrated and the process repeated twice to obtain the Compound (T1-2) triethylammonium salt. 
     b) A solution of tert-butyl (2-hydroxyethyl)(methyl)carbamate (84 mg, 0.44 mmol) in DCM (3 ml) with pyridine (0.072 mL, 0.88 mmol) was added to a solution of 15% phosgene solution in toluene (0.88 ml) in DCM (10 ml) at −78° C. The mixture was stirred for 15 mins, then warmed to room temperature and concentrated to give 1-((tert-butoxycarbonyl) (methyl)amino)propan-2-yl carbonochloridate. 
     Step 2: Compound (T1-2) Et 3 N salt was resuspended in anhydrous pyridine (1 ml) and then added to 1-((tert-butoxycarbonyl)(methyl)amino)propan-2-yl carbonochloridate. The mixture was stirred for 30 mins and then water was added. The mixture was concentrated, dissolved in DMSO-water and purified by reverse phase ISCO using C18 column, 15.5 g aq column, eluted with 2-40% acetonitrile-H 2 O containing 10 mM Et 3 N HOAc. Fractions containing desired Boc protected monoadduct were collected and lyophilized (33 mg, 43% yield). M+1=906.1, tr=0.785 min. 
     Step 3: TFA (2 mL) was added to a flask containing 4-methylbenzenethiol sodium salt and the mixture was stirred until complete dissolution and then added to another flask containing the boc protected monoadduct from step 3 (33 mg, 0.030 mmol. TFA was immediately removed and the mixture was then dissolved in DMSO and purified by reverse phase ISCO using 15.5 g C18 aq column, eluted with 2-20% acetonitrile-H 2 O containing 0.05% TFA. Fractions containing desired product were concentrated to obtain (CDNI-5) (21 mg, 55% yield) as TFA salt. LCMS M+1=806.0, tr=0.586 min. 
     Example 2-6: Synthesis of (CDNI-6) 
     
       
         
         
             
             
         
       
     
     Intermediate (CDNI-6) was prepared using the methods described for the synthesis of intermediate (CDNI-3), except Compound (T1-5) was used in place of Compound (T1-2). Intermediate (CDNI-6) (25.6 mg, 66.8% yield) as TFA salt. LCMS M+1=794.1, tr=0.518 min. 
     Example 2-7: Synthesis of (CDNI-7) 
     
       
         
         
             
             
         
       
     
     
       
         
         
             
             
         
       
     
     Intermediate (CDNI-7) was prepared using the methods described for the synthesis of intermediate (CDNI-4), except Compound (T1-5) was used in place of Compound (T1-2). Intermediate (CDNI-7) (10.0 mg, 8% yield) as TFA salt. LCMS M+1=792.2, tr=0.381 min. 
     Example 2-8: Synthesis of (CDNI-8) 
     
       
         
         
             
             
         
       
     
     Intermediate (CDNI-8) was prepared using the methods described for the synthesis of intermediate (CDNI-3), except Compound (T1-3) was used in place of Compound (T1-2). 
     Example 2-9: Synthesis of (CDNI-9a) and of (CDNI-9b) 
     a) Synthesis of (CDNI-9a): 
     
       
         
         
             
             
         
       
     
     Intermediate (CDNI-9a) was prepared using the methods described for the synthesis of intermediate (CDNI-3), except Compound (T1-6) was used in place of Compound (T1-2). Intermediate (CDNI-9a) (32.1 mg, 39.0% yield) (LCMS M+1=796.0, tr=0.406 min). However, Step 1 for the preparation of 2-((tert-butoxycarbonyl)(methyl)amino)ethyl carbonochloridate was modified as follows: 
     Tert-butyl (2-hydroxyethyl)(methyl)carbamate (175 mg, 0.736 mmol) and K2CO3 (43 mg, 0.626 mmol) were added to a flask under N 2 ., and then toluene (10 mL) was added and the mixture cooled to −15° C. The mixture was stirred and a solution of phosgene in toluene (1.1 mmol, 15% in toluene) was added dropwise. The mixture was stirred at low temperature (−15° C. to 0° C.) for an additional 30 mins, warmer to room temperature and stirred for another hour. The mixture was filtered by syringe filter (0.45 micron pore), and the solvent was removed to give 2-((tert-butoxycarbonyl)(methyl)amino)ethyl carbonochloridate as a clear pare yellow oil which was used directly without further purification. 
     b) Synthesis of (CDNI-9b): 
     
       
         
         
             
             
         
       
     
     Intermediate (CDNI-9b) was also obtained during the synthesis of Intermediate (CDNI-9a). CDN intermediate (CDNI-9a) and CDN intermediate (CDNI-9b) could not separated. (CDNI-9a). CDN intermediate (CDNI-9a) and CDN intermediate (CDNI-9b) (32.1 mg, 39.0% yield) (LCMS M+1=796.0, tr=0.406 min). 
     Example 2-10: Synthesis of (2R,3R,3aR,5R,7aR,9R,10R,10aR,12R,14aR)-2-(6-amino-9H-purin-9-yl)-9-(6-((3-aminopropyl)amino)-9H-purin-9-yl)-3,10-difluoro-5,12-dimercaptooctahydro-2H,7H-difuro[3,2-d:3′,2′-j][1,3,7,9]tetraoxa[2,8]diphosphacyclododecine 5,12-dioxide (CDNI-10) 
     
       
         
         
             
             
         
       
     
     Step 1: HOAc (0.020 ml) and tert-butyl (3-oxopropyl)carbamate (10 mg, 0.058 mmol) were added to a suspension of Compound (T1-1) (5 mg, 0.0056 mmol) in MeOH (1 ml) and the mixture was heated to 50° C. for 16 hours (LCMS showed slow imine formation M+1 850.2 tr=0.680 min) NaBH 3 CN (0.35 mg, 0.0056 mmol) was then added and the reaction was stirred at room temperature for 2 hours. LCMS indicated ˜25% conversion. M+1=852.1 tr=0.708 min. An additional 5 mg of tert-butyl (3-oxopropyl)carbamate was added and the mixture was heated at 50° C. for 2 hours, followed by addition of 5 mg NaBH 3 CN. The mixture was stirred for 1 hour and conversion monitored by LCMS. The process of adding 5 mg additional tert-butyl (3-oxopropyl)carbamate and 5 mg additional NaBH 3 CN was repeated until ˜50% conversion was achieved. The mixture was concentrated, the residue dissolved in 2 ml MeOH and purified by mass triggered reverse phase HPLC, using C18 column, eluted with 13-29% acetonitrile-H 2 O containing 0.05% TFA. Fractions containing desired product were concentrated to obtain tert-butyl (3-((9-((2R,3R,3aR,5R,7aR,9R,10R,10aR,12R,14aR)-9-(6-amino-9H-purin-9-yl)-3,10-difluoro-5,12-dimercapto-5,12-dioxidooctahydro-2H,7H-difuro[3,2-d:3′,2′-j][1,3,7,9]tetraoxa[2,8]diphosphacyclododecin-2-yl)-9H-purin-6-yl)amino)propyl)carbamate as TFA salt. LCMS M+1=852.1 tr=0.695 min. 
     Step 2: tert-butyl (3-((9-((2R,3R,3aR,5R,7aR,9R,10R,10aR,12R,14aR)-9-(6-amino-9H-purin-9-yl)-3,10-difluoro-5,12-dimercapto-5,12-dioxidooctahydro-2H,7H-difuro[3,2-d:3′,2′-j][1,3,7,9]tetraoxa[2,8]diphosphacyclododecin-2-yl)-9H-purin-6-yl)amino)propyl)carbamate (1 mg, 0.001 mmol) was treated with TFA (1 ml) and was immediately concentrated. H 2 O and ACN (1:1) was added and the sample was lyophilized to give (2R,3R,3aR,5R,7aR,9R,10R,10aR,12R,14aR)-2-(6-amino-9H-purin-9-yl)-9-(6-((3-aminopropyl)amino)-9H-purin-9-yl)-3,10-difluoro-5,12-dimercaptooctahydro-2H,7H-difuro[3,2-d:3′,2′-j][1,3,7,9]tetraoxa[2,8]diphosphacyclododecine 5,12-dioxide (0.9 mg, 30% yield) as TFA salt. LCMS M+1=748.0, tr=0.227 min. 
     Example 2-11 
     a) Synthesis of ((2S,4S)-4-fluoropyrrolidin-2-yl)methyl (9-((2R,3R,3aR,5R,7aR,9R,10R,10aR,12S,14aR)-9-(6-amino-9H-purin-9-yl)-3,10-difluoro-5,12-dimercapto-5,12-dioxidooctahydro-2H,7H-difuro[3,2-d:3′,2′-j][1,3,7,9]tetraoxa[2,8]diphosphacyclododecin-2-yl)-9H-purin-6-yl)carbamate (CDNI-11a) 
     
       
         
         
             
             
         
       
     
     Step 1: Compound (T1-6) Et 3 N salt (224 mg, 0.25 mmol) with pyridine (88 uL, 7.0 equiv) in NMP (0.5 mL) and DCM (1.5 mL) was added to (2S,4S)-tert-butyl 2-(((chlorocarbonyl)oxy)methyl)-4-fluoropyrrolidine-1-carboxylate (LI-6) in DCM (1.5 mL) over 5 minutes. The mixture was stirred at room temperature for one hour. Water was added to the reaction and it was stirred for another 10 mins and then concentrated. The mixture was suspended in DMSO and purified by ISCO using 15.5 g C18 aq column, eluted with ACN-water 5-50%, aq phase containing 10 mM HOAc-Et 3 N to give the diadduct, di-tert-butyl 5,5′-(((((((2R,3R,3aR,5R,7aR,9R,10R,10aR,12S,14aR)-3,10-difluoro-5,12-dimercapto-5,12-dioxidooctahydro-2H,7H-difuro[3,2-d:3′,2′-j][1,3,7,9]tetraoxa[2,8]diphosphacyclododecine-2,9-diyl)bis(9H-purine-9,6-diyl))bis(azanediyl))bis(carbonyl))bis(oxy))bis(methylene))(3S,3&#39;S,5S,5&#39;S)-bis(3-fluoropyrrolidine-1-carboxylate), (149.5 mg). LCMS M+1=1185.1, tr=0.944 min. 
     Step 2: The diadduct (149.5 mg) from step 1 was dissolved in ACN (5 ml) and then water (10 ml) was added, followed by 0.6 g NaOH. The mixture was stirred at 50° C. for 4 hours, then neutralized with 4M HCl and then concentrated. The residue was purified by reverse phase ISCO, C18 column, eluted with 10-50 acetonitrile-H 2 O containing 10 mM Et 3 N HOAc to give the protected monoadduct, tert-butyl (2S,4S)-2-((((9-((2R,3R,3aR,5R,7aR,9R,10R,10 aR,12S,14aR)-9-(6-amino-9H-purin-9-yl)-3,10-difluoro-5,12-dimercapto-5,12-dioxidooctahydro-2H,7H-difuro[3,2-d:3′,2′-j][1,3,7,9]tetraoxa[2,8]diphosphacyclododecin-2-yl)-9H-purin-6-yl)carbamoyl)oxy)methyl)-4-fluoropyrrolidine-1-carboxylate, (32.0 mg). LCMS M+1=940.1, tr=0.750 min. 
     Step 3: TFA (2.0 ml) was added to a flask containing monoadduct from step 2 (32.0 mg, 0.028 mmol) and the mixture was stirred for 2 mins and then concentrated. The residue was dissolved in DMSO and purified by ISCO using C18 aq column, eluted with 5-30% ACN-water containing 0.05% TFA to give ((2S,4S)-4-fluoropyrrolidin-2-yl)methyl (9-((2R,3R,3aR,5R,7aR,9R,10R,10aR,12S, 14aR)-9-(6-amino-9H-purin-9-yl)-3,10-difluoro-5,12-dimercapto-5,12-dioxidooctahydro-2H,7H-difuro[3,2-d:3′,2′-j][1,3,7,9]tetraoxa[2,8]diphosphacyclododecin-2-yl)-9H-purin-6-yl)carbamate (CDNI-11a) (13.1 mg, 44.0% yield) (LCMS M+1=840.0, tr=0.407 min). 
     b) Synthesis of ((2S,4S)-4-fluoropyrrolidin-2-yl)methyl (9-((2R,3R,3aR,5S,7aR,9R,10R,10aR,12R,14aR)-9-(6-amino-9H-purin-9-yl)-3,10-difluoro-5,12-dimercapto-5,12-dioxidooctahydro-2H,7H-difuro[3,2-d:3′,2′-j][1,3,7,9]tetraoxa[2,8]diphosphacyclododecin-2-yl)-9H-purin-6-yl)carbamate (CDNI-11 b) 
     
       
         
         
             
             
         
       
     
     Intermediate (CDNI-11b) was also obtained during the synthesis of Intermediate (CDNI-1a). CDN intermediate (CDNI-11a) and CDN intermediate (CDNI-11b) could not separated. (CDNI-1a). CDN intermediate (CDNI-11a) and CDN intermediate (CDNI-9b) (13.1 mg, 44.0% yield) (LCMS M+1=840.0, tr=0.407 min). 
     Example 2-12: Synthesis of N-(9-((2R,3R,5R,7aR,9R,10R,12R,14aR)-9-(6-amino-9H-purin-9-yl)-3,10-difluoro-5,12-dimercapto-5,12-dioxidooctahydro-2H,7H-difuro[3,2-d:3′,2′-j][1,3,7,9]tetraoxa[2,8]diphosphacyclododecin-2-yl)-9H-purin-6-yl)-4-(methylamino)butanamide (CDNI-12) 
     
       
         
         
             
             
         
       
     
     Step 1: 4-((tert-butoxycarbonyl)(methyl)amino)butanoic anhydride (241 mg, 0.580 mmol) was added to a solution of Compound (T1-1) Et 3 N salt (40 mg, 0.045 mmol) in pyridine (5 ml) and heated to 50° C. and stirred for 72 hours. DMAP (10 mg) and 50 mg more anhydride were added and the reaction was stirred at 50° C. for 8 hours and then concentrated and purified using reverse phase ISCO with 15 g C18 aq column, eluted with 5-45% acetonitrile-H 2 O (aqueous phase containing 10 mM Et 3 N HOAc). Fractions containing desired product were collected and lyophilized to obtain boc-protected intermediate CDNI-12 as an Et 3 N salt (8 mg, 16% yield). LCMS M+1=894.0, tr=0.776 min. 
     Note: 4-((tert-butoxycarbonyl)(methyl)amino)butanoic anhydride was synthesized as described in the synthesis of CDNI-4. 
     Step 2: TFA (1 ml) was added to a flask containing boc-protected intermediate CDNI-12 Et 3 N salt (8 mg, 0.007 mmol) and then immediately concentrated. The residue was purified by reverse phase ISCO using 15 g C18 column, eluted with 5-45% acetonitrile-H 2 O containing 0.05% TFA. Fractions containing desired product were concentrated to obtain intermediate CDNI-12 as a TFA salt (3.7 mg, 49.6% yield). LCMS M+1=794.0, tr=0.636 min. 
     Example 2-13: Synthesis of 4-amino-N-(9-((2R,3R,5R,7aR,9R,10R,12R,14aR)-9-(6-amino-9H-purin-9-yl)-3,10-difluoro-5,12-dimercapto-5,12-dioxidooctahydro-2H,7H-difuro[3,2-d:3′,2′-j][1,3,7,9]tetraoxa[2,8]diphosphacyclododecin-2-yl)-9H-purin-6-yl)butanamide (CDNI-13) 
     
       
         
         
             
             
         
       
     
     Step 1: 4-((tert-butoxycarbonyl)amino)butanoic anhydride (LI-8) was added to a solution of Compound (T1-1) Et 3 N salt (30 mg, 0.033 mmol) in pyridine (5 ml) (390 mg, 1.00 mmol) and heated at 50° C. for 3 days. The reaction mixture was then concentrated and the crude was purified by reverse phase ISCO using 15 g C18 column, eluted with 5-60% acetonitrile-H 2 O (aqueous phase containing 10 mM Et 3 N HOAc). Fractions containing the desired product were isolated and concentrated to obtain boc-protected intermediate CDNI-13 as Et 3 N salt (10 mg, 28% yield). LCMS M+1=880.1, tr=0.731 min. 
     Step 2: TFA (2 ml) was added to a flask containing boc-protected intermediate CDNI-12 Et 3 N salt (10 mg, 0.009 mmol) and immediately concentrated. The crude was purified by reverse phase ISCO using 15 g C18 aq column, eluted with 5-60% acetonitrile-H 2 O containing 0.05% TFA. Fractions containing the desired product were combined and lyophilized to obtain intermediate CDNI-13 as TFA salt (11.2 mg, 96% yield). LCMS M+1-H 2 O=762.0, tr=0.608 min. 
     Example 2-14: Synthesis of tert-butyl ((S)-1-((4-((9-((2R,3R,3aR,5R,7aR,9R,10R,10aR,12R,14aR)-9-(6-amino-9H-purin-9-yl)-3,10-difluoro-5,12-dimercapto-5,12-dioxidooctahydro-2H,7H-difuro[3,2-d:3′,2′-j][1,3,7,9]tetraoxa[2,8]diphosphacyclododecin-2-yl)-9H-purin-6-yl)amino)-4-oxobutyl)amino)-1-oxo-5-ureidopentan-2-yl)carbamate (CDNI-14) 
     
       
         
         
             
             
         
       
     
     Step 1: To a solution of (S)-2-((tert-butoxycarbonyl)amino)-5-ureidopentanoic acid (Boc-Cit-OH purchased from Bachem) (2.7 mg, 0.01 mmol) in DMF (1 ml) was added DIEA (0.017 mL, 0.10 mmol) and then HATU (3.8 mg, 0.01 mmol). The reaction mixture was stirred at rt for 5 mins and then was added to a solution of CDN intermediate (CDNI-13) TFA salt (10 mg, 0.01 mmol) in DMF and this mixture was stirred at rt for 5 hrs and then concentrated. The residue was purified by reverse phase ISCO using 15 g C18 aq column, eluted with 5-40% acetonitrile-H 2 O (aqueous phase containing 10 mM Et 3 N HOAc). Fractions containing desired product were concentrated to obtain boc-protected intermediate CDNI-14 as an Et 3 N salt (2.9 mg, 24% yield). LCMS M+1=1037.1, tr=0.699 min. 
     Step 2: TFA (1 ml) was added to a flask containing boc-protected intermediate CDNI-14 Et 3 N salt (2.9 mg, 0.0028 mmol) and the solution was stirred for 1 min and then concentrated to give CDN intermediate (CDNI-14) as TFA salt (2.9 mg, 100% yield). LCMS M+1=937.1, tr=0.598 min. 
     Example 2-15: Synthesis of (S)-2-((S)-2-amino-3-methylbutanamido)-N-(4-((9-((2R,3R,3aR,5R,7aR,9R,10R,10aR,12R,14aR)-9-(6-amino-9H-purin-9-yl)-3,10-difluoro-5,12-dimercapto-5,12-dioxidooctahydro-2H,7H-difuro[3,2-d:3′,2′-j][1,3,7,9]tetraoxa[2,8]diphosphacyclododecin-2-yl)-9H-purin-6-yl)amino)-4-oxobutyl)-5-ureidopentanamide (CDNI-15) 
     
       
         
         
             
             
         
       
     
     Step 1: To a vial containing (tert-butoxycarbonyl)-L-valine (Boc-Val-OH purchased from Novabiochem) (1.2 mg, 0.0056 mmol) was added DMF (1 ml) and then HATU (2.1 mg, 0.0056 mmol) and DIEA (3.6 mg, 0.028 mmol) were added. The mixture was stirred for 2 mins and then added to a solution containing intermediate CDNI-14 TFA salt (2.9 mg, 0.0028 mmol) in DMF (1 ml). The reaction was stirred at rt for 1 day and then concentrated. The residue was purified by reverse phase ISCO using 15 g C18 aq column, eluted with 5-40% acetonitrile-H 2 O (aqueous phase containing 10 mM Et 3 N HOAc). Fractions containing desired product were concentrated to obtain boc-protected intermediate CDNI-15 as Et 3 N salt (1.8 mg, 48% yield). LCMS M+1=1136.2, tr=0.791 min. 
     Step 2: TFA (1 ml) was added to a flask containing boc-protected intermediate CDNI-15 Et 3 N salt (1.8 mg, 0.0013 mmol) and the solution was stirred for 1 min and then concentrated to give intermediate CDNI-15 as TFA salt (1.7 mg, 100%). The compound was used in the next step without further purification. LCMS M+1=1036.1, tr=0.621 min. 
     Example 2-16: Synthesis of (2S,3S,4S,5R,6S)-6-(4-((((2-(((9-((2R,3R,3aR,5R,7aR,9R,10R,10aR,12R,14aR)-9-(6-amino-9H-purin-9-yl)-3,10-difluoro-5,12-dimercapto-5,12-dioxidooctahydro-2H,7H-difuro[3,2-d:3′,2′-j][1,3,7,9]tetraoxa[2,8]diphosphacyclododecin-2-yl)-9H-purin-6-yl)carbamoyl)oxy)ethyl)(methyl)carbamoyl)oxy)methyl)-2-(3-aminopropanamido)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid (CDNI-16) 
     
       
         
         
             
             
         
       
     
     Step 1: To a solution of intermediate CDNI-1 TFA salt (15 mg, 0.015 mmol) and (2S,3R,4S,5S,6S)-2-(2-(3-((((9H-fluoren-9-yl) methoxy)carbonyl)amino)propanamido)-4-((((4-nitrophenoxy)carbonyl)oxy)methyl)phenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (see Bioconjugate Chem. 2006, 17, 831-840) (16 mg, 0.018 mmol) in DMF (1 ml) was added DIEA (0.026 ml, 0.15 mmol) and HOAT (2.0 mg, 0.015 mmol). The reaction was stirred at rt for 16 hrs. Solvent was then removed by high vacuum and the crude was purified by reverse phase ISACO using 15 g C18 column, eluted with 5-60% acetonitrile-H 2 O (aqueous phase containing 10 mM Et 3 N HOAc). Fractions containing desired product were concentrated to obtain Fmoc protected intermediate CDNI-16 as Et 3 N salt (20.2 mg, 78% yield). LCMS M/2+1=785.8, tr=1.094 min. 
     Step 2: A solution of LiOH (9.3 mg, 0.388 mmol) in water was added to a vial containing Fmoc protected intermediate CDNI-16 (20.2 mg, 0.011 mmol) Et 3 N salt and MeOH (4 mL) and the mixture was stirred at rt for 16 hrs. It was then neutralized with HOAc and concentrated. The crude was purified by reverse phase ISCO using 43 g C18 aq column, eluted with 5-35% acetonitrile-H 2 O (aqueous phase containing 10 mM Et 3 N HOAc). Fractions containing desired product were concentrated to obtain intermediate CDNI-16 as Et 3 N salt (23.2 mg, 135% yield). LCMS M+1=1207.9, tr=0.811 min. 
     Example 2-17: Synthesis of ((2S,4S)-4-fluoropyrrolidin-2-yl)methyl (9-((2R,3R,3aR,5R,7aR,9R,10R,10aR,12R,14aR)-9-(6-amino-9H-purin-9-yl)-3,10-difluoro-5,12-dimercapto-5,12-dioxidooctahydro-2H,7H-difuro[3,2-d:3′,2′-j][1,3,7,9]tetraoxa[2,8]diphosphacyclododecin-2-yl)-9H-purin-6-yl)carbamate (CDNI-17) 
     
       
         
         
             
             
         
       
     
     Intermediate (CDNI-17) was synthesized using the method described for CDNI intermediate (CDNI-11), except Compound (T1-6) Et 3 N salt was replaced with Compound (T1-1) Et 3 N salt. 
     Example 2-18: Synthesis of 2-azidoethyl (9-((2R,3R,3aR,5R,7aR,9R,10R,10aR,12R,14aR)-9-(6-amino-9H-purin-9-yl)-3,10-difluoro-5,12-dimercapto-5,12-dioxidooctahydro-2H,7H-difuro[3,2-d:3′,2′-j][1,3,7,9]tetraoxa[2,8]diphosphacyclododecin-2-yl)-9H-purin-6-yl)carbamate (CDNI-18) 
     
       
         
         
             
             
         
       
     
     Step 1: A solution of diphosgene (275 mg, 1.41 mmol) was added to a solution of 2-azidoethanol (87 mg, 1.00 mmol) in DCM (10 ml) at −78° C. and the mixture was slowly warmed to rt. After 15 mins the solution became clear. The reaction was concentrated and solvent and other volatile reagents were removed under vacuum to obtain 2-azidoethyl carbonochloridate which was used in step 2 without further purification. 
     Step 2: 2-azidoethyl carbonochloridate (149 mg, 1.00 mmol) in DCM (1 ml) was added in portions over 30 mins to Compound (T1-1) Et 3 N salt (30 mg, 0.033 mmol) dissolved in pyridine (2 ml). Then Et 3 N (0.03 ml) was added and the mixture was stirred at rt for 2 hrs. The solution was concentrated and water and acetonitrile were then added. 1N NaOH (5 ml) was then added and the reaction was stirred at 60° C. for 2 hrs, Both mono- and diadduct were formed. The reaction was neutralized with HOAc, concentrated and then suspended in DMSO and purified by reverse phase ISCO using 43 g C18 aq column, eluted with 5-35%, acetonitrile-water (aqueous phase containing 10 mM Et 3 N HOAc). Fractions containing mono-adduct were collected and concentrated to give CDNI intermediate (CDNI-18) as Et 3 N salt (20 mg, 45% yield). LCMS M+1=808.0, tr=0.764 min. 
     Example 2-19: Synthesis of N-(9-((2R,3R,3aR,5R,7aR,9R,10R,10aR,12R,14aR)-9-(6-amino-9H-purin-9-yl)-3,10-difluoro-5,12-dimercapto-5,12-dioxidooctahydro-2H,7H-difuro[3,2-d:3′,2′-j][1,3,7,9]tetraoxa[2,8]diphosphacyclododecin-2-yl)-9H-purin-6-yl)-4-azidobutanamide (CDNI-19) 
     
       
         
         
             
             
         
       
     
     Step 1: 4-azidobutanoic acid (259 mg, 2.01 mmol) was dissolved in DCM (5 ml) and oxalyl chloride (190 mg, 1.5 mmol) was added, followed by DMF (0.005 ml). The reaction was stirred at rt for 1 hr, and then concentrated to obtain 4-azidobutanoyl chloride, which was used in the next step without further purification. 
     Step 2: 4-azidobutanoyl chloride (94 mg, 0.64 mmol) was dissolved in DCM (0.32 ml) and added to a solution of di-2′-F—RR-CDA Et 3 N salt (30 mg, 0.033 mmol) in pyridine (3 ml). The reaction was stirred at 70° C. for 0.5 h and then quenched with 2 drops of water and concentrated. The crude was purified by reverse phase ISCO using 50 g C18 aq column, eluted with 5-50% acetonitrile-H 2 O (aqueous phase containing 10 mM Et 3 N HOAc). Fractions containing the desired product were isolated and lyophilized to give CDN intermediate (CDNI-19) as Et 3 N salt (19.7 mg, 58.4% yield). LCMS M+1=806.0, tr=0.807 min. 
     Example 2-20: Synthesis of 3-azidopropyl (9-((2R,3R,3aR,5R,7aR,9R,10R,10aR,12R,14aR)-9-(6-amino-9H-purin-9-yl)-3,10-difluoro-5,12-dimercapto-5,12-dioxidooctahydro-2H,7H-difuro[3,2-d:3′,2′-j][1,3,7,9]tetraoxa[2,8]diphosphacyclododecin-2-yl)-9H-purin-6-yl)carbamate (CDNI-20) 
     
       
         
         
             
             
         
       
     
     CDN intermediate (CDNI-20) was synthesized using the method described for the synthesis of CDN intermediate (CDNI-18) except 3-azidopropan-1-ol was used in place of 2-azidoethanol. CDN intermediate (CDNI-20) Et 3 N salt (16.3 mg, 47% yield). LCMS M+1=822.0, tr=0.830 min. 
     Example 2-21: Synthesis of a mixture of 4-amino-N-(9-((2R,3R,5S,7aR,9R,10R,12R,14aR)-9-(6-amino-9H-purin-9-yl)-3,10-difluoro-5,12-dimercapto-5,12-dioxidooctahydro-2H,7H-difuro[3,2-d:3′,2′-j][1,3,7,9]tetraoxa[2,8]diphosphacyclododecin-2-yl)-9H-purin-6-yl)butanamide (CDNI-21a) and N-(9-((2R,3R,5R,7aR,9R,10R,12S,14aR)-9-(6-amino-9H-purin-9-yl)-3,10-difluoro-5,12-dimercapto-5,12-dioxidooctahydro-2H,7H-difuro[3,2-d:3′,2′-j][1,3,7,9]tetraoxa[2,8]diphosphacyclododecin-2-yl)-9H-purin-6-yl)-4-(methylamino)butanamide (CDNI-21b) 
     
       
         
         
             
             
         
       
     
     Step 1: NaH (60% dispersion in oil, 38.5 mg, 0.962 mmol) was added to a solution of Compound (T1-6) Et 3 N salt (86.3 mg, 0.096 mmol) in DMF (3 ml) and the mixture was stirred for 1 min before the addition of 4-((tert-butoxycarbonyl)amino)butanoic anhydride (347 mg, 0.894 mmol). The reaction was stirred at rt for 1 hr and then quenched with HOAc (0.2 ml). The reaction was concentrated and purified using reverse phase ISCO with 15 g C18 aq column, eluted with 5-45% acetonitrile-H 2 O (aqueous phase containing 10 mM Et 3 N HOAc). Fractions containing desired product were collected and lyophilized to obtain boc protected CDN intermediate (CDNI-21a) and boc protected CDN intermediate (CDNI-21b) as Et 3 N salt (20 mg, 19% yield). LCMS M+1=880.0, tr=0.782 min. The mixture was not separated. Note: 4-((tert-butoxycarbonyl)(methyl)amino)butanoic anhydride was synthesized as described in the synthesis of CDNI-4. 
     Step 2: To a flask containing boc protected CDN intermediate (CDNI-21a) and boc protected CDN intermediate (CDNI-21b) Et 3 N salt (20 mg, 0.018 mmol) was added acetonitrile (5 ml) and TFA (1 ml) and the mixture was stirred for 30 mins and then concentrated. The residue was purified by reverse phase ISCO using 15 g C18 column, eluted with 5-50% acetonitrile-H 2 O containing 0.05% TFA. Fractions containing desired product were concentrated to obtain a mixture of CDN intermediate (CDNI-21a) and CDN intermediate (CDNI-21b) as TFA salt (13.4 mg, 72% yield). LCMS M+1-H 2 O=762, tr=0.268 min. 
     Example 2-22: Synthesis of 4-((S)-2-((S)-2-amino-3-methylbutanamido)-5-ureidopentanamido)benzyl (2S,4S)-2-((((9-((2R,3R,3aR,5R,7aR,9R,10R,10aR,12S,14aR)-9-(6-amino-9H-purin-9-yl)-3,10-difluoro-5,12-dimercapto-5,12-dioxidooctahydro-2H,7H-difuro[3,2-d:3′,2′-j][1,3,7,9]tetraoxa[2,8]diphosphacyclododecin-2-yl)-9H-purin-6-yl)carbamoyl)oxy)methyl)-4-fluoropyrrolidine-1-carboxylate (CDNI-22a) and 4-((S)-2-((S)-2-amino-3-methylbutanamido)-5-ureidopentanamido)benzyl (2S,4S)-2-((((9-((2R,3R,3aR,5S,7aR,9R,10R,10aR,12R,14aR)-9-(6-amino-9H-purin-9-yl)-3,10-difluoro-5,12-dimercapto-5,12-dioxidooctahydro-2H,7H-difuro[3,2-d:3′,2′-j][1,3,7,9]tetraoxa[2,8]diphosphacyclododecin-2-yl)-9H-purin-6-yl)carbamoyl)oxy)methyl)-4-fluoropyrrolidine-1-carboxylate (CDNI-22b) 
     
       
         
         
             
             
         
       
     
     Step: Fmoc-Va-Cit-PABC-PNP (25.2 mg, 0.033 mmol) was added to a solution of CDN intermediate (CDNI-11a) and (CDNI-11b) (31.1 mg, 0.030 mmol) in DMF (1 ml), followed by the addition of DIEA (26.0 uL, 19.3 mg, 0.149 mmol) and HOAT (4.1 mg, 0.030 mmol). The reaction was stirred at rt overnight, water (1.0 mL) was then added and the solution concentrated. The residue was dissolved in DMSO and purified by ISCO by using 50.0 g C18 aq column, eluted with 5-60% ACN in water with 10 mM TEA-HOAc. Fractions containing desired product were concentrated to obtain compound Fmoc protected CDN intermediate (CDNI-22a and CDNI-22b) (42.2 mg, 80% yield) as TEA salt. LCMS M/2+1=734.30, tr=1.002 min. 
     Step 2: Piperidine (180.0 uL, 0.19 mmol) was added to a solution of Fmoc protected CDN intermediate (CDNI-22) (32.0 mg, 0.019 mmol) TEA salt in DMF (Volume: 3.0 mL) and the mixture was stirred at rt for 30 mins and then concentrated. The residue was purified by reverse phase ISCO 50 g C18 aq column, eluted with 5-35% acetonitrile-H 2 O containing 0.05% TFA. Fractions containing desired product were concentrated to obtain CDN intermediate (CDNI-22a and CDN22b) (20.0 mg, 67.8%) as TFA salt. LCMS M/2+1=623.3, tr=0.790 min. 
     Example 2-23: Synthesis of 2-(methylamino)ethyl (9-((1S,3R,6R,8R,9S,11R,14R,16R,17R,18R)-16-(6-amino-9H-purin-9-yl)-17,18-difluoro-3,11-dimercapto-3,11-dioxido-2,4,7,10,12,15-hexaoxa-3,11-diphosphatricyclo[12.2.1.16,9]octadecan-8-yl)-9H-purin-6-yl)carbamate (CDNI-23) 
     
       
         
         
             
             
         
       
     
     CDN intermediate (CDNI-23) was synthesized using the method described for the synthesis of CDN intermediate (CDNI-1) except Compound (T1-1) Et 3 N salt was replaced with Compound (T2-46) Et 3 N salt. 
     Boc-protected CDN intermediate (CDNI-23): LCMS M+1=796.0, tr=0.625 min.  1 H NMR (500 MHz, DMSO-d 6 ) δ 10.71 (s, 1H), 9.36 (d, J=6.1 Hz, 2H), 8.92 (s, 1H), 8.73 (s, 2H), 8.39 (s, 1H), 6.27 (dd, J=44.7, 8.4 Hz, 2H), 5.79-5.33 (m, 4H), 4.75-4.55 (m, 3H), 4.38 (s, 1H), 4.00 (dd, J=12.5, 5.4 Hz, 4H), 3.35 (dd, J=10.3, 6.4 Hz, 1H), 3.25 (s, 1H), 3.12 (tt, J=7.4, 3.7 Hz, 1H). 
     CDN intermediate (CDNI-23) TFA salt (8.2 mg, 55.0% yield). LCMS M+1=796.0, tr=0.625 min.  1 H NMR (500 MHz, DMSO-d 6 ) δ 10.71 (s, 1H), 9.36 (d, J=6.1 Hz, 2H), 8.92 (s, 1H), 8.73 (s, 2H), 8.39 (s, 1H), 6.27 (dd, J=44.7, 8.4 Hz, 2H), 5.79-5.33 (m, 4H), 4.75-4.55 (m, 3H), 4.38 (s, 1H), 4.00 (dd, J=12.5, 5.4 Hz, 4H), 3.35 (dd, J=10.3, 6.4 Hz, 1H), 3.25 (s, 1H), 3.12 (tt, J=7.4, 3.7 Hz, 1H). 
     Example 2-24: Synthesis of (2R,3R,3aR,5R,7aR,9R,10R,10aR,12S,14aR)-2-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)-9-(6-amino-9H-purin-9-yl)-10-fluoro-5,12-dimercapto-5,12-dioxidooctahydro-2H,7H-difuro[3,2-d:3′,2′-j][1,3,7,9]tetraoxa[2,8]diphosphacyclododecin-3-yl (2-(methylamino)ethyl) carbonate (CDNI-24) 
     
       
         
         
             
             
         
       
     
     CDN intermediate (CDNI-24) was synthesized using the method described for the synthesis of CDN intermediate (CDNI-3) except Compound (T1-2) Et 3 N salt was replaced with Compound (T1-13) Et 3 N salt. 
     Boc-protected CDN intermediate (CDNI-24): LCMS M+1=910.1, tr=0.731 min.  1 H NMR (500 MHz, Methanol-d 4 ) δ 8.46 (s, 1H), 8.20 (d, J=7.6 Hz, 2H), 6.36 (d, J=17.1 Hz, 1H), 6.07 (d, J=11.8 Hz, 1H), 5.77-5.56 (m, 2H), 5.34 (s, 1H), 5.24-5.04 (m, 1H), 4.60 (dt, J=12.3, 2.7 Hz, 1H), 4.42 (d, J=10.2 Hz, 3H), 4.32 (d, J=8.0 Hz, 3H), 4.08-3.95 (m, 2H), 3.64 (t, J=5.9 Hz, 5H), 3.58 (s, 2H), 3.03 (q, J=7.3 Hz, 31H), 2.96 (s, 4H), 2.92 (s, 9H), 1.22 (t, J=7.3 Hz, 42H). 
     CDN intermediate (CDNI-24) TFA salt (8.1 mg, 71.7% yield). LCMS M+1=810.2, tr=0.346 min.  1 H NMR (500 MHz, DMSO-d 6 ) δ 10.80 (s, 1H), 9.36 (d, J=42.0 Hz, 2H), 8.48 (d, J=45.8 Hz, 2H), 8.27 (s, 1H), 6.70 (s, 2H), 6.41 (d, J=16.4 Hz, 1H), 6.06 (d, J=7.3 Hz, 1H), 5.70-5.38 (m, 2H), 5.16 (dtd, J=26.2, 9.3, 4.6 Hz, 1H), 4.90 (ddd, J=11.5, 5.4, 2.9 Hz, 1H), 4.59 (ddd, J=12.9, 6.7, 2.4 Hz, 1H), 4.40 (dd, J=11.4, 5.3 Hz, 2H), 4.26 (ddd, J=17.0, 8.5, 5.9 Hz, 1H), 4.23-4.06 (m, 1H), 3.92-3.71 (m, 2H), 3.43-3.17 (m, 2H), 3.13 (td, J=7.3, 4.8 Hz, 1H), 2.67 (t, J=5.2 Hz, 3H). 
     Example 2-25: Synthesis (2R,3R,3aR,5R,7aR,9R,10R,10aS,12R,14aR)-2,9-bis(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)-10-hydroxy-5,12-dimercapto-5,12-dioxidooctahydro-2H,7H-difuro[3,2-d:3′,2′-j][1,3,7,9]tetraoxa[2,8]diphosphacyclododecin-3-yl (2-(methylamino)ethyl) carbonate (CDNI-25) 
     
       
         
         
             
             
         
       
     
     CDN intermediate (CDNI-24) was synthesized using the method described for the synthesis of CDN intermediate (CDNI-3) except Compound (T1-2) Et 3 N salt was replaced with Compound (T1-16) Et 3 N salt. 
     Boc-protected CDN intermediate (CDNI-25): LCMS M+1=924.2. tr=0.813 min. 
     CDN intermediate (CDNI-25) TFA salt (5.9 mg, 46.2% yield). LCMS M+1=824.0 tr=0.410 min.  1 H NMR (500 MHz, DMSO-d 6 ) δ 10.64 (d, J=12.1 Hz, 1H), 9.26 (d, J=105.9 Hz, 1H), 8.04 (d, J=5.7 Hz, 1H), 6.59 (s, 2H), 5.96 (d, J=7.8 Hz, 1H), 5.80-5.61 (m, 1H), 4.81 (ddd, J=72.1, 9.8, 4.4 Hz, 1H), 4.57-4.43 (m, 1H), 4.29-3.88 (m, 3H), 3.28-2.97 (m, 1H. 
     Example 2-26: Synthesis ((2R,3R,3aR,5R,7aR,9R,10R,10aR,12S,14aR)-2,9-bis(6-amino-9H-purin-9-yl)-10-fluoro-5,12-dimercapto-5,12-dioxidooctahydro-2H,7H-difuro[3,2-d:3′,2′-j][1,3,7,9]tetraoxa[2,8]diphosphacyclododecin-3-yl D-prolinate (CDNI-26) 
     
       
         
         
             
             
         
       
     
     Step 1: A solution of dicyclohexylcarbodiimide (0.51 eq) in 5 ml of anhydrous DCM is added under nitrogen drop wise, with stirring, to a solution of (R)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (purchased from Combi-Blocks) (2.152 g, 10 mmol) in anhydrous dichloromethane (45 ml). The solution was stirred for 150 min and the resulting urea precipitate was removed by filtration and the filtrate was concentrated to about 5 ml, and then filtered through syringe filter. The solvent was removed under vacuum to give (R)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic anhydride as a sticky oil (2.169 g, 100% yield). 
     Step 2: (R)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic anhydride (501 mg, 1.117 mmol) in NMP (3 mL) was added to Compound (T1-20) sodium salt (55 mg, 0.074 mmol) in pyridine (1.5 mL) and the mixture was stirred at rt for two days. n-Butylamine (0.1 mL) in water (1.0 mL) was then added and the mixture was stirred at rt for 10 mins. The pyridine and water were then removed under vacuum and the NMP was removed by lyophilization. The crude was purified by reverse phase ISCO using 50 g C18 aq column, eluted with 5-55% acetonitrile-H 2 O (aqueous phase containing 10 mM Et 3 N HOAc) to the boc-protected diadducts of CDN intermediate (CDNI-26). All diadducts were collected, dried by lyophilization. 
     Step 3: The boc-protected diadduct was dissolved in MeOH (5 mL) in a 30 mL pressure vessel equipped with a Teflon valve. The vessel was placed in an oil bath heated at 110° C. for 5 hours. Volatiles were evaporated, and the residues was purified by reverse phase ISCO using 50 g C18 aq. column, eluted with 5-55% acetonitrile-H 2 O (aqueous phase containing 10 mM Et 3 N HOAc). Fractions containing the desired product were combined and lyophilized to obtain boc-protected CDN intermediate (CDNI-26) as Et 3 N salt (18.9 mg). LCMS M+1=890.0, tr=0.722 min. 
     Step 4: To a vial containing boc-protected CDN intermediate (CDNI-26) Et 3 N salt (30.0 mg, 0.034 mmol) was added TFA (2 ml). The mixture was concentrated immediately and then concentrated. The crude was purified by reverse phase ISCO using 50 g C18 column, eluted with 5-40% acetonitrile-H 2 O (aqueous phase containing 10 mM Et 3 N HOAc). Fractions containing desired product were concentrated to obtain CDN intermediate (CDNI-26) as TEA salt (12.4 mg, 37.1% yield). LCMS M+1=790.1, tr=0.350 min. 
     Example 2-27: Synthesis of a mixture of CDN intermediate (CDNI-27a) and CDN intermediate (CDNI-27b) 
     
       
         
         
             
             
         
       
     
     The mixture of CDN Intermediate (CDNI-27a) and CDN Intermediate (CDNI-27b) was prepared using the methods described for the synthesis of intermediate (CDNI-3), except Compound (T1-56) was used in place of Compound (T1-2), the reaction mixture of step was stirred for 2 hours instead of 30 mins and in step 1 purification used 5-50% acetonitrile-H 2 O (aqueous phase containing 10 mM Et 3 N HOAc). 
     CDN Intermediate (CDNI-27a) and CDN Intermediate (CDNI-27b) as TEA salt (3.7 mg, 55.9% yield). LCMS M+1=822.0, tr=0.319 min. 
     Note: The mixture was not separated and 2-((tert-butoxycarbonyl)(methyl)amino)ethyl carbonochloridate was synthesized as described in the synthesis of CDNI-9 except the initial temperature was −30° C. instead of −15° C. 
     Example 2-28: Synthesis (2R,3R,3aR,5S,7aR,9R,10R,10aR,12R,14aR)-9-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)-2-(6-amino-9H-purin-9-yl)-10-fluoro-5,12-dimercapto-5,12-dioxidooctahydro-2H,7H-difuro[3,2-d:3′,2′-j][1,3,7,9]tetraoxa[2,8]diphosphacyclododecin-3-yl (2-(methylamino)ethyl) carbonate (CDNI-28) 
     
       
         
         
             
             
         
       
     
     CDN intermediate (CDNI-28) was synthesized using the method described for the synthesis of CDN intermediate (CDNI-3) except Compound (T1-2) Et 3 N salt was replaced with Compound (T1-11) Et 3 N salt, the reaction time in Step 2 was 2 hrs rather than 30 mins and purification of CDN intermediate (CDNI-28) was by reverse phase ISCO using 15 g C18 column, eluted with 5-40% acetonitrile-H 2 O (aqueous phase containing 10 mM Et 3 N HOAc). 
     Boc-protected CDN intermediate (CDNI-28) as Et 3 N salt (8.9 mg, 52.1% yield). LCMS M+1=910.1. tr=0.731 min. 
     CDN intermediate (CDNI-28) as TEA salt (6.5 mg, 62.4% yield). LCMS M+1=810.0 tr=0.350 min. 
     Example 2-29: Synthesis (2R,3R,3aR,7aR,9R,10R,10aR,14aR)-2-(6-((3-amino-2-hydroxypropyl)amino)-9H-purin-9-yl)-9-(6-amino-9H-purin-9-yl)-3,10-difluoro-5,12-dihydroxyoctahydro-2H,7H-difuro[3,2-d:3′,2′-j][1,3,7,9]tetraoxa[2,8]diphosphacyclododecine 5,12-dioxide (CDNI-29) 
     
       
         
         
             
             
         
       
     
     Step 1: To a solution of Compound (T1-1) Et 3 N salt (30 mg, 0.033 mmol) in DMF (3 ml) was added tert-butyl (oxiran-2-ylmethyl)carbamate (57.9 mg, 0.334 mmol) and DIEA (43.2 mg, 0.334 mmol). The mixture was heated to 100° C. for 4 hours and the solvent was removed. The crude product was purified by reverse phase ISCO using 50 g C18 aq column, eluted with 5-45% acetonitrile-H 2 O (aqueous phase containing 10 mM Et 3 N HOAc). Fractions containing boc protected CDN intermediate (CDNI-29) were isolated and lyophilized to obtain Boc protected CDN intermediate (CDNI-29) as Et 3 N salt (20 mg, 58% yield). LCMS M+1=836.0, tr=0.538 min. 
     Step 2: To a 25 ml round-bottom flask containing boc protected CDN intermediate (CDNI-29) Et 3 N salt (20 mg, 0.019 mmol) was added TFA (1 ml, 13 mmol). The mixture was stirred for 1 min and then concentrated. The residue was purified by reverse phase ISCO using 50 g C18 aq column, eluted with 5-35% acetonitrile-H 2 O (aqueous phase containing 10 mM Et 3 N HOAc). Fractions containing desired product were concentrated to obtain CDN intermediate (CDNI-29) as Et 3 N salt (11.1 mg, 62% yield). LCMS M+1=736.0, tr=0.235 min. 
     Example 3: Synthesis of Exemplary Linker-Drug Compounds 
     Example 3-1: Synthesis of Compound 12 (C12) 
     
       
         
         
             
             
         
       
     
     Step 1: 
     Compound (T1-2) (5 mg, 0.007 mmol) disodium salt was dissolved in anhydrous pyridine (1 ml) followed by the addition of Et 3 N (0.005 ml). The mixture was sonicated and then linker intermediate (LI-1) (30 mg, 0.068 mmol) was added. The reaction mixture was stirred for 30 mins at room temperature and monitored by LCMS. The mixture was concentrated and then dissolved in MeOH-water, followed by purification by mass triggered reverse phase HPLC, using C18 column, eluted with 5-55% acetonitrile-H 2 O containing 0.05% TFA. Fractions containing the desired boc-protected carbonate (2 mg, 22%) were collected LCMS M+1=1111.1, tr=0.898 min. 
     Step 2. 
     TFA (1 ml) was added to a vial containing the carbonate from step 1 (2 mg, 0.0015 mmol) and then immediately concentrated. The residue was then dissolved in MeOH and purified by ISCO using Ig C18 column, eluted with 5-50% ACN-water containing 0.05% TFA. Fractions containing the desired product were combined and lyophilized to give the de-protected carbonate (1.0 mg, 11% yield) as TFA salt. LCMS M/2+1=506.2, tr=0.669 min. 
     Step 3. 
     DIEA (15 mg, 0.116 mmol) and then HATU (3.4 mg, 0.0089 mmol) were added to a solution of 3-(2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethoxy)propanoic acid (Mal-PEG1-Acid) (1.9 mg, 0.0089 mmol) in DMF (1 ml) and the reaction mixture was stirred at room temperature for 5 mins. 10% of this reaction mixture was then added to a flask containing the de-protected carbonate obtained in step 2 (1.0 mg, 0.00089 mmol) in 0.5 ml DMF. The reaction was stirred at room temperature for 2 hours and then purified by mass-triggered reverse phase HPLC, using C18 column, eluted with 5-37% acetonitrile-H 2 O containing 0.05% TFA. The fractions containing desired product were concentrated to obtain Compound (C12) (0.7 mg, 57% yield) as TFA salt. LCMS M+1=1206.3, M/2+1=603.7, tr=0.784 min. 
     Example 3-2: Synthesis of Compound 13 (C13) 
     
       
         
         
             
             
         
       
     
     18-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-5,5,9,12-tetramethyl-8,13-dioxo-16-oxa-3,4-dithia-9,12-diazaoctadecyl (4-nitrophenyl) carbonate (LI-2) (2.5 mg, 0.0039 mmol) and DIEA (0.013 mmol) in DMF (1 ml) and the mixture was stirred at room temperature for 5 hours. The crude was purified by mass-triggered reverse phase HPLC, using C18 column, eluted with 20-33% acetonitrile-H2O containing 0.05% TFA. Fractions containing desired product were concentrated to compound A2 (2.2 mg, 38.1% yield) as TFA salt. LCMS M/2+1=654.2, tr=0.799 min. 
     Example 3-3: Synthesis of Compound 14 (C14) 
     
       
         
         
             
             
         
       
     
     CDN intermediate (CDNI-3) ((7.4 mg, 0.0073 mol) TFA salt was dissolved in anhydrous DMF (2 ml) and 4-((S)-2-((S)-2-(6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-8,13-yl)hexanamido)-3-methylbutanamido)-5-ureidopentanamido)benzyl (4-nitrophenyl) carbonate (MC-vc-pab PNP purchased from Levena Biopharma, San Diego) (6.3 mg, 0.009 mmol) was added, followed by addition of DIEA (11 mg, 0.084 mmol) and HOAT (4 mg, 0.029 mmol). The mixture was stirred at room temperature for 3 days and monitored by LCMS until completion of the reaction. The mixture was then purified by mass triggered reverse phase HPLC, using C18 column, eluted with 5-35% acetonitrile-H 2 O containing 0.05% TFA. Fractions containing the desired product were combined and concentrated to obtain Compound (C14) (3.6 mg, 25.8% yield) as a TFA salt. LCMS M/2+1=695.8, tr=0.783 min. 
     Example 3-4: Synthesis of Compound 15 (C15) 
     
       
         
         
             
             
         
       
     
     CDN intermediate (CDNI-4) (13.5 mg, 0.015 mmol) TFA salt in DMF was added to a solution of linker intermediate (LI-3) (10.5 mg, 0.015 mmol, 1.0 equiv), followed by the addition of DIEA (7.75 mg, 0.060 mmol) and HOAT (2.45 mg, 0.018 mmol). The mixture was stirred at room temperature for 16 hrs and then concentrated. The residue was dissolved in DMSO and purified by ISCO by using 15.5 gram, C18 aq column, eluted with 5-40% ACN in water with 10 mM TFA-HOAc. Fractions containing desired product were concentrated to obtain Compound (C15) (12.2 mg, 50% yield) as TEA salt. M+1=1346.20, tr=0.732 min. 
     Example 3-5: Synthesis of Compound 16 (C16) 
     
       
         
         
             
             
         
       
     
     Compound (C16) was synthesized using the methods describe for the synthesis of Compound (C15), except CDN intermediate (CDNI-5) TFA salt was used in place of CDN intermediate (CDNI-4). 
     Compound (C16) (7.6 mg, 31.3% yield) as TFA salt. LCMS M/2+1=681.8, tr=1.025 min. 
     Example 3-6: Synthesis of Compound 17 (C17) 
     
       
         
         
             
             
         
       
     
     TEA (6.7 mg, 0.066 mmol) and HATU (5.0 mg, 0.013 mmol) was added to a solution of 3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propanoic acid (2.2 mg, 0.013 mmol)) in DMF (1 mL) and the mixture was stirred for 5 mins. CDN intermediate (CDNI-3) (15 mg, 0.013 mmol) in DMF (1 ml) was then added and the mixture was stirred for 18 hrs at room temperature and then concentrated. The residue was dissolved in DMSO (2 ml) and then purified by mass triggered reverse phase HPLC, using C18 column, eluted with 5-25% acetonitrile-H2O containing 0.05% TFA. Fractions containing desired product were lyophilized to obtain Compound (C17) (14.3 mg, 88% yield) as TFA salt. LCMS M+1=943.1 tr=0.561 min. 
     Example 3-7: Synthesis of Compound 18 (C18) 
     
       
         
         
             
             
         
       
     
     CDN intermediate (CDNI-3) (20 mg, 0.018 mmol), DIEA (23 mg, 0.18 mmol) and HOAT (2.4 mg, 0.018 mmol) were added to a solution of linker intermediate (LI-3) (13.5 mg, 0.019 mmol) in DMF (1 mL) and the mixture was stirred for 18 hours at room temperature and then concentrated. The residue was dissolved in DMSO (2 ml) and then was pre-purified by ISCO using 15.5 g C18 column, eluted with 5-35% ACN-water containing 0.05% TFA. Fractions containing the desired product were combined and then purified by mass triggered reverse phase HPLC, C18 column, eluted with 10-30% acetonitrile-H 2 O containing 0.05% TFA. Fractions containing the desired product were combined, and lyophilized to obtain Compound (C18) (12.3 mg, 39.8% yield) as TFA salt. LCMS M+1=1348.2, M/2+1=674.8, tr=0.842 min. 
     Example 3-8: Synthesis of Compound 1 (C1) 
     
       
         
         
             
             
         
       
     
     Linker intermediate (LI-3) (36.7 mg, 0.053 mmol) was added to a solution of CDN intermediate (CDNI-1) (60 mg, 0.053 mmol) in DMF (5 ml), followed by the addition of DIEA (68.2 mg, 0.527 mmol) and HOAT (7.2 mg, 0.053 mmol). The mixture was stirred at room temperature for 16 hrs and then concentrated. The residue was dissolved in DMSO and pre-purified by ISCO by using 15.5 g C18 aq column, eluted with 5-35% ACN in water with 0.05% TFA. After purification, fractions were concentrated and then purified by mass triggered reverse phase HPLC, C18 column, eluted with 5-33% acetonitrile-H2O containing 0.05% TFA. Fractions containing desired product were concentrated to obtain Compound (C1) (55.4 mg, 68.1% yield) as TFA salt. LCMS M/2+1=676.8, M+1=1352.3, tr=0.753 min.  1 H NMR (500 MHz, DMSO-d 6 ) δ 10.01 (s, 1H), 9.42 (b, 1H), 8.56 (d, J=15.2 Hz, 1H), 8.31 (s, 1H), 8.16 (dd, J=13.1, 7.4 Hz, 1H), 8.04 (d, J=8.4 Hz, 1H), 7.62 (d, J=8.1 Hz, 1H), 7.48 (d, J=8.0 Hz, 1H), 7.32 (d, J=8.1 Hz, 1H), 7.18 (s, 1H), 7.02 (s, 2H), 6.43 (d, J=16.6 Hz, 2H), 6.18 (s, 2H), 5.61 (s, 1H), 5.50 (s, 1H), 5.13 (m, 3H), 5.02 (s, 1H), 4.93 (s, 1H), 4.55-4.34 (m, 6H), 4.27 (t, J=5.3 Hz, 2H), 4.19 (dd, J=8.5, 6.7 Hz, 1H), 3.87 (d, J=12.1 Hz, 2H), 3.63 (q, J=7.0, 6.6 Hz, 2H), 3.54 (s, 2H), 3.19-2.88 (m, 5H), 2.48 (q, J=7.4 Hz, 1H), 2.07-1.94 (m, 1H), 1.75 (m, 1H), 1.65 (m, 1H), 1.46 (m, 3H), 0.87 (dd, J=13.9, 6.8 Hz, 6H). 
     Example 3-9: Synthesis of Compound 2 (C2) 
     
       
         
         
             
             
         
       
     
     TEA (1.3 mg, 0.013 mmol) and HATU (5 mg, 0.013 mmol) were added to a solution of 3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propanoic acid (2.2 mg, 0.013 mmol) in DMF (1 mL) and the mixture was stirred for 5 mins. A solution of CDN intermediate (CDNI-1) TFA salt (15 mg, 0.013 mmol) in DMF (1 ml) was then added and the mixture was stirred for 18 hrs at room temperature and then concentrated. The residue was dissolved in DMSO (2 ml) and then purified by mass triggered reverse phase HPLC using C18 column, eluted with 5-25% acetonitrile-H 2 O containing 0.05% TFA. Fractions containing desired product were lyophilized to obtain Compound (C2) (8.7 mg, 59% yield) as TFA salt. LCMS M+1=947.1, tr=0.646 min. 
     Example 3-10: Synthesis of Compound 3 (C3) 
     
       
         
         
             
             
         
       
     
     Compound (C3) was synthesized using the methods describe for the synthesis of Compound (C2), except linker intermediate (LI-4) was used in place of 3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propanoic acid. 
     Compound (C3) (4.5 mg, 26% yield) as TFA salt. LCMS M+1=1243.3, tr=0.924 min. 
     Example 3-11: Synthesis of Compound 4 (C4) 
     
       
         
         
             
             
         
       
     
     Compound (C4) was synthesized using the methods describe for the synthesis of Compound (C2), except bis(perfluorophenyl) 3,3′-oxydipropionate (purchased from Broadpharm, San Diego) was used in place of 3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propanoic acid. Compound (C4) (10.5 mg, 46.5% yield) as TFA salt. LCMS M+1=1106.0, tr=0.930 min. 
     Example 3-12: Synthesis of Compound 5 (C5) 
     
       
         
         
             
             
         
       
     
     Step 1: DIEA (0.033 mL, 0.186 mmol) was added to a solution of CDN intermediate (CDNI-2) (26.6 mg, 0.019 mmol) and 2,5-dioxopyrrolidin-1-yl 2-(((((9H-fluoren-9-yl)methoxy)carbonyl)amino)oxy)acetate (15.28 mg, 0.037 mmol) in DMF (1 ml). The mixture was stirred at room temperature for 1 h and then concentrated. The residue was purified by reverse phase ISCO C18 50 g column, eluted with 10-50% acetonitrile-H 2 O aqueous containing 10 mM HOAc Et 3 N. Fractions containing desired product were concentrated to obtain 4-((95,125)-1-(9H-fluoren-9-yl)-9-isopropyl-3,7,10-trioxo-12-(3-ureidopropyl)-2,5-dioxa-4,8,11-triazatridecan-13-amido)benzyl (2-(((9-((2R,3R,3aR,5R,7aR,9R,10R,10aR,12R,14aR)-9-(6-amino-9H-purin-9-yl)-3,10-difluoro-5,12-dimercapto-5,12-dioxidooctahydro-2H,7H-difuro[3,2-d:3′,Z-j][1,3,7,9]tetraoxa[2,8]diphosphacyclododecin-2-yl)-9H-purin-6-yl)carbamoyl)oxy)ethyl)(methyl)carbamate (6 mg, 25% yield) as Et 3 N salt. LCMS M/2+1=748.8, tr=0.966 min. 
     Step 2: 44(95,125)-1-(9H-fluoren-9-yl)-9-isopropyl-3,7,10-trioxo-12-(3-ureidopropyl)-2,5-dioxa-4,8,11-triazatridecan-13-amido)benzyl (2-(((9-((2R,3R,3aR,5R,7aR,9R,10R,10aR,12R,14aR)-9-(6-amino-9H-purin-9-yl)-3,10-difluoro-5,12-dimercapto-5,12-dioxidooctahydro-2H,7H-difuro[3,2-d:3′,2′-j][1,3,7,9]tetraoxa[2,8]diphosphacyclododecin-2-yl)-9H-purin-6-yl)carbamoyl)oxy)ethyl)(methyl)carbamate (6.0 mg, 0.0035 mmol) triethylammonium salt was dissolved in ACN (2 ml) and water (2 ml) and LiOH (20 mg) was added. The mixture was stirred at room temperature for 4 hrs, neutralized with HOAc (0.06 ml) and then concentrated. The residue was purified by reverse phase ISCO 15.5 g C18 aq column, eluted with 5-40% acetonitrile-H 2 O containing 0.05% TFA. Fractions containing desired product were concentrated to obtain Compound (C5) (2.8 mg, 36.9% yield) as TFA salt. LCMS M/2+1=637.8 tr=0.676 min. 
     Example 3-13: Synthesis of Compound 6 (C6) 
     
       
         
         
             
             
         
       
     
     Compound (C6) was synthesized using the methods describe for the synthesis of Compound (C14), except CDN intermediate (CDNI-1) was used in place of CDN intermediate (CDNI-3). Compound (C6) (1.2 mg, 24% yield) as TFA salt. LCMS M/2+1=697.8, M+1=1394.5, tr=0.782 min. 
     Example 3-14: Synthesis of Compound 7 (C7) 
     
       
         
         
             
             
         
       
     
     Compound (C7) was synthesized using the methods describe for the synthesis of Compound (C4), except CDN intermediate (CDNI-2) was used in place of CDN intermediate (CDNI-1). Compound (C7) (5.3 mg, 55.3% yield) as TFA salt. LCMS M/2+1=756.3, tr=0.975 min. 
     Example 3-15: Synthesis of Compound 8 (C8) 
     
       
         
         
             
             
         
       
     
     DIEA (0.01 ml, 0.056 mmol) was added to a solution of CDN intermediate (CDNI-2) (8 mg, 0.0056 mmol) and bis(2,5-dioxopyrrolidin-1-yl) 3,3′-oxydipropionate (5.98 mg, 0.017 mmol) ((Bis-PEG1-NHS ester purchased from Broadpharm, San Diego) in DMF (1 ml). The mixture was stirred at room temperature for 2 hours and then concentrated. The residue was purified by mass triggered reverse phase HPLC, using C18 column, eluted with 10-33% acetonitrile-H 2 O containing 0.05% TFA. Fractions containing desired product were lyophilized to obtain Compound (C8) (5.7 mg, 62.2% yield) as TFA salt. LCMS M/2+1=721.8, tr=0.755 min. 
     Example 3-16: Synthesis of Compound 9 (C9) 
     
       
         
         
             
             
         
       
     
     Compound (C9) was synthesized using the methods describe for the synthesis of Compound (C1), except linker intermediate (LI-5) was used in place of linker intermediate (LI-3). Compound (C9) (6.8 mg, 52.6% yield) as TFA salt. LCMS M/2+1=698.8, tr=0.758 min. 
     Example 3-17: Synthesis of Compound 10 (C10) 
     
       
         
         
             
             
         
       
     
     Compound (C10) was synthesized using the methods describe for the synthesis of Compound (C1), except linker intermediate (LI-2) was used in place of linker intermediate (LI-3). 
     Compound (C10) (7.3 mg, 55.3% yield) as TFA salt. LCMS M+1=1311.2, M/2+1=656.2, tr=0.845 min. 
     Example 3-18: Synthesis of Compound 11 (C11) 
     
       
         
         
             
             
         
       
     
     Compound (C11) was synthesized using the methods describe for the synthesis of Compound (C1), except 1-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-3,6,9,12-tetraoxapentadecan-15-oic acid (MPEG4-acid purchased from Broadpharm, San Diego) was used in place of linker intermediate (LI-3). 
     Compound (C11) 10.9 mg (37.6% yield) LCMS M+1=1123.1, tr=0.722 min. 
     Example 3-19: Synthesis of Compound 19 (C19) 
     
       
         
         
             
             
         
       
     
     Compound (C19) was synthesized using the methods describe for the synthesis of Compound (C2), except CDN intermediate (CDNI-10) was used in place of CDN intermediate (CDNI-1) and 4-((S)-2-((S)-2-(6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanamido)-3-methylbutanamido)-5-ureidopentanamido)benzyl (4-nitrophenyl) carbonate (MC-vc-pab-PNP purchased from Levena Biopharma, San Diego) was used in place of 3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propanoic acid. 
     Compound (C19) (1.1 mg, 20% yield) as TFA salt. LCMS M/2+1=675.8 tr=0.776 min. 
     Example 3-20: Synthesis of Compound 20 (C20) 
     
       
         
         
             
             
         
       
     
     Compound (C20) was synthesized using the methods describe for the synthesis of Compound (C1), except CDN intermediate (CDNI-6) was used in place of CDN intermediate (CDNI-1). Compound (C20) (4.2 mg, 30% yield) as TFA salt. LCMS M/2+1=675.8, M+1=1350.3, tr=0.751 min. 1H NMR (500 MHz, DMSO-d6) δ 9.99 (s, 1H), 9.28 (s, 2H), 8.98 (s, 3H), 8.14 (d, J=7.4 Hz, 2H), 8.04 (d, J=8.3 Hz, 2H), 7.99 (s, 1H), 7.64 (d, J=8.2 Hz, 2H), 7.36 (d, J=8.1 Hz, 2H), 7.03 (s, 2H), 6.49 (d, J=46.4 Hz, 2H), 6.03 (s, 1H), 5.70 (d, J=49.8 Hz, 2H), 5.21-4.83 (m, 5H), 4.68-4.32 (m, 9H), 4.28-4.13 (m, 2H), 3.13 (qd, J=7.3, 4.9 Hz, 2H), 3.02 (d, J=11.7 Hz, 6H), 1.97 (dt, J=12.7, 6.2 Hz, 1H), 1.86-1.55 (m, 2H), 1.45 (d, J=32.2 Hz, 2H), 1.31-1.11 (m, 4H), 0.86 (dd, J=16.0, 6.7 Hz, 8H). 
     Example 3-21: Synthesis of Compound 21 (C21) 
     
       
         
         
             
             
         
       
     
     Compound (C21) was synthesized using the methods describe for the synthesis of Compound (C1), except CDN intermediate (CDNI-7) was used in place of CDN intermediate (CDNI-1). Compound (C21) (12.2 mg, 50% yield) as TEA salt. M+1=1348.20, tr=0.721 min. 
     Example 3-22: Synthesis of Compound 22 (C22) 
     
       
         
         
             
             
         
       
     
     Compound (C22) was synthesized using the methods describe for the synthesis of Compound (C19), except CDN intermediate (CDNI-8) was used in place of CDN intermediate (CDNI-10). Compound (C22) (0.9 mg, 34.1% yield) as TFA salt. LCMS M/2+1=695.8, M+1=1391, tr=0.695 min. 
     Example 3-23 
     Synthesis of Compound 23a (C23a) 
     
       
         
         
             
             
         
       
     
     Compound (C23a) was synthesized using the methods describe for the synthesis of Compound (C1), except CDN intermediate (CDNI-9) was used in place of CDN intermediate (CDNI-1). Compound (C23a) (12.7 mg, 51.7% yield) as TFA salt. LCMS M/2+1=676.7, tr=0.700 min. 
     b) Synthesis of Compound 23b (C23b) 
     
       
         
         
             
             
         
       
     
     Compound (23b) was obtained during the synthesis of Compound (23a). Compound (C23a) and Compound (23b) were not separated. (12.7 mg, 51.7% yield) as TFA salt. LCMS M/2+1=676.7, tr=0.700 min. 
     Example 3-24: Synthesis of Compound 24 (C24) 
     
       
         
         
             
             
         
       
     
     HATU (1.9 mg, 0.005 mmol) was added to a mixture of (Z)-6-(((1-ethoxyethylidene)amino)oxy)hexanoic acid (1.2 mg, 0.0056 mmol) and DIEA (2.2 mg, 0.017 mmol) in DMF (1 ml). The mixture was then stirred at room temperature for 5 min and then added to a solution of CDN intermediate (CDNI-2) (4 mg, 0.0028 mmol) in DMF (1 ml). The mixture was then stirred for 5 hours at room temperature for 16 hours and then concentrated to give the protected derivative ethyl (Z)-N-((6-(((S)-1-(((S)-1-((4-((((2-(((9-((2R,3R,3aR,5R,7aR,9R,10R,10aR,12R,14aR)-9-(6-amino-9H-purin-9-yl)-3,10-difluoro-5,12-dimercapto-5,12-dioxidooctahydro-2H,7H-difuro[3,2-d:3′,2′-j][1,3,7,9]tetraoxa[2,8]diphosphacyclododecin-2-yl)-9H-purin-6-yl)carbamoyl)oxy)ethyl)(methyhcarbamoyl)oxy)methyl)phenyl)amino)-1-oxo-5-ureidopentan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)amino)-6-oxohexyl)oxy)acetimidate. LCMS M/2+1=700.8, tr=0.890 min. 
     Purification of the residue by reverse phase HPLC, ISCO C18 50 g column, eluted with 10-50% acetonitrile-H 2 O containing 0.05% TFA resulted in loss of the protecting group. Fractions containing desired product Compound (C-24) were concentrated further purified by reverse phase ISCO C18 column, eluted with 5-40% acetonitrile-H 2 O containing 0.05% TFA to obtain Compound (C-24) (2.2 mg, 47.9% yield) as TFA salt. LCMS M/2+1=665.8, tr=0.697 min. 
     Note: Z)-6-(((1-ethoxyethylidene)amino)oxy)hexanoic acid was prepared from ethyl-(N-hedroxyacetimidate and 6-bromohexanoic acid in the presence of LiOH using the method described in Biomacromolecules 6(5) 2648, 2005. 
     Example 3-25 
     a) Synthesis of Compound 25a (C25a) 
     
       
         
         
             
             
         
       
     
     Compound (C25a) was synthesized using the methods describe for the synthesis of Compound (C1), except CDN intermediate (CDNI-11) was used in place of CDN intermediate (CDNI-1). Compound (C25a) (7.5 mg, 37.1% yield) as TFA salt. LCMS M/2+1=698.8, tr=0.715 min. 
     b) Synthesis of Compound 25b (C25b) 
     
       
         
         
             
             
         
       
     
     Compound (25b) was obtained during the synthesis of Compound (25a). Compound (C23a) and Compound (25b) were not separated. (7.5 mg, 37.1% yield) as TFA salt. LCMS M/2+1=698.8, tr=0.715 min 
     Example 3-26: Synthesis of Compound 26 (C26) 
     
       
         
         
             
             
         
       
     
     DIEA (0.019 mL, 0.110 mmol) and HATU (9.2 mg, 0.024 mmol) were added to a solution of 1-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-3,6,9,12-tetraoxapentadecan-15-oic acid (Mal-PEG4-acid) (8.4 mg, 0.024 mmol) in DMF (1 ml) and the mixture was stirred for 5 mins and then added a solution of CDN intermediate (CDNI-7) (25 mg, 0.022 mmol) in DMF (1 ml). The reaction was then stirred at room temperature for 16 hrs and then concentrated. The residue was purified by reverse phase ISCO C18 column, eluted with 5-40% acetonitrile-H 2 O with the aqueous phase containing 10 mM Et 3 N HOAc. Fractions containing desired product were lyophilized to obtain Compound (C-26) (23.2 mg, 76% yield) as TEA salt. LCMS M+1=1121.1 tr=0.733 min. 1H NMR (500 MHz, DMSO-d 6 ) δ 8.66 (d, J=3.7 Hz, 2H), 7.96-7.75 (m, 2H), 7.06 (s, 2H), 6.32 (d, J=14.0 Hz, 1H), 6.26 (d, J=3.1 Hz, 1H), 5.81 (t, J=5.8 Hz, 1H), 5.63 (d, J=52.4 Hz, 1H), 5.24-5.00 (m, 2H), 4.58-4.26 (m, 6H), 3.89-3.72 (m, 3H), 3.72-3.63 (m, 2H), 3.64-3.54 (m, 3H), 3.54-3.47 (m, 12H), 3.16 (s, 2H), 3.01 (q, J=7.2 Hz, 15H), 2.95 (s, 1H), 2.74-2.61 (m, 2H), 1.94 (s, 1H), 1.13 (t, J=7.2 Hz, 21H). 
     Example 3-27: Synthesis of Compound 27 (C27) 
     
       
         
         
             
             
         
       
     
     Compound (C27) was synthesized using similar methods describe for the synthesis of Compound (C15), except CDN intermediate (CDNI-12) was used in place of CDN intermediate (CDNI-4) and the C18 column was eluted with 5-50% acetonitrile-H 2 O (aqueous phase containing 10 mM Et 3 N HOAc). Fractions containing the desired product were concentrated to obtain Compound (C27) as Et 3 N salt (1 mg, 11% yield). LCMS M/2+1=675.8, tr=0.758 min. 
     Example 3-28: Synthesis of Compound 28 (C28) 
     
       
         
         
             
             
         
       
     
     Compound (C28) was synthesized using similar methods describe for the synthesis of Compound (C15), except CDN intermediate (CDNI-13) was used in place of CDN intermediate (CDNI-4). Compound (C28) (5.8 mg, 30% yield). LCMS M/2+1=668.8, tr=0.724 min. 
     Example 3-29: Synthesis of Compound 29 (C29) 
     
       
         
         
             
             
         
       
     
     2,5-dioxopyrrolidin-1-yl 3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propanoate (purchased from Combi-Blocks)(0.5 mg, 0.002 mmol) and DIEA (1.7 mg, 0.013 mmol) were added to a solution of intermediate CDNI-15 TFA salt (1.7 mg, 0.0013 mmol) in DMF (1 ml) and the reaction was stirred at rt for 72 hrs and then concentrated. The crude was purified by reverse phase ISCO using 15 g C18 aq column, eluted with 5-40% acetonitrile-H 2 O (aqueous phase containing 10 mM Et 3 N HOAc). Fractions containing desired product were concentrated to obtain Compound 29 (C29) as an Et 3 N salt (2.3 mg, 111% yield). LCMS M+1=1187.1, tr=0.675 min. 
     Example 3-30: Synthesis of Compound 30 (C30) 
     
       
         
         
             
             
         
       
     
     Compound (C30) was synthesized using similar methods describe for the synthesis of Compound (C29), except CDN intermediate (CDNI-16) was used in place of CDN intermediate (CDNI-15), the reaction mixture was stirred for 16 hrs and the crude was purified by reverse phase ISCO with 50 g C18 aq column and eluted with 5-35% acetonitrile-water (aqueous phase containing 10 mM Et 3 N HOAc). Fractions with the desired product were combined and lyophilized to give Compound 30 (C30) as Et 3 N salt (3.8 mg, 14% yield). LCMS M/2+1=680.2, tr=0.705 min. 
     Example 3-31: Synthesis of Compound 31 (C31) 
     
       
         
         
             
             
         
       
     
     Compound (C31) was synthesized using the methods describe for the synthesis of Compound (C1), except CDN intermediate (CDNI-17) TFA salt was used in place of CDN intermediate (CDNI-1), the reaction was stirred at rt for 20 hours and purification was by ISCO using 15.5 C18 aq column, eluted with 5-40% acetonitrile-H 2 O containing 10 mM Et 3 N-HOAc. Fractions containing desired product were concentrated to obtain Compound 31 (C31) (4.3 mg, 76% yield) as TEA salt. LCMS M/2+1=698.8, tr=0.800 min. 
     Example 3-32: Synthesis of Compound 32 (C32) 
     
       
         
         
             
             
         
       
     
     A solution of CDN intermediate (CDNI-18) Et 3 N salt (20 mg, 0.022 mmol) and 1-(prop-2-yn-1-yl)-1H-pyrrole-2,5-dione (11.7 mg, 0.087 mmol) in 1:2 mixture of water-t-BuOH (4.5 ml) was degassed with N2, and a degassed solution of sodium L-ascobate (21.5 mg, 0.109 mmol) in water was added, followed by a degassed solution CuSO 4  (10.4 mg, 0.065 mmol) in water. The reaction mixture was stirred at rt for 1 hr and then lyophilized. The crude was purified by reverse phase ISCO using 50 g C18 column, eluted with 10-30% acetonitrile-H 2 O (aqueous phase containing 10 mM Et 3 N HOAc). Fractions containing the desired product were combined and lyophilized and repurify with reverse phase ISCO using 50 g C18 column, eluted with 10-30% acetonitrile-H 2 O containing 0.05% TFA. Fractions containing desired product were lyophilized to obtain Compound 32 (C32) as TFA salt (1.9 mg, 6% yield). LCMS M+1=943.0, tr=0.725 min. 
     Example 3-33: Synthesis of Compound 33 (C33) 
     
       
         
         
             
             
         
       
     
     Compound (C33) was synthesized using the methods describe for the synthesis of Compound (C32), except CDN intermediate (CDNI-19) TFA salt was used in place of CDN intermediate (CDNI-18). Compound (C33) TFA salt (2.7 mg, 10% yield). LCMS M+1=941.0, tr=0.725 min. 
     Example 3-34: Synthesis of Compound 34 (C34) 
     
       
         
         
             
             
         
       
     
     Compound (C34) was synthesized using the methods describe for the synthesis of Compound (C32), except CDN intermediate (CDNI-20) TFA salt was used in place of CDN intermediate (CDNI-18). LCMS M+1=957.1, tr=0.693 min. 
     Example 3-35: Synthesis of Compound 35 (C35) 
     
       
         
         
             
             
         
       
     
     Compound (C35) was synthesized using the methods describe for the synthesis of Compound (C1), except CDN intermediate (CDNI-10) TFA salt was used in place of CDN intermediate (CDNI-1), the reaction was stirred at rt for 1 day and purification was reverse phase ISCO using C18 column, eluted with 5-35% acetonitrile-H 2 O (aqueous phase containing 10 mM Et 3 N HOAc). Fractions containing desired product were concentrated to obtain Compound 35 (C35) as Et 3 N salt (4.0 mg, 120% yield). LCMS M+1=1308.1, tr=0.761 min. 
     Example 3-36: Synthesis of a Mixture of Compound 36a (C36a) and Compound 36b (C36b) 
     
       
         
         
             
             
         
       
     
     The mixture of Compound 36a (C36a) and Compound 36b (C36b) was obtained using the methods describe for the synthesis of Compound (C1), except the mixture of CDN intermediates (CDNI-21a) and (CDNI-21b) TFA salt was used in place of CDN intermediate (CDNI-1), and an initial purification was by reverse phase ISCO using 15 g C18 column, eluted with 5-45% acetonitrile-H 2 O (aqueous phase containing 10 mM Et 3 N HOAc). Fractions containing desired product were concentrated and further purified by reverse phase ISCO by using 50 g C18 aq column, eluted with 5-35% acetonitrile-water with 0.05% TFA. Fractions containing desired product were concentrated and lyophilized to obtain to obtain the mixture of Compound 36a (C36a) and Compound 36b (C36b) as TFA salt (8.3 mg, 41% yield). LCMS M+1=1336.1, tr=0.799 min. 
     Example 3-37: Synthesis of a Mixture of Compound 37a (C37a) and Compound 37b (C367b) 
     
       
         
         
             
             
         
       
     
     DIEA (11.0 mg, 0.086 mmol) was added to a solution of CDN intermediate (CDNI-22a and CDI-22b) (12.6 mg, 0.0086 mmol) and bis(perfluorophenyl) 3,3′-oxydipropionate (Bis-PEG1-PFP ester purchased from Broadpharm) (12.7 mg, 0.026 mmol) in DMF (1 ml). The reaction was stirred at rt for 2 hours and then concentrated. The residue was purified by reverse phase ISCO by using 30 g C18 aq column, eluted with 5-100% acetonitrile-water with 0.05% TFA. Fractions containing desired product were concentrated and lyophilized to obtain mixture of Compound 37a and 37b (C37a and C37b) as TFA salt (6.2 mg, 38.6% yield). LCMS M/2+1=778.3, tr=0.974 min. 
     Example 3-38: Synthesis of Compound 38 (C38) 
     
       
         
         
             
             
         
       
     
     Compound (C38) was synthesized using similar methods describe for the synthesis of Compound (C15), except CDN intermediate (CDNI-12) was used in place of CDN intermediate (CDNI-23) and the C18 column was eluted with 5-50% acetonitrile-H 2 O (aqueous phase containing 10 mM Et 3 N HOAc). Fractions containing the desired product were concentrated to obtain Compound (C38) as Et 3 N salt (11.6 mg, 88% yield) as Et 3 N salt. LCMS M/2+1=676.8, tr=0.742 min.  1 H NMR (500 MHz, DMSO-d 6 ) δ 10.80 (s, 1H), 9.99 (s, 1H), 9.37 (s, 1H), 8.97 (s, 1H), 8.68 (s, 1H), 8.23 (s, 1H), 8.13 (d, J=7.5 Hz, 1H), 8.04 (d, J=8.4 Hz, 1H), 7.62 (t, J=10.0 Hz, 2H), 7.44 (s, 2H), 7.34 (t, J=9.9 Hz, 2H), 7.03 (s, 1H), 6.27 (d, J=8.8 Hz, 1H), 6.17 (d, J=8.8 Hz, 1H), 6.02 (s, 1H), 5.72-5.55 (m, 1H), 5.55-5.39 (m, 3H), 5.05 (s, 1H), 4.54 (ddd, J=27.3, 20.2, 2.4 Hz, 2H), 4.41 (td, J=8.1, 5.2 Hz, 1H), 4.31 (s, 2H), 4.19 (dd, J=8.5, 6.7 Hz, 1H), 4.05-3.91 (m, 3H), 3.72-3.60 (m, 1H), 3.59 (d, J=5.9 Hz, 2H), 3.11-3.02 (m, 1H), 3.00 (d, J=9.6 Hz, 3H), 2.80 (qd, J=13.5, 6.4 Hz, 16H), 2.52-2.42 (m, 1H), 1.94 (s, 3H), 1.73 (s, 1H), 1.69-1.57 (m, 1H), 1.52-1.34 (m, 2H), 1.02 (t, J=7.2 Hz, 20H), 0.86 (dd, J=15.8, 6.8 Hz, 5H). 
     Example 3-39: Synthesis of Compound 39 (C39) 
     
       
         
         
             
             
         
       
     
     Compound (C39) was synthesized using similar methods describe for the synthesis of Compound (C18), except CDN intermediate (CDNI-24) was used in place of CDN intermediate (CDNI-3) and the C18 column was eluted with 5-40% acetonitrile-H 2 O (aqueous phase containing 10 mM Et 3 N HOAc). Fractions containing the desired product were concentrated to obtain Compound (C39) as Et 3 N salt: (4.9 mg, 41.6% yield). LCMS M/2+1=683.8, tr=0.709 min.  1 H NMR (500 MHz, DMSO-d 6 ) δ 9.99 (s, 1H), 8.35 (s, 1H), 8.21 (s, 1H), 8.17-7.99 (m, 3H), 7.68-7.52 (m, 2H), 7.33 (s, 5H), 7.03 (s, 2H), 6.57 (s, 2H), 6.30 (d, J=16.6 Hz, 1H), 6.02 (dd, J=55.5, 30.4 Hz, 2H), 5.60 (dd, J=52.2, 3.8 Hz, 1H), 5.42 (d, J=30.9 Hz, 3H), 5.01 (d, J=12.8 Hz, 2H), 4.39 (d, J=12.6 Hz, 2H), 4.30 (d, J=10.7 Hz, 4H), 4.27-4.06 (m, 4H), 3.92-3.74 (m, 2H), 3.69-3.50 (m, 3H), 3.14-2.83 (m, 5H), 2.69 (q, J=7.2 Hz, 33H), 1.86-1.56 (m, 1H), 1.56-1.31 (m, 2H), 1.05 (t, J=7.2 Hz, 44H), 0.86 (dd, J=15.5, 6.8 Hz, 6H). 
     Example 3-40: Synthesis of Compound 40 (C40) 
     
       
         
         
             
             
         
       
     
     Compound (C40) was synthesized using similar methods describe for the synthesis of Compound (C18), except CDN intermediate (CDNI-25) was used in place of CDN intermediate (CDNI-3). Compound (C40) as Et 3 N salt: (8.0 mg, 74% yield). LCMS M/2+1=690.8, tr=0.771 min.  1 H NMR (500 MHz, DMSO-d 6 ) δ 10.02 (s, 1H), 8.14 (d, J=7.5 Hz, 1H), 8.04 (t, J=8.9 Hz, 3H), 7.63 (d, J=8.0 Hz, 2H), 7.33 (d, J=9.4 Hz, 2H), 7.03 (s, 2H), 6.71 (d, J=67.7 Hz, 5H), 6.03 (s, 2H), 5.78 (d, J=7.4 Hz, 1H), 5.59 (s, 1H), 5.45 (s, 2H), 5.15 (dt, J=9.2, 4.2 Hz, 1H), 5.06-4.83 (m, 3H), 4.58 (t, J=6.3 Hz, 1H), 4.42 (d, J=6.6 Hz, 1H), 4.33-4.09 (m, 6H), 4.06-3.86 (m, 2H), 3.65 (td, J=8.1, 6.7 Hz, 1H), 3.15-2.82 (m, 4H), 2.66 (q, J=7.2 Hz, 33H), 1.80-1.54 (m, 1H), 1.54-1.34 (m, 2H), 1.04 (t, J=7.2 Hz, 45H), 0.86 (dd, J=16.3, 6.8 Hz, 5H). 
     Example 3-41: Synthesis of Compound 41 (C41) 
     
       
         
         
             
             
         
       
     
     Compound (C41) was synthesized using similar methods describe for the synthesis of Compound (C18), except CDN intermediate (CDNI-26) TEA salt was used in place of CDN intermediate (CDNI-3) and Linker intermediate (LI-9) was used in place of Linker intermediate (LI-3). Fractions containing the desired product were combined and lyophilized to obtain Compound (C41) as Et 3 N salt (2.3 mg, 11% yield). LCMS M/2+1=702.3, tr=0.691 min. 
     Example 3-42: Synthesis of the Mixture of Compound 42a (C42a) and Compound 42b (C42b) 
     
       
         
         
             
             
         
       
     
     The mixture of Compound (C42a) and Compound (C42b) was synthesized using similar methods describe for the synthesis of Compound (C18), except the mixture of CDN intermediate (CDNI-27a) and CDN intermediate (CDNI-27b) was used in place of CDN intermediate (CDNI-3) and the C18 column was eluted with 5-40% acetonitrile-H 2 O (aqueous phase containing 10 mM Et 3 N HOAc). The mixture of Compound (C42a) and Compound (C42b) was obtained as Et 3 N salt (2.0 mg, 33% yield). LCMS M/2+1=689.8, tr=0.694 min. 
     Example 3-43: Synthesis of Compound 43 (C43) 
     
       
         
         
             
             
         
       
     
     Compound (C43) was synthesized using similar methods describe for the synthesis of Compound (C18), except CDN intermediate (CDNI-28) TEA salt was used in place of CDN intermediate (CDNI-3). Fractions containing the desired product were combined and lyophilized to obtain Compound (C43) as Et 3 N salt (3.3 mg, 31.1% yield). LCMS M/2+1=683.8, tr=0.813 min. 
     Example 3-44: Synthesis of a Mixture of Compound 44a (C44a) and Compound 44b (C44b) 
     
       
         
         
             
             
         
       
     
     Compound (C1) (20 mg, 0.013 mmol) was dissolved in 3:7 MeOH and DMSO (1 ml) and maintained at rt for 1 month. The mixture was purified by reverse phase ISCO using 50 g C18 aq column, eluted with 5-40% ACN-water with 0.05% TFA. Fractions containing Compound (C44a) and Compound (C44b) were isolated and lyophilized to obtain the mixture of Compound (C44a) and Compound (C44b) as TFA salt (4.5 mg, 21% yield). LCMS M/2+1=668.8, tr=0.694 min. 
     Example 3-45: Synthesis of Compound 45 (C45) 
     
       
         
         
             
             
         
       
     
     Compound (C45) was synthesized using similar methods describe for the synthesis of Compound (C18), except CDN intermediate (CDNI-29) TEA salt was used in place of CDN intermediate (CDNI-3). Fractions containing the desired product were combined and lyophilized to obtain Compound (C45) as Et 3 N salt (7.2 mg, 38% yield). LCMS M+1=1292.1, tr=0.631 min. 
     Example 4: Generation of Anti-DC-SIGN Antibodies 
     Generation of Expression Constructs for Human and Cynomolous Monkey DC-SIGN 
     Full length human DC-SIGN DNA (SEQ ID NO: 306) was synthesized based on amino acid sequences from the Uniprot databases (Q9NNX6, SEQ ID NO:303), the cyno DC-SIGN DNA (SEQ ID NO: 312) was synthesized based on cyno DC-SIGN amino acid sequence (SEQ ID NO: 311). All synthesized DNA fragments were cloned into appropriate expression vectors. 
     
       
         
           
               
             
               
                 TABLE 21 
               
               
                   
               
               
                 Amino Acid and Nucleotide Sequence Information for DC-SIGN proteins 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                 Human DC- 
                 MSDS KEPRLQQLGL LEEEQLRGLG 
                 SEQ ID 
               
               
                 SIGN 
                 FRQTRGYKSL AGCLGHGPLV LQLLSFTLLA GLLVQVSKVP SSISQEQSRQ 
                 NO: 303 
               
               
                 Full length AA 
                 DAIYQNLTQL KAAVGELSEK SKLQEIYQEL TQLKAAVGEL PEKSKLQEIY 
                   
               
               
                   
                 QELTRLKAAV GELPEKSKLQ EIYQELTWLK AAVGELPEKS KMQEIYQELT 
                   
               
               
                   
                 RLKAAVGELP EKSKQQEIYQ ELTRLKAAVG ELPEKSKQQE IYQELTRLKA 
                   
               
               
                   
                 AVGELPEKSK QQEIYQELTQ LKAAVERLCH PCPWEWTFFQ GNCYFMSNSQ 
                   
               
               
                   
                 RNWHDSITAC KEVGAQLVVI KSAEEQNFLQ LQSSRSNRFT WMGLSDLNQE 
                   
               
               
                   
                 GTWQWVDGSP LLPSFKQYWN RGEPNNVGEE DCAEFSGNGW NDDKCNLAKF 
                   
               
               
                   
                 WICKKSAASC SRDEEQFLSP APATPNPPPA 
                   
               
               
                   
               
               
                 Full length 
                 AT GAGTGACTCC AAGGAACCAA 
                 SEQ ID 
               
               
                 DNA 
                 GACTGCAGCA GCTGGGCCTC CTGGAGGAGG AACAGCTGAG AGGCCTTGGA 
                 NO: 306 
               
               
                   
                 TTCCGACAGA CTCGAGGATA CAAGAGCTTA GCAGGGTGTC TTGGCCATGG 
                   
               
               
                   
                 TCCCCTGGTG CTGCAACTCC TCTCCTTCAC GCTCTTGGCT GGGCTCCTTG 
                   
               
               
                   
                 TCCAAGTGTC CAAGGTCCCC AGCTCCATAA GTCAGGAACA ATCCAGGCAA 
                   
               
               
                   
                 GACGCGATCT ACCAGAACCT GACCCAGCTT AAAGCTGCAG TGGGTGAGCT 
                   
               
               
                   
                 CTCAGAGAAA TCCAAGCTGC AGGAGATCTA CCAGGAGCTG ACCCAGCTGA 
                   
               
               
                   
                 AGGCTGCAGT GGGTGAGCTT CCAGAGAAAT CTAAGCTGCA GGAGATCTAC 
                   
               
               
                   
                 CAGGAGCTGA CCCGGCTGAA GGCTGCAGTG GGTGAGCTTC CAGAGAAATC 
                   
               
               
                   
                 TAAGCTGCAG GAGATCTACC AGGAGCTGAC CTGGCTGAAG GCTGCAGTGG 
                   
               
               
                   
                 GTGAGCTTCC AGAGAAATCT AAGATGCAGG AGATCTACCA GGAGCTGACT 
                   
               
               
                   
                 CGGCTGAAGG CTGCAGTGGG TGAGCTTCCA GAGAAATCTA AGCAGCAGGA 
                   
               
               
                   
                 GATCTACCAG GAGCTGACCC GGCTGAAGGC TGCAGTGGGT GAGCTTCCAG 
                   
               
               
                   
                 AGAAATCTAA GCAGCAGGAG ATCTACCAGG AGCTGACCCG GCTGAAGGCT 
                   
               
               
                   
                 GCAGTGGGTG AGCTTCCAGA GAAATCTAAG CAGCAGGAGA TCTACCAGGA 
                   
               
               
                   
                 GCTGACCCAG CTGAAGGCTG CAGTGGAACG CCTGTGCCAC CCCTGTCCCT 
                   
               
               
                   
                 GGGAATGGAC ATTCTTCCAA GGAAACTGTT ACTTCATGTC TAACTCCCAG 
                   
               
               
                   
                 CGGAACTGGC ACGACTCCAT CACCGCCTGC AAAGAAGTGG GGGCCCAGCT 
                   
               
               
                   
                 CGTCGTAATC AAAAGTGCTG AGGAGCAGAA CTTCCTACAG CTGCAGTCTT 
                   
               
               
                   
                 CCAGAAGTAA CCGCTTCACC TGGATGGGAC TTTCAGATCT AAATCAGGAA 
                   
               
               
                   
                 GGCACGTGGC AATGGGTGGA CGGCTCACCT CTGTTGCCCA GCTTCAAGCA 
                   
               
               
                   
                 GTATTGGAAC AGAGGAGAGC CCAACAACGT TGGGGAGGAA GACTGCGCGG 
                   
               
               
                   
                 AATTTAGTGG CAATGGCTGG AACGACGACA AATGTAATCT TGCCAAATTC 
                   
               
               
                   
                 TGGATCTGCA AAAAGTCCGC AGCCTCCTGC TCCAGGGATG AAGAACAGTT 
                   
               
               
                   
                 TCTTTCTCCA GCCCCTGCCA CCCCAAACCC CCCTCCTGCG 
                   
               
               
                   
               
               
                 ECD AA 
                 KV PSSISQEQSR QDAIYQNLTQ LKAAVGELSE 
                 SEQ ID 
               
               
                   
                 KSKLQEIYQE LTQLKAAVGE LPEKSKLQEI YQELTRLKAA VGELPEKSKL 
                 NO: 307 
               
               
                   
                 QEIYQELTWL KAAVGELPEK SKMQEIYQEL TRLKAAVGEL PEKSKQQEIY 
                   
               
               
                   
                 QELTRLKAAV GELPEKSKQQ EIYQELTRLK AAVGELPEKS KQQEIYQELT 
                   
               
               
                   
                 QLKAAVERLC HPCPWEWTFF QGNCYFMSNS QRNWHDSITA CKEVGAQLVV 
                   
               
               
                   
                 IKSAEEQNFL QLQSSRSNRF TWMGLSDLNQ EGTWQWVDGS PLLPSFKQYW 
                   
               
               
                   
                 NRGEPNNVGE EDCAEFSGNG WNDDKCNLAK FWICKKSAAS CSRDEEQFLS 
                   
               
               
                   
                 PAPATPNPPP A 
                   
               
               
                   
               
               
                 ECD DNA 
                 AAGGTCCCCA GCTCCATAAG TCAGGAACAA TCCAGGCAAG ACGCGATCTA 
                 SEQ ID 
               
               
                   
                 CCAGAACCTG ACCCAGCTTA AAGCTGCAGT GGGTGAGCTC TCAGAGAAAT 
                 NO: 308 
               
               
                   
                 CCAAGCTGCA GGAGATCTAC CAGGAGCTGA CCCAGCTGAA GGCTGCAGTG 
                   
               
               
                   
                 GGTGAGCTTC CAGAGAAATC TAAGCTGCAG GAGATCTACC AGGAGCTGAC 
                   
               
               
                   
                 CCGGCTGAAG GCTGCAGTGG GTGAGCTTCC AGAGAAATCT AAGCTGCAGG 
                   
               
               
                   
                 AGATCTACCA GGAGCTGACC TGGCTGAAGG CTGCAGTGGG TGAGCTTCCA 
                   
               
               
                   
                 GAGAAATCTA AGATGCAGGA GATCTACCAG GAGCTGACTC GGCTGAAGGC 
                   
               
               
                   
                 TGCAGTGGGT GAGCTTCCAG AGAAATCTAA GCAGCAGGAG ATCTACCAGG 
                   
               
               
                   
                 AGCTGACCCG GCTGAAGGCT GCAGTGGGTG AGCTTCCAGA GAAATCTAAG 
                   
               
               
                   
                 CAGCAGGAGA TCTACCAGGA GCTGACCCGG CTGAAGGCTG CAGTGGGTGA 
                   
               
               
                   
                 GCTTCCAGAG AAATCTAAGC AGCAGGAGAT CTACCAGGAG CTGACCCAGC 
                   
               
               
                   
                 TGAAGGCTGC AGTGGAACGC CTGTGCCACC CCTGTCCCTG GGAATGGACA 
                   
               
               
                   
                 TTCTTCCAAG GAAACTGTTA CTTCATGTCT AACTCCCAGC GGAACTGGCA 
                   
               
               
                   
                 CGACTCCATC ACCGCCTGCA AAGAAGTGGG GGCCCAGCTC GTCGTAATCA 
                   
               
               
                   
                 AAAGTGCTGA GGAGCAGAAC TTCCTACAGC TGCAGTCTTC CAGAAGTAAC 
                   
               
               
                   
                 CGCTTCACCT GGATGGGACT TTCAGATCTA AATCAGGAAG GCACGTGGCA 
                   
               
               
                   
                 ATGGGTGGAC GGCTCACCTC TGTTGCCCAG CTTCAAGCAG TATTGGAACA 
                   
               
               
                   
                 GAGGAGAGCC CAACAACGTT GGGGAGGAAG ACTGCGCGGA ATTTAGTGGC 
                   
               
               
                   
                 AATGGCTGGA ACGACGACAA ATGTAATCTT GCCAAATTCT GGATCTGCAA 
                   
               
               
                   
                 AAAGTCCGCA GCCTCCTGCT CCAGGGATGA AGAACAGTTT CTTTCTCCAG 
                   
               
               
                   
                 CCCCTGCCAC CCCAAACCCC CCTCCTGCG 
                   
               
               
                   
               
               
                 CRD AA 
                 ER LCHPCPWEWT FFQGNCYFMS NSQRNWHDSI 
                 SEQ ID 
               
               
                   
                 TACKEVGAQL VVIKSAEEQN FLQLQSSRSN RFTWMGLSDL NQEGTWQWVD 
                 NO: 309 
               
               
                   
                 GSPLLPSFKQ YWNRGEPNNV GEEDCAEFSG NGWNDDKCNL AKFWICKKSA 
                   
               
               
                   
                 ASCSRDEEQF LSPAPATPNP PPA 
                   
               
               
                   
               
               
                 CRD DNA 
                 GAACGCCTGT GCCACCCCTG TCCCTGGGAA TGGACATTCT TCCAAGGAAA 
                 SEQ ID 
               
               
                   
                 CTGTTACTTC ATGTCTAACT CCCAGCGGAA CTGGCACGAC TCCATCACCG 
                 NO: 310 
               
               
                   
                 CCTGCAAAGA AGTGGGGGCC CAGCTCGTCG TAATCAAAAG TGCTGAGGAG 
                   
               
               
                   
                 CAGAACTTCC TACAGCTGCA GTCTTCCAGA AGTAACCGCT TCACCTGGAT 
                   
               
               
                   
                 GGGACTTTCA GATCTAAATC AGGAAGGCAC GTGGCAATGG GTGGACGGCT 
                   
               
               
                   
                 CACCTCTGTT GCCCAGCTTC AAGCAGTATT GGAACAGAGG AGAGCCCAAC 
                   
               
               
                   
                 AACGTTGGGG AGGAAGACTG CGCGGAATTT AGTGGCAATG GCTGGAACGA 
                   
               
               
                   
                 CGACAAATGT AATCTTGCCA AATTCTGGAT CTGCAAAAAG TCCGCAGCCT 
                   
               
               
                   
                 CCTGCTCCAG GGATGAAGAA CAGTTTCTTT CTCCAGCCCC TGCCACCCCA 
                   
               
               
                   
                 AACCCTCCTC CTGCG 
                   
               
               
                   
               
               
                 Cyno DC-SIGN 
                 MSDSKEPRLQ QLDLLEEEQL GGVGFRQTRG YKSLAGCLGH GPLVLQLLSF 
                 SEQ ID 
               
               
                 Full length AA 
                 TLLAGLLVQV SKVPSSLSQG QSKQDAIYQN LTQLKVAVSE LSEKSKQQEI 
                 NO: 311 
               
               
                   
                 YQELTRLKAA VGELPEKSKQ QEIYEELTRL KAAVGELPEK SKLQEIYQEL 
                   
               
               
                   
                 TRLKAAVGEL PEKSKQQEIY QELSRLKAAV GDLPEKSKQQ EIYQKLTQLK 
                   
               
               
                   
                 AAVDGLPDRS KQQEIYQELI QLKAAVDLEG WTDTGIWTTS SEPSPDRPPP 
                   
               
               
                   
                 TERLCHPCPW EWTFFQGNCY FMSNSQRNWH DSITACQEVG AQLVVIKSAE 
                   
               
               
                   
                 EQNFLQLQSS RSNRFTWMGL SDLNHEGTWQ WVDGSPLLPS FKQYWNKGEP 
                   
               
               
                   
                 NNVGEEDCAE FSGNGWNDDK CNLAKFWICK KSAASCSGDE ERLLSPAPTT 
                   
               
               
                   
                 PNPPPE 
                   
               
               
                   
               
               
                 Full length 
                 atgtcggactcgaaggaaccaagactgcagcaactcgacctccttgaagaagaacagctcgg 
                 SEQ ID 
               
               
                 DNA 
                 cggagtgggattccggcagaccaggggttacaagagcctggccggttgcctgggtcacggcc 
                 NO: 312 
               
               
                   
                 ctttggtgcttcagctgctgtcgttcaccctgctggccggactgcttgtgcaagtctccaaa 
                   
               
               
                   
                 gtcccgtcctcgctgagccaggggcagtccaagcaggacgcgatctaccaaaacctgacaca 
                   
               
               
                   
                 gctcaaggtggccgtgtcagagctgtccgagaagtcgaagcagcaagagatctaccaagagt 
                   
               
               
                   
                 tgacgcgactcaaagcagccgtgggcgaacttcccgagaagtcaaagcagcaggaaatctac 
                   
               
               
                   
                 gaggaattgacccgcctgaaggccgccgtgggagagctgccagaaaagtcgaagctgcagga 
                   
               
               
                   
                 gatataccaagaactcacccggctcaaggccgctgtgggagaactgccggagaagtccaaac 
                   
               
               
                   
                 aacaggaaatctaccaggaactgagcagactcaaggcagccgtcggcgatctccccgaaaag 
                   
               
               
                   
                 tctaaacagcaggagatctatcagaagctgactcagctgaaggcggccgtggacgggctgcc 
                   
               
               
                   
                 cgatcggtccaagcaacaggaaatctaccaggagctgatccaactgaaggctgccgtggacc 
                   
               
               
                   
                 tggaagggtggactgacaccgggatttggactacctcatcggaaccgagccctgatcgccct 
                   
               
               
                   
                 ccgcctaccgagaggttgtgtcacccgtgcccatgggagtggacgttcttccaaggaaactg 
                   
               
               
                   
                 ttactttatgagcaacagccagcggaattggcacgattccattaccgcgtgccaggaagtgg 
                   
               
               
                   
                 gcgcccagctggtcgtgatcaagtccgcggaggagcagaacttcctgcagctccagagcagc 
                   
               
               
                   
                 cggtccaaccgcttcacctggatgggcctctccgacctgaaccatgagggaacttggcagtg 
                   
               
               
                   
                 ggtggacggttccccgctgctgccctcattcaagcagtactggaacaagggagaaccgaaca 
                   
               
               
                   
                 acgtcggagaggaagattgcgccgagttttccgggaacggatggaacgacgacaagtgcaat 
                   
               
               
                   
                 ctggccaagttctggatttgcaagaagtccgctgcatcctgctcgggcgacgaggagcgcct 
                   
               
               
                   
                 gctgtcccccgcgcccaccacccctaaccctcccccggaatgatag 
                   
               
               
                   
               
               
                 ECD AA 
                 QPSKQD AIYQNLTQLK VAVSELSEKS 
                 SEQ ID 
               
               
                   
                 KQQEIYQELT RLKAAVGELP EKSKQQEIYE ELTRLKAAVG ELPEKSKLQE 
                 NO: 313 
               
               
                   
                 IYQELTRLKA AVGELPEKSK QQEIYQELSR LKAAVGDLPE KSKQQEIYQK 
                   
               
               
                   
                 LTQLKAAVDG LPDRSKQQEI YQELIQLKAA VDLEGWTDTG IWTTSSEPSP 
                   
               
               
                   
                 DRPPPTERLC HPCPWEWTFF QGNCYFMSNS QRNWHDSITA CQEVGAQLVV 
                   
               
               
                   
                 IKSAEEQNFL QLQSSRSNRF TWMGLSDLNH EGTWQWVDGS PLLPSFKQYW 
                   
               
               
                   
                 NKGEPNNVGE EDCAEFSGNG WNDDKCNLAK FWICKKSAAS CSGDEERLLS 
                   
               
               
                   
                 PAPTTPNPPP 
                   
               
               
                   
               
               
                 ECD DNA 
                 TC CAAGCAGGAC GCGATCTACC 
                 SEQ ID 
               
               
                   
                 AAAACCTGAC ACAGCTCAAG GTGGCCGTGT CAGAGCTGTC CGAGAAGTCG 
                 NO: 314 
               
               
                   
                 AAGCAGCAAG AGATCTACCA AGAGTTGACG CGACTCAAAG CAGCCGTGGG 
                   
               
               
                   
                 CGAACTTCCC GAGAAGTCAA AGCAGCAGGA AATCTACGAG GAATTGACCC 
                   
               
               
                   
                 GCCTGAAGGC CGCCGTGGGA GAGCTGCCAG AAAAGTCGAA GCTGCAGGAG 
                   
               
               
                   
                 ATATACCAAG AACTCACCCG GCTCAAGGCC GCTGTGGGAG AACTGCCGGA 
                   
               
               
                   
                 GAAGTCCAAA CAACAGGAAA TCTACCAGGA ACTGAGCAGA CTCAAGGCAG 
                   
               
               
                   
                 CCGTCGGCGA TCTCCCCGAA AAGTCTAAAC AGCAGGAGAT CTATCAGAAG 
                   
               
               
                   
                 CTGACTCAGC TGAAGGCGGC CGTGGACGGG CTGCCCGATC GGTCCAAGCA 
                   
               
               
                   
                 ACAGGAAATC TACCAGGAGC TGATCCAACT GAAGGCTGCC GTGGACCTGG 
                   
               
               
                   
                 AAGGGTGGAC TGACACCGGG ATTTGGACTA CCTCATCGGA ACCGAGCCCT 
                   
               
               
                   
                 GATCGCCCTC CGCCTACCGA GAGGTTGTGT CACCCGTGCC CATGGGAGTG 
                   
               
               
                   
                 GACGTTCTTC CAAGGAAACT GTTACTTTAT GAGCAACAGC CAGCGGAATT 
                   
               
               
                   
                 GGCACGATTC CATTACCGCG TGCCAGGAAG TGGGCGCCCA GCTGGTCGTG 
                   
               
               
                   
                 ATCAAGTCCG CGGAGGAGCA GAACTTCCTG CAGCTCCAGA GCAGCCGGTC 
                   
               
               
                   
                 CAACCGCTTC ACCTGGATGG GCCTCTCCGA CCTGAACCAT GAGGGAACTT 
                   
               
               
                   
                 GGCAGTGGGT GGACGGTTCC CCGCTGCTGC CCTCATTCAA GCAGTACTGG 
                   
               
               
                   
                 AACAAGGGAG AACCGAACAA CGTCGGAGAG GAAGATTGCG CCGAGTTTTC 
                   
               
               
                   
                 CGGGAACGGA TGGAACGACG ACAAGTGCAA TCTGGCCAAG TTCTGGATTT 
                   
               
               
                   
                 GCAAGAAGTC CGCTGCATCC TGCTCGGGCG ACGAGGAGCG CCTGCTGTCC 
                   
               
               
                   
                 CCCGCGCCCA CCACCCCTAA CCCTCCCCCG GAA 
                   
               
               
                   
               
               
                 CRD AA 
                 OPERLC HPCPWEWTFF QGNCYFMSNS 
                 SEQ ID 
               
               
                   
                 QRNWHDSITA CQEVGAQLVV IKSAEEQNFL QLQSSRSNRF TWMGLSDLNH 
                 NO: 315 
               
               
                   
                 EGTWQWVDGS PLLPSFKQYW NKGEPNNVGE EDCAEFSGNG WNDDKCNLAK 
                   
               
               
                   
                 FWICKKSAAS CSGDEERLLS PAPTTPNPPP E 
                   
               
               
                   
               
               
                 CRD DNA 
                 GA GAGGTTGTGT CACCCGTGCC 
                 SEQ ID 
               
               
                   
                 CATGGGAGTG GACGTTCTTC CAAGGAAACT GTTACTTTAT GAGCAACAGC 
                 NO: 316 
               
               
                   
                 CAGCGGAATT GGCACGATTC CATTACCGCG TGCCAGGAAG TGGGCGCCCA 
                   
               
               
                   
                 GCTGGTCGTG ATCAAGTCCG CGGAGGAGCA GAACTTCCTG CAGCTCCAGA 
                   
               
               
                   
                 GCAGCCGGTC CAACCGCTTC ACCTGGATGG GCCTCTCCGA CCTGAACCAT 
                   
               
               
                   
                 GAGGGAACTT GGCAGTGGGT GGACGGTTCC CCGCTGCTGC CCTCATTCAA 
                   
               
               
                   
                 GCAGTACTGG AACAAGGGAG AACCGAACAA CGTCGGAGAG GAAGATTGCG 
                   
               
               
                   
                 CCGAGTTTTC CGGGAACGGA TGGAACGACG ACAAGTGCAA TCTGGCCAAG 
                   
               
               
                   
                 TTCTGGATTT GCAAGAAGTC CGCTGCATCC TGCTCGGGCG ACGAGGAGCG 
                   
               
               
                   
                 CCTGCTGTCC CCCGCGCCCA CCACCCCTAA CCCTCCCCCG GAA 
                   
               
               
                   
               
               
                 Human DC- 
                 KV PSSISQEQSR QDAIYQNLTQ LKAAVGELSE 
                 SEQ ID 
               
               
                 SIGN ECD- 
                 KSKLQEIYQE LTQLKAAVGE LPEKSKLQEI YQELTRLKAA VGELPEKSKL 
                 NO: 317 
               
               
                 AviHis 
                 QEIYQELTWL KAAVGELPEK SKMQEIYQEL TRLKAAVGEL PEKSKQQEIY 
                   
               
               
                   
                 QELTRLKAAV GELPEKSKQQ EIYQELTRLK AAVGELPEKS KQQEIYQELT 
                   
               
               
                   
                 QLKAAVERLC HPCPWEWTFF QGNCYFMSNS QRNWHDSITA CKEVGAQLVV 
                   
               
               
                   
                 IKSAEEQNFL QLQSSRSNRF TWMGLSDLNQ EGTWQWVDGS PLLPSFKQYW 
                   
               
               
                   
                 NRGEPNNVGE EDCAEFSGNG WNDDKCNLAK FWICKKSAAS CSRDEEQFLS 
                   
               
               
                   
                 PAPATPNPPP AGSGGGLNDI FEAQKIEWHE HHHHHH 
                   
               
               
                   
               
               
                 Human DC- 
                 MQLLSCIALS LALVTNSTER LCHPCPWEWT FFQGNCYFMS NSQRNWHDSI 
                 SEQ ID 
               
               
                 SIGN CRD- 
                 TACKEVGAQL VVIKSAEEQN FLQLQSSRSN RFTWMGLSDL NQEGTWQWVD 
                 NO: 318 
               
               
                 AviHis 
                 GSPLLPSFKQ YWNRGEPNNV GEEDCAEFSG NGWNDDKCNL AKFWICKKSA 
                   
               
               
                   
                 ASCSRDEEQF LSPAPATPNP PPAGSGGGLN DIFEAQKIEW HEHHHHHH 
                   
               
               
                   
               
               
                 Human DC- 
                 MKTFILLLWV LLLWVIFLLP GATAQPSKVP SSISQEQSRQ DAIYQNLTQL 
                 SEQ ID 
               
               
                 SIGN ECD- 
                 KAAVGELSEK SKLQEIYQEL TQLKAAVGEL PEKSKLQEIY QELTRLKAAV 
                 NO: 319 
               
               
                 FLAGHis 
                 GELPEKSKLQ EIYQELTWLK AAVGELPEKS KMQEIYQELT RLKAAVGELP 
                   
               
               
                   
                 EKSKQQEIYQ ELTRLKAAVG ELPEKSKQQE IYQELTRLKA AVGELPEKSK 
                   
               
               
                   
                 QQEIYQELTQ LKAAVERLCH PCPWEWTFFQ GNCYFMSNSQ RNWHDSITAC 
                   
               
               
                   
                 KEVGAQLVVI KSAEEQNFLQ LQSSRSNRFT WMGLSDLNQE GTWQWVDGSP 
                   
               
               
                   
                 LLPSFKQYWN RGEPNNVGEE DCAEFSGNGW NDDKCNLAKF WICKKSAASC 
                   
               
               
                   
                 SRDEEQFLSP APATPNPPPA DYKDDDDKHH HHHH 
               
               
                   
               
            
           
         
       
     
     Generation of Cell Lines Stably Expressing DC-SIGN 
     Stable full length DC-SIGN-expressing and full length L-SIGN expressing K562 cell lines were generated using retroviral transduction. HEK293T cells were co-transfected with a DC-SIGN retroviral expression vector and a pCL-10A1 packaging vector (Novus, USA, cat#NBP2-2942) using Fugene 6 transfection reagent (Promega, USA, cat# E2692) following manufacturer&#39;s recommendation. Cells were incubated in a 37° C. humidified CO 2  incubator and viral supernatant was collected 48 hours post-transfection. K562 cells were grown to near confluency. Viral transduction was performed by adding viral supernatant in the presence of 8 μg polybrene/ml (final concentration) (EMD Millipore, cat#TR-1003-G). Following incubation for 3-6 hours at 37° C., fresh media was added. Cells were then cultured under appropriate selection conditions to produce stable L-SIGN or DC-SIGN expressing cell lines. 
     Stable human DC-SIGN expressing and cynomolgus monkey DC-SIGN expressing CHO cell lines were generated using plasmid DNA. Proprietary CHO cells were nucleoporated with a human or cynomolgus monkey DC-SIGN gene in the pD649 expression vector (DNA2.0). Nucleoporation was performed using the Lonza SG Cell line 96-well Nucleoporation kit (Cat# V4SC-3096). Cells and plasmid DNA were mixed with SG buffer and supplement, following manufacturer&#39;s recommendation. The 96-well nucleoporation plate was placed in a Nucleofector™ 96-well Shuttle™ (Lonza) and processed using program CHO S (FF-137). Nucleoporated cells were allowed to sit for 30 min at RT before diluting. Viability and cell density measurements were performed using VICELL (Beckman Coulter). Cells were seeded into a 96-well plate at 40,000 cells/well into 100 uL of proprietary DM122 media and incubated at 37° C., 10% CO2 at 4 hrs after seeding, selection was added to the cells (4 ug/mL of puromycin (InvivoGen) for cynomolgus monkey and 100 nM methotrexate (Sigma) for human DC-SIGN). Every 7 days, cells were passed 1:5 into fresh selection media for 3 passages. Cells were expanded into shake flasks at 37° C., 10% CO 2  and kept at densities 0.1million cells/mL to 2 million cells/mL. After 4 weeks, cells were FACS sorted using a 2008 FACS Aria to obtain cell pools with high expression levels for both cell lines. 
     Hybridoma Generation, Antibodies 282 and 1G12 
     Bcl-2 transgenic mice (C57BL/6-Tgn (bcl-2) 22 WEHI strain) were immunized with antigen using a procedure that calls for Repetitive Immunization at Multiple Sites (RIMMS) (Kilpatrick K E, et al., Hybridoma 16(4):381-9 (1997)). Briefly, mice were injected with 1-3 μg of DC-SIGN immunogen (Recombinant Human DC-SIGN/CD209 Fc Chimera Protein, CF, R&amp;D systems Cat No: 161-DC-050) at 8 specific sites proximal to peripheral lymph nodes (PLNs). This procedure was repeated 8 times over a 12 day period. On Day 12, a test bleed was collected and the serum antibody titer was analyzed by FACS. Two days after the boost, a test bleed was collected and serum antibody titer was analyzed by FACS. In some instances, BALB/c mice were immunized subcutaneously with antigen once a month for 3 months followed by an intravenous boost. Two days after the boost, a test bleed was collected and serum antibody titer was analyzed by FACS. Spleens and pooled PLNs were removed from high titer mice. To harvest lymphocytes, spleens and PLNs were washed twice with DMEM, and then dissociated by passage through a 70 micron screen (Falcon #352350). The resulting lymphocytes were washed 2 additional times prior to fusion in Cytofusion media (BTXpress Cytofusion® Electroporation Medium cat#47001). 
     Ten days after fusion, hybridoma plates were screened for the presence of human DC-SIGN-specific antibodies using flow cytometry. To confirm specific binding of candidate antibodies to cell surface-expressed human DC-SIGN, three cell lines were used: human DC-SIGN stably overexpressing K562, human L-SIGN stably overexpressing K562 or parental K562. Cells were rinsed thoroughly with PBS. Cells were biotinylated and labeled with a fluorescent dye according to manufacturer&#39;s instructions (FluoReporter™ Cell-Surface Biotinylation Kit, Thermo Fisher Scientific Cat# F-20650; PE-Cy7 Streptavidin, ThermoFisher Scientific Cat# SA1012; APC Streptavidin, Biolegend Cat#405207; APC/Cy7 Streptavidin, Biolegend Cat#405208). Cells were resuspended at approximately 1×10 6  cells/ml in FACS buffer (PBS with 2% FBS+0.1% NaN 3 ). In a 384-well plate, 20 μL of hybridoma supernatant was pre-seeded, and 20 μL of cell suspension was added. Cells were incubated for 1 hour at 4° C., washed twice with cold FACS buffer, and resuspended in 20 μL of FACS buffer containing secondary antibody at a 1:400 dilution (Goat anti-mouse IgG BV421, Sirigen, custom order). After additional incubation for 45 min at 4° C., cells were washed twice with FACS buffer and resuspended in 20 μL of FACS buffer with 2 μg/ml propidium iodide (Sigma Aldrich Cat# P4864). Geometric mean fluorescence intensity was calculated on live single cells using FlowJo™ software. 
     Hybridoma Generation 2, Antibodies 960K03, 958N02, 956P16, 952G04, 952D15, 914M09, 906C18, 956E02, 550E03, 942K11 
     Ablexis Alivamab Kappa (AMM-K) and Lambda (AMM-L) mice were immunized with antigen using a procedure that calls for Repetitive Immunization at Multiple Sites (RIMMS) (Kilpatrick K E, et al., Hybridoma 16(4):381-9 (1997)). Briefly, mice were injected with 22.5 μg of full length ECD-AviHis (SEQ ID NO: 317) protein at 8 specific sites proximal to peripheral lymph nodes (PLNs). This procedure was repeated 8 times over a 20 day period. On Day 18, a test bleed was collected and the serum antibody titer was analyzed by FACS and ELISA prior to hybridoma fusion. To harvest lymphocytes, spleens and lymph nodes were mechanically dissociated in PBS, and then passaged through a 70 micron screen (Falcon #352350). RBCs were lysed using Red Blood Cell Lysing Buffer (SigmaR7757-100 ml) as per manufacturer&#39;s instructions. CD3 positive splenocytes were removed using micro bead magnetic columns from Miltenyi as per their instructions (Anti-IgM #130-047-301 and anti-CD3 #130-094-973). The resulting lymphocytes were washed 2 additional times prior to fusion in Electrofusion IsoOsmolar Buffer (Eppendorf, #4308 070 536). 
     For the fusion, F0 myeloma cells were mixed with lymphocytes at a 1:4 ratio. The cell mixture was centrifuged, suspended in Electrofusion IsoOsmolar Buffer and subsequently added to an electrofusion chamber (Harvard Apparatus Coaxial chamber 9ML Part #470020). Electrofusion was carried out per manufacturer&#39;s instructions using the CEEF-50B Hybrimune/Hybridoma system (Cyto Pulse Sciences, Inc). Fused cells were allowed to recover for 5 minutes in the chamber, diluted 1:10 in media without hypoxanthine-aminopterin-thymidine (HAT) [DMEM+20% FBS, 1% Penicillin-Streptomycin-Glutamine (PSG), 1× Non-Essential Amino Acids (NEAA), 0.5× Hybridoma Fusion and Cloning Supplement (Roche; HFCS) and placed at 37° C. and 5% CO 2  for one hour. Next, 4×HAT medium (DMEM+20% FBS, 1% PSG, 1×NEAA, 4×HAT, 0.5×HFCS) was added to bring the concentration of HAT to 1×, and the density was adjusted to 66,000 cells/ml. The cells were plated in 384-well plates at 60 μl/well. 
     FACS Screening 
     Ten days after fusion, hybridoma plates were screened for the presence of human DC-SIGN-specific antibodies using flow cytometry. To confirm specific binding of candidate antibodies to cell surface-expressed human DC-SIGN, three cell lines were used: human DC-SIGN stably overexpressing CHO, cynomolgus DC-SIGN stably overexpressing CHO, and parental non-transfected CHO cells. Cells were rinsed thoroughly with PBS. Cells were biotinylated and labeled with a fluorescent dye according to manufacturer&#39;s instructions (FluoReporter™ Cell-Surface Biotinylation Kit, Thermo Fisher Scientific Cat# F-20650; PE-Cy7 Streptavidin, ThermoFisher Scientific Cat# SA1012; APC Streptavidin, Biolegend Cat#405207; APC/Cy7 Streptavidin, Biolegend Cat#405208). Cells were resuspended at approximately 1×10 6  cells/ml in FACS buffer (PBS with 2% FBS+0.1% NaN 3 ). In a 384-well plate, 20 μL of hybridoma supernatant was pre-seeded, and 20 μL of cell suspension was added. Cells were incubated for 1 hour at 4° C., washed twice with cold FACS buffer, and resuspended in 20 μL of FACS buffer containing secondary antibody at a 1:400 dilution (Goat anti-mouse IgG BV421, Sirigen, custom order). After additional incubation for 45 min at 4° C., cells were washed twice with FACS buffer and resuspended in 20 μL of FACS buffer with 2 μg/ml propidium iodide (Sigma Aldrich Cat# P4864). Geometric mean fluorescence intensity was calculated on live single cells using FlowJo™ software. 
     Hits from the primary cell-based flow cytometry screen were confirmed in a secondary flow cytometry screen like above, but with two additional cell lines: human DC-SIGN stably overexpressing K562, and human L-SIGN stably overexpressing K562 cells. Hybridomas expressing antibodies that bound to both human DC-SIGN expressing CHO and human DC-SIGN expressing K562 cells, but not CHO parental cells or L-SIGN-K562 cells, were called positive. Positive cells were expanded for cryo preservation and also split into 45 mL protein production cultures in hybridoma serum-free medium with HT Media Supplement (50×) Hybri-Max™ (Sigma, cat# H0137) in CellStar® Autoflasks™ (Greiner Bio-One). Production cultures were maintained in a shaking incubator at 37° C. and 5% CO 2  for approximately 8 days. Cells were then pelleted, and supernatants were taken through purification over Protein G resin. Proteins were subsequently buffer exchanged into PBS using NAP-10™ columns (GE Healthcare). 
     Antibody Sequencing and Vector Preparation 
     Variable region (VH and VL) DNA sequences of hybridomas were obtained for each of the selected hybridomas. Variable region DNA products from murine monoclonal antibodies 2B2 and 1G12 were amplified by rapid amplification of cDNA ends (RACE) from RNA obtained from each selected hybridoma cell line using standard methods. Variable region DNA products from monoclonal antibodies 960K03, 958N02, 956P16, 952G04, 952D15, 914M09, 906C18, 956E02, 550E03, 942K11 were amplified by PCR from selected hybridoma cell line using standard methods and pooled primers to signal peptide and constant regions of the antibody genes. 
     For preparation of recombinant antibodies, DNA sequences coding for the hybridoma VL and VH domain were subcloned into expression vectors containing the respective human heavy or light chain constant region sequences (IgG1, kappa). In some instances this resulted in chimeric antibody chains comprising a murine variable region and human constant region. In some instances this resulted in fully human antibody sequence. In some instances, expression vectors contained wild type human constant region sequences. In some instances, expression vectors contained human constant region sequences comprising site-specific cysteine mutations as has been described previously in WO 2014/124316 and WO 2015/138615. For example, cysteines were introduced at one or more of the following positions (all positions by EU numbering) in an anti-DC-SIGN antibody: (a) positions 152 and/or 375 of the antibody heavy chain, and (b) position 165 of the antibody light chain. In some instances, constant region sequences comprise mutations known in the art to alter binding to Fc-receptors (e.g., D265A/P329A mutations in the heavy chain) to include constructs having reduced Fc effector function. In some instances, expression vectors contain constant regions comprising combinations of the modifications described above. In some instances, expression vectors contained mouse constant region sequences (IgG2a, kappa), either wild-type or with one or more mutations analagous to those described above (e.g. E152C, A375C, D265A, P329A), resulting in fully mouse antibody sequences. Heavy and light chains were cloned into individual expression vectors to allow co-transfection. 
     Humanization of Antibodies 282 and 1G12 
     Variable region constructs were designed for humanization and optimization of sequences (e.g., removal of post-translational modifications, non-preferred sites, etc.). 
     Corresponding DNA sequences coding for humanized VL and VH domains were ordered at GeneArt (Life Technologies Inc. Regensburg, Germany), including codon optimization for  Cricetulus griseus . Sequences coding for VL and VH domains were subcloned from the GeneArt derived vectors into expression vectors suitable for protein production in mammalian cells as described above for parental sequences. In some instances, the expression vector for the heavy chain comprised a truncation resulting in expression of a Fab fragment, and in some instances this constant region sequence was modified with a site-specific cysteine mutation at position 152 as described above, and additionally in some instances there was a sequence encoding a His-tag fused to the C-terminus of the Fab heavy chain coding sequence. Heavy and light chains were cloned into individual expression vectors to allow co-transfection. 
     Optimization of Antibodies 960K03, 958N02, 956P16, 952G04, 952D15 
     Variable region constructs were designed for optimization of sequences by removal of post-translational modifications, non-preferred sites etc. Substitutions were made by site directed mutagenesis using standard methods. Heavy and light chains were cloned into individual expression vectors to allow co-transfection. 
     Antibody Production 
     Recombinant antibodies (IgG1, kappa) were produced by co-transfection of heavy chain and light chain vectors into Freestyle™ 293 expression cells (Invitrogen, USA) using standard methods known in the art and similar to those described previously in Meissner, et al., Biotechnol Bioeng. 75:197-203 (2001). 
     Following transfection, the cells were cultured for one to two weeks prior to antibody purification from supernatant. 
     Alternatively, recombinant antibodies were produced by co-transfection of heavy chain and light chain vectors into CHO cells using methods known in the art. Following transfection, the cells were kept in culture for up to two weeks prior to antibody purification from supernatant. 
     To generate stable cell lines for antibody production, vectors were co-transfected by nucleofection (Nucleofector™ 96-well Shuttle™; Lonza) into CHO cells using manufacturer&#39;s recommendations, and cultured under selection conditions for up to four weeks in shake flasks. Cells were harvested by centrifugation, and supernatant recovered for antibody purification. 
     Antibodies and antibody fragmentsy were purified using Pprotein A, Protein G or MabSelect SuRe (GE Healthcare Life Sciences) columns. Prior to loading the supernatant, the resin was equilibrated with PBS. Following binding of the sample, the column was washed with PBS, and the antibody was eluted with Thermo (Pierce) IgG Elution Buffer pH 2.8 (cat#21004). The eluate fractions were neutralized with sodium citrate tribasic dehydrate buffer, pH 8.5 (Sigma Aldrich cat# S4641-1 Kg). Buffer exchange was performed by dialyzing overnight or by NAP-10™ columns (GE Healthcare), typically into PBS, pH 7.2. In some instances, antibodies may be further purified. One example is to apply the antibody to a size exclusion chromatography (SEC) column such as one with Superdex™ 200 resin (GE Healthcare) and collect the peak corresponding to the monomer species. 
     Summary of Antibodies 
     Table 8 sets forth the relevant sequence information for parental and humanized anti-DC-SIGN antibodies derived from murine hybridomas. Throughout this application, when describing the antibodies, the term “Hybridoma” is used interchangeably and may refer to the antibody that is derived from the hybridoma. 
     Example 5: Biochemical Characterization of Antibodies 
     Affinities of Anti-DC-SIGN Antibodies to DC-SIGN 
     The affinity of various antibodies and ADCs to DC-SIGN and its species orthologues was determined using FACS. Purified IgGs were titrated to determine EC50 values for binding to cell surface expressed DC-SIGN. 
     For this purpose, human DC-SIGN expressing or cynomolgus monkey DC-SIGN expressing stable CHO cell lines or K562 expressing DC-SIGN or K562 expressing L-SIGN cell lines were checked for density and viability using VICELL (Beckman Coulter), and washed once with 4° C. PBS. Cells were stained with DAPI (0.5 ug/mL) diluted in PBS for 30 min on ice. Cells were diluted into 4° C. FACS buffer (PBS, 10 mM EDTA, 2% FBS). 125 μl of cells were seeded (10,000 cells/well) into 96-well v-bottom plates (Nunc cat#442587) and centrifuged for 4 min at 1500 rpm at 4° C. Supernatant was removed. Cells were incubated with a serial dilution of each anti-DC-SIGN antibody in FACS buffer at concentrations ranging across several logs with a top concentration no higher than 50 μg/mL for 60 minutes at 4° C. Following incubation, cells were spun down (1500 rpm, 4 min, 4° C.) and washed two times with FACS buffer. A fluorophore-conjugated anti-hFc gamma-AF-647 (Southern Biotechnology) detection antibody was added at 1:400 and samples were incubated for 1 h on ice in the dark. Following incubation, FACS buffer was added, and the cells were spun down (1500 rpm, 4 min, 4° C.) and washed two times with FACS buffer. After the final wash, cells were resuspended in Fixative Buffer (Biolegend, 420801) and 90 μl of FACS buffer followed by readout on the flow cytometry machine (BD LSRFortessa Cell Analyzer; Cat #647177). Geometric Mean fluorescence intensity (MFI) of live, single cells was calculated in Flowjo 10.4.2 and exported into Graphpad Prism7 for EC50 determination. 
     Selectivity was assessed by measuring apparent binding affinities to isogenic cell pairs engineered to overexpress DC-SIGN as well as cell lines expressing DC-SIGN paralog L-SIGN. Anti-DC-SIGN antibodies bind in a specific manner to DC-SIGN expressing cells only, as shown in Table 22 below. 
     In a similar experiment the antibodies were tested for cross-reactivity using engineered isogenic matched cell line. All antibodies except 892D15 and 942K11 were found to specifically bind human and cynomolgus monkey DC-SIGN at similar apparent affinities, as shown in Table 22 below. 
     
       
         
           
               
             
               
                 TABLE 22 
               
             
            
               
                   
               
               
                 Binding of Various Anti-DC-SIGN Antibodies to DC-SIGN and L-SIGN Expressing Cells 
               
            
           
           
               
               
               
               
               
            
               
                   
                 human DC-SIGN CHO 
                 cyno DC-SIGN CHO 
                 human DC-SIGN K562 
                 human L-SIGN K562 
               
               
                 Antibody Name 
                 EC50 (ug/mL) ave. 
                 EC50 (ug/mL) ave. 
                 EC50 (ug/mL) 
                 EC50 (ug/mL) 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 2B2 Hz 
                 0.06 
                 0.04 
                 0.27 
                 &gt;10 
               
               
                 960K03 N92S 
                 0.06 
                 0.08 
                 0.049 
               
               
                 958N05 S93A 
                 0.13 
                 0.16 
                 0.060 
                 &gt;10 
               
               
                 960K03 N92Q 
                 0.08 
                 0.04 
                 0.021 
                 &gt;10 
               
               
                 952P16 N92Q 
                 0.06 
                 0.04 
                 0.024 
                 &gt;10 
               
               
                 952G04 N92Q 
                 0.07 
                 0.02 
                 0.017 
                 &gt;10 
               
               
                 2B2 Chimeric 
                 0.23 
                 0.32 
                 0.28 
                 &gt;10 
               
               
                 960K03 Parental 
                 0.10 
                 0.02 
               
               
                 958N05 Parental 
                 0.07 
                 0.08 
                 0.05 
               
               
                 952P16 Parental 
                 0.06 
                 0.02 
                 0.04 
               
               
                 952G04 Parental 
                 0.11 
                 0.19 
                 0.26 
               
               
                 892D15 Parental 
                 0.15 
                 15.69 
                 &gt;10 
               
               
                 914M09 Parental 
                 0.10 
                 0.08 
                 0.25 
                 &gt;10 
               
               
                 906C18 Parental 
                 0.21 
                 0.77 
                 1.72 
                 &gt;10 
               
               
                 956 E02 Parental 
                 0.12 
                 0.13 
               
               
                 942K11 Parental 
                 0.20 
                 11.57 
               
               
                 550 E03 Parental 
                 0.26 
                 0.39 
                 1.50 
                 &gt;10 
               
               
                 1G12 Hz 
                 0.07 
                 0.06 
                 0.021 
                 &gt;10 
               
               
                 1G12 mouse 
               
               
                 1G12 Parental 
                 0.06 
                 0.07 
                 0.02 
                 &gt;10 
               
               
                   
               
            
           
         
       
     
     Affinities of Anti-DC-SIGN Antibodies to DC-SIGN 
     The affinity of various antibodies to DC-SIGN Carbohydrate Recognition Domain (CRD) was determined using Biacore. Purified IgGs for the parental antibodies were titrated to determine Kd values for binding to purified antigen domain by two methods described below. 
     In method 1 DC-SIGN was used as the ligand (surface attached) and the antibody the analyte (injected at different concentrations). The DC-SIGN CRD was captured via the His tag on a CM5 chip that was prepared by immobilizing 12000RU NeutrAvidin followed by capturing ˜550RU of Tris-NTA biotin. Fresh DC-SIGN was used for each dose. Each cycle consisted of charging the surface with a 120s pulse of 5 mM NiCl 2 , capturing the same amount of DC-SIGN, injecting the antibody at the desired concentration, and stripping the Ni 2+  with pulses of 350 mM EDTA and 500 mM imidazole to remove all DC-SIGN. Antibodies were injected at concentrations between 250 and 31 nM for 180s and allowed to dissociate for 600s. The reverse orientation was used in method 2-antibody the ligand and DC-SIGN the analyte. A CM5 chip was first prepared with mouse anti-human IgG Fc and used to capture the antibodies. Fresh antibody was used for each dose where each cycle consisted of capturing the same amount of antibody (˜100RU), injecting the desired concentration of DC-SIGN, and stripping the surface of all captured antibody with two 30s pulses of 10 mM glycine pH 2.0. DC-SIGN was injected for 180s at concentrations between 500 and 1.95 nM and dissociated for 600s. All experiments were conducted on a GE Biacore 8K at 25° C. with a flow rate of 30 uL/min in 10 mM HEPES, 500 mM NaCl, 2.5 mM Imidazole, 0.05% Tween 20, pH 7.4. Kinetic parameters were calculated using the 8K analysis software. 
     
       
         
           
               
             
               
                 TABLE 23 
               
             
            
               
                   
               
               
                 Binding of Various Anti-DC-SIGN Antibodies to DC- 
               
               
                 SIGN Carbohydrate Recognition Domain by Biacore 
               
            
           
           
               
               
               
            
               
                   
                   
                 high density 
               
               
                   
                   
                 DC-SIGN 
               
               
                   
                 Ab on chip 
                 CRD on chip 
               
               
                   
                 (nM) 
                 (nM) 
               
               
                   
                   
               
            
           
           
               
               
               
               
            
               
                   
                 960 K03 
                 955 
                 0.8 
               
               
                   
                 906C18 
                 1950 
                 16 
               
               
                   
                 914M09 
                 830 
                 10 
               
               
                   
                 956 E02 
                 999 
                 13 
               
               
                   
                 942K11 
                 1260 
                 180 
               
               
                   
                 550Ee03 
                 523 
                 5.8 
               
               
                   
                 952P16 
                 395 
                 3.8 
               
               
                   
                 952G04 
                 346 
                 3.7 
               
               
                   
                 958N05 
                 174 
                 1.7 
               
               
                   
                 892D15 
                 47600 
                 111 
               
               
                   
                 2b2 
                 32 
                 0.5 
               
               
                   
                   
               
            
           
         
       
     
     Epitope Binning Using Octet Red96 System 
     Epitope binning of anti-DC-SIGN parental antibodies was performed using the Octet Red96 system (ForteBio, USA) that measures biolayer interferometry (BLI). For this purpose the DC-SIGN extracellular domain with the AviHis tag (SEQ ID NO: 317) was biotinylated via an AviTag™ utilizing BirA biotin ligase according to Manufacturer&#39;s recommendations (Avidity, LLC, USA cat# BirA500). The biotinylated immunogen scaffold was loaded at 0.4 μg/ml onto pre-equilibrated streptavidin sensors (ForteBio, USA). The sensors were then transferred to a solution containing 100 nM antibody A in 1× kinetics buffer (ForteBio, USA). Sensors were briefly washed in 1× kinetics buffer and transferred to a second solution containing 33.3 nM of competitor antibody B. Binding kinetics parameters were determined from raw data using the Octet Red96 system analysis software (Version 6.3, ForteBio, USA). Antibodies were tested in all pairwise combinations, as both Antibody A and as competitor antibody B. 
     
       
         
           
               
             
               
                 TABLE 24 
               
             
            
               
                   
               
               
                 Antibody Binning Results 
               
            
           
           
               
               
               
            
               
                   
                 Bin 
                 Antibody 
               
               
                   
                   
               
               
                   
                 1 
                 2B2, 892D15, 960K03, 906C18, 952P16, 942G04 
               
               
                   
                 2 
                 914M09, 956E02 
               
               
                   
                 3 
                 942K11 
               
               
                   
                   
               
            
           
         
       
     
     Epitope Mapping Using Hydrogen/Deuterium Exchange Mass Spectrometry (HD×MS) 
     Additional epitope mapping was carried out for antibody 2B2 using HD×MS. DC-SIGN ECD (SEQ ID NO: 319) was concentrated 5× using a 10 kDa MWCO micro-concentrator. 5 μg of protein was used in each sample and DCSIGN ECD/mAb complexes were prepared by mixing an equimolar amount of DC-SIGN ECD (SEQ ID NO: 319) and each mAb separately. Complexes were allowed to form for 30 min. at room temp before labeling. 
     For non-deuterated, deuterated controls and deuterated complexes, each sample was diluted with the appropriate volume of labeling buffer (50 mM Phosphate buffer, pH 7.6 or pH 8.6, 150 mM NaCl in H 2 O) to bring the total volume to 10 μL. Solutions were placed in 1.5 mL vials and placed in a rack at either 0° C. or 20° C. The labeling step for all samples was performed with the addition of 50 μL of labeling buffer (50 mM Phosphate buffer, pH 7.6 or 8.6, 150 mM NaCl in H 2 O) to each sample. Solutions were incubated for 5 min. Vials were transferred to an ice water bath and 250 μL of reduction buffer (8M GndHCl, 1M TCEP, pH2.5) was added and mixed. After 2 min, 300 μL of ice cold quench buffer (0.25% formic acid, 12.5% glycerol) was added and the solutions were immediately frozen in liquid nitrogen. Vials were transferred to the −70° C. freezer attached to a PAL autosampler for HDx analysis. Samples were thawed for 2 min and 500 μL was injected through an in-line pepsin column into the LC-MS system. Proteolytic peptides were sequenced by tandem mass spectrometry (MS/MS) and deuteration values were extracted using HDExaminer. 
     
       
         
           
               
             
               
                 TABLE 25 
               
             
            
               
                   
               
               
                 Antibody 2B2 protected exchange of the amide 
               
               
                  hydrogens in the peptides with the sequences 
               
            
           
           
               
               
               
            
               
                 Peptide 
                   
                   
               
               
                 protected 
                 Amino acid sequence 
               
               
                   
               
               
                 1 
                 VVIKSAEEQNF 
                 SEQ ID NO: 320 
               
               
                   
               
               
                 2 
                 LQLQSSRSNRFTWMGLSDL 
                 SEQ ID NO: 321 
               
               
                   
               
               
                 3 
                 NQEGTWQWVDGSPLL 
                 SEQ ID NO: 322 
               
               
                   
               
               
                 4 
                 NQEGTWQWVDGSPLLPSF 
                 SEQ ID NO: 323 
               
               
                   
               
            
           
         
       
     
     Example 6: Preparation of Anti-DC-SIGN-STING Agonist Conjugates 
     A) Preparation of Anti-DC-SIGN Antibody with Specific Cysteine (Cys) Mutations 
     Preparation of anti-DC-SIGN antibodies and other antibodies with site-specific cysteine mutations has been described previously in WO 2014/124316 and WO 2015/138615, each of which was incorporated by reference herein. 
     Reduction, Reoxidation and Conjugation of Cys Mutant Anti-DC-SIGN Antibodies to STING Agonists 
     Some compounds described herein comprising a linker were conjugated to Cys residues engineered into an antibody similar to what is described in Junutula J R, et al., Nature Biotechnology 26:925-932 (2008). 
     Because engineered Cys residues in antibodies expressed in mammalian cells are modified by adducts (disulfides) such as glutathione (GSH) and/or cysteine during biosynthesis (Chen et al. 2009), the modified Cys as initially expressed is unreactive to thiol reactive reagents such as maleimido or bromo-acetamide or iodo-acetamide groups. To conjugate engineered Cys residues, glutathione or cysteine adducts need to be removed by reducing disulfides, which generally entails reducing all disulfides in the expressed antibody. This can be accomplished by first exposing antibody to a reducing agent such as dithiothreitol (DTT) followed by reoxidation of all native disulfide bonds of the antibody to restore and/or stabilize the functional antibody structure. Accordingly, in order to reduce native disulfide bonds and disulfide bonds between the cysteine or GSH adducts of engineered Cys residue(s), freshly prepared DTT was added to previously purified Cys mutant antibodies to a final concentration of 10 mM. After antibody incubation with DTT at 37° C. for 30 minutes, mixtures were buffer exchanged to PBS pH 8.0 by passing through PD-10 columns (GE Healthcare). Alternatively, DTT can be removed by a dialysis step. Samples were incubated at room temperature for up to two days. The reoxidation process was monitored by reverse-phase HPLC, which is able to separate antibody tetramer from individual heavy and light chain molecules. Reactions were analyzed on a PRLP-S 4000A column (50 mm×2.1 mm, Agilent) heated to 80° C. and column elution was carried out by a linear gradient of 30-60% acetonitrile in water containing 0.1% TFA at a flow rate of 1.5 mL/min. The elution of proteins from the column was monitored at 280 nm. Incubation was allowed to continue until reoxidation was complete. After reoxidation, a maleimide-containing compound selected from compound (C1), (C2), (C3), (C4), (C5), (C6), (C7), (C8), (C9), (C10), (C11), (C12), (C13), (C14), (C15), (C16), (C17), (C18), (C19), (C20), (C21), (C22), (C23a), (C23b), (C24), (C25a), (C25b), (C26), (C27), (C28), (C29), (C30), (C31), (C32), (C33), (C34), (C35), (C36a), (C36b), (C37a), (C37b), (C38), (C39), (C40), (C41), (C42a), (C42b), (C43), (C44a), (C44b) or (C45) was added to reoxidized antibody in PBS buffer (pH 7.2) at molar ratios of typically 1:1, 1.5:1, 2.5:1, or 5:1 to engineered Cys, and incubations were carried out for up to 60 minutes at room temperature. Excess free compound was removed by purification over Protein A resin by standard methods followed by buffer exchange into PBS. 
     Cys mutant antibodies or antibody fragments were alternatively reduced and reoxidized using an on-resin method. Protein A Sepharose beads (1 mL per 10 mg antibody) were equilibrated in PBS (no calcium or magnesium salts) and then added to an antibody sample in batch mode. For Fab samples with a C-terminal His-tag, Ni-NTA resin (Qiagen) was substituted for this step, and the samples were treated similarly to full length antibodies in all other respects. A stock of 0.5 M cysteine was prepared by dissolving 850 mg of cysteine HCl in 10 mL of a solution prepared by adding 3.4 g of NaOH to 250 mL of 0.5 M sodium phosphate pH 8.0 and then 20 mM cysteine was added to the antibody/bead slurry, and mixed gently at room temperature for 30-60 minutes. Beads were loaded to a gravity column and washed with 50 bed volumes of PBS in less than 30 minutes, then the column was capped with beads resuspended in one bed volume of PBS. To modulate the rate of reoxidation, 50 nM to 1 μM copper chloride was optionally added. The reoxidation progress was monitored by removing a small test sample of the resin, eluting in IgG Elution buffer (Thermo), and analyzing by RP-HPLC as described above. Once reoxidation progressed to desired completeness, conjugation could be initiated immediately by addition of 1-5 molar equivalent of compound over engineered cysteines, and allowing the mixture to react for 5-10 minutes at room temperature before the column was washed with at least 20 column volumes of PBS. Antibody conjugates were eluted with IgG elution buffer and neutralized with 0.1 volumes 0.5 M sodium phosphate pH 8.0 and buffer exchanged to PBS. Alternatively, instead of initiating conjugation with antibody on the resin, the column was washed with at least 20 column volumes of PBS, and antibody was eluted with IgG elution buffer and neutralized with buffer pH 8.0. Antibodies were then either used for conjugation reactions or flash frozen for future use. 
     Anti-DC-SIGN Fab fragments were reduced, re-oxidized, and conjugated using a similar on-resin method. For Fab samples with a C-terminal His-tag, Ni-NTA resin (Qiagen) was substituted for this step, and the samples were treated similarly to full length antibodies for reduction and re-oxidation. As with the full length antibodies, the reduction is used to uncap the native and engineered cysteines (e.g. HC-E152C or HC-E152C-LC-S165C), and the re-oxidation of the native disulfides, including the interchain disulfide, leaves only the introduced cysteines available for combination. 
     Conjugates were typically buffer exchanged to PBS pH 7.2 and analyzed by methods described below. In some instances, conjugates were further purified by standard preparative size exclusion chromatography methods. 
     A general reaction scheme for conjugation of the compounds (C1), (C2), (C3), (C4), (C5), (C6), (C7), (C8), (C9), (C10), (C11), (C12), (C13), (C14), (C15), (C16), (C17), (C18), (C19), (C20), (C21), (C22), (C23a), (C23b), (C24), (C25a), (C25b), (C26), (C27), (C28), (C29), (C30), (C31), (C32), (C33), (C34), (C35), (C36a), (C36b), (C37a), (C37b), (C38), (C39), (C40), (C41), (C42a), (C42b), (C43), (C44a), (C44b) or (C45) to an antibody having free thiols (obtained using the methods described above) is given below: 
     
       
         
         
             
             
         
       
     
     Here, D-L-R 15  represents any one of compounds (C1), (C2), (C3), (C4), (C5), (C6), (C7), (C8), (C9), (C10), (C11), (C12), (C13), (C14), (C15), (C16), (C17), (C18), (C19), (C20), (C21), (C22), (C23a), (C23b), (C24), (C25a), (C25b), (C26), (C27), (C28), (C29), (C30), (C31), (C32), (C33), (C34), (C35), (C36a), (C36b), (C37a), (C37b), (C38), (C39), (C40), (C41), (C42a), (C42b), (C43), (C44a), (C44b) or (C45), where D represent the cyclic dinucleotide in each respective compound, L is the linker moiety in each respective compound and R 15  is the maleimide group in each respective compound. 
     Properties of the Anti-DC-SIGN-STING Agonist Conjugates 
     Antibody-STING agonist conjugates were analyzed to determine extent of conjugation. A compound-to-antibody ratio was extrapolated from LC-MS data for reduced and deglycosylated samples. LC-MS allows quantitation of the average number of molecules of linker-payload (compound) attached to an antibody in a conjugate sample. HPLC separates antibody into light and heavy chains, and separates heavy chain (HC) and light chain (LC) according to the number of linker-payload groups per chain. Mass spectral data enables identification of the component species in the mixture, e.g., LC, LC+1, LC+2, HC, HC+1, HC+2, etc. From the average loading on the LC and HC chains, the average compound to antibody ratio can be calculated for an antibody conjugate. A compound-to-antibody ratio for a given conjugate sample represents the average number of compound (linker-payload) molecules attached to a tetrameric antibody containing two light chains and two heavy chains. 
     Conjugates were profiled using analytical size-exclusion chromatography (AnSEC) on Zenix C-300 3 um 7.8×150 mm column (Sepax Technologies). Alternatively, samples were tested on a KW-803 column (TIC Cat#6960940). The purity with respect to aggregation was analyzed based on analytical size exclusion chromatography (AnSEC) and reported as the percent monomer based on AUC of the assigned monomer peak. 
     Most conjugates achieved high compound-to-antibody ratio and were mainly monomeric. Conjugation through this method results in conjugation efficiencies of greater than 90% for most compounds (Table 26, below). The majority of the conjugates achieve greater than 95% purity as assessed by AnSEC (Table 26). These results suggest that conjugates described herein can be made efficiently and have favorable characteristics. 
     In the Examples below, unless otherwise indicated, all DC-SIGN conjugates used were the DAR4 version. 
     
       
         
           
               
             
               
                 TABLE 26 
               
             
            
               
                   
               
               
                 Properties of anti-DC-SIGN-STING agonist conjugates 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 Linker- 
                   
                 Compound-to- 
                 Conjugation 
                   
               
               
                 Antibody 
                 Payload 
                 Payload 
                 antibody ratio 
                 Efficiency (%) 
                 % Monomer 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 2B2 Hz 
                 C1 
                 T1-1 
                 3.9 
                 98 
                 99 
               
               
                 2B2 Hz 
                 C2 
                 T1-1 
                 3.6 
                 90 
                 ND  a   
               
               
                 2B2 Hz 
                 C18 
                 T1-2 
                 4.0 
                 100 
                 ND  a   
               
               
                 2B2 Hz 
                 C23 
                 T1-6 
                 3.2 
                 80 
                 ND  a   
               
               
                 2B2 Hz 
                 C36 
                 T1-6 
                 3.6 
                 90 
                 ND  a   
               
               
                 2B2 Hz 
                 C29 
                 T1-1 
                 3.6 
                 90 
                 ND  a   
               
               
                 2B2 Hz 
                 C31 
                 T1-1 
                 3.6 
                 90 
                 ND  a   
               
               
                 2B2 Hz DAR2-1 (e152) 
                 C1 
                 T1-1 
                 1.8 
                 90 
                 99 
               
               
                 2B2 Hz DAR2-2 (s375) 
                 C1 
                 T1-1 
                 2.0 
                 100 
                 99 
               
               
                 2B2 Hz Fab (DAR1) 
                 C1 
                 T1-1 
                 0.9 
                 88 
                 99 
               
               
                 2B2 Hz Fab2 (DAR2) 
                 C1 
                 T1-1 
                 1.7 
                 83 
                 96 
               
               
                 2B2 Chimeric 
                 C1 
                 T1-1 
                 3.8 
                 95 
                 98 
               
               
                 550 E03 Parental 
                 C1 
                 T1-1 
                 3.7 
                 93 
                 97 
               
               
                 952P16 Parental 
                 C1 
                 T1-1 
                 3.9 
                 97 
                 98 
               
               
                 952G04 Parental 
                 C1 
                 T1-1 
                 3.9 
                 97 
                 99 
               
               
                 958N05 Parental 
                 C1 
                 T1-1 
                 3.8 
                 96 
                 98 
               
               
                 892D15 Parental 
                 C1 
                 T1-1 
                 3.8 
                 96 
                 99 
               
               
                 960K03 Parental 
                 C1 
                 T1-1 
                 4.2 
                 106 
                 96 
               
               
                 906C18 Parental 
                 C1 
                 T1-1 
                 3.9 
                 97 
                 96 
               
               
                 914M09 Parental 
                 C1 
                 T1-1 
                 4.0 
                 100 
                 99 
               
               
                 956 E02 Parental 
                 C1 
                 T1-1 
                 3.8 
                 95 
                 98 
               
               
                 942K11 Parental 
                 C1 
                 T1-1 
                 3.8 
                 96 
                 98 
               
               
                 958N05 S93A 
                 C31 
                 T1-1 
                 3.9 
                 98 
                 96 
               
               
                 958N05 S93A 
                 C18 
                 T1-2 
                 3.9 
                 97 
                 95 
               
               
                 960K03 N92S 
                 C31 
                 T1-1 
                 3.8 
                 96 
                 96 
               
               
                 960K03 N92S 
                 C18 
                 T1-2 
                 TBD  b   
                 TBD  b   
                 94/99 c   
               
               
                 1G12 mouse 
                 C1 
                 T1-1 
                 3.5 
                 88 
                 99 
               
               
                 2B2 Hz 
                 C31 
                 T1-1 
                 4.0 
                 100 
                 98 
               
               
                 2B2 Hz 
                 C18 
                 T1-2 
                 3.8 
                 95 
                 94 
               
               
                 2B2 Hz DAR2-1 (e152) 
                 C18 
                 T1-2 
                 1.8 
                 90 
                 99 
               
               
                 2B2 Hz DAR2-1 (e152) 
                 C31 
                 T1-1 
                 2.0 
                 100 
                 98 
               
               
                 Control DAPA DAR4 
                 C31 
                 T1-1 
                 4.0 
                 100 
                 94 
               
               
                 Control DAPA DAR4 
                 C18 
                 T1-2 
                 4.0 
                 100 
                 94 
               
               
                   
               
               
                   a  ND: not determined 
               
               
                   b  TBD: to be determined 
               
               
                   c Values reported before and after preparative SEC. 
               
            
           
         
       
     
     Example 7: DC-SIGN Immunoconjugates are Able to Activate Human DCs and Macrophages In Vitro 
     Primary human monocytes were isolated from a leukapheresis using magnetic bead selection and frozen for storage in liquid nitrogen. For monocyte DC (moDC) differentiation, cells were thawed and incubated in media containing GM-CSF and IL-4 for 7 days. For M2 macrophages (M2 moMacs), cells were thawed and incubated for 6 days with M-CSF containing media and then polarized with the addition of IL-4 for 24 hours. After the differentiation process for both moDC and moMacs, media was washed off and replaced with fresh media containing isotype control (DAPA version of Trastuzumab) C1, or DC-SIGN antibody C1 conjugates. Free T1-1 compound was used as a control. 24 hours after incubation with indicated compounds, cells were evaluated by flow cytometry for activation. 
     As shown in  FIG. 1 , all DC-SIGN antibody C1 immunoconjugates induced downregulation of DC-SIGN on monocyte dendritic cells and macrophages, indicating target engagement ( FIGS. 1A and 1C ). All DC-SIGN antibody C1 immunoconjugates induced monocyte dendritic cell and macrophage activation as measured by CD86 upregulation ( FIGS. 1B and 1D ). 
     The differentiated moDC and moMacs were also treated with isotype control (DAPA) or humanized 2B2 (DAPA) conjugated to C1, C18 or C31 payloads. Free T1-1 compound was used as a control. 24 hours after incubation with indicated compounds, cells were evaluated by flow cytometry for activation. 
     As shown in  FIG. 2 , 2B2 (DAPA) immunoconjugates of C1, C18 and C31 induced downregulation of DC-SIGN on monocyte dendritic cells and macrophages ( FIGS. 2A and 2C ), indicating target engagement. 2B2 (DAPA) immunoconjugates of C1, C18 and C31 induced monocyte dendritic cell and macrophage activation as measured by CD86 upregulation ( FIGS. 2B and 2D ). 
     DAR2 version of the 2B2 (DAPA) C1 immunoconjugates were tested for activity on human monocyte DCs and macrophages. After the differentiation process, moDC and moMacs were treated with humanized (Hz) 2B2 (DAPA) C1, isotype control (DAPA) C1, Hz 2B2 (DAPA) DAR2 C1, or T1-1. 24 hours after incubation with indicated compounds, cells were evaluated by flow cytometry for activation. 
     As shown in  FIG. 3 , Hz 2B2 (DAPA) C1 and Hz 2B2 (DAPA) DAR2 C1 induced downregulation of DC-SIGN on monocyte dendritic cells and macrophages ( FIGS. 3A and 3C ), indicating target engagement. Hz 2B2 (DAPA) C1 and Hz 2B2 (DAPA) DAR2 C1 induced monocyte dendritic cell and macrophage activation as measured by CD86 upregulation ( FIGS. 3B and 3D ). 
     Primary human monocytes were isolated from a leukapheresis using magnetic bead selection and frozen for storage in liquid nitrogen. For monocyte DC (moDC) differentiation, cells were thawed and incubated in media containing GM-CSF and IL-4 for 7 days. After the differentiation process for both moDC and moMacs, media was washed off and replaced with fresh media containing isotype control (DAPA) or 960K03 (DAPA) conjugated to C31 payload. Free T1-1 compound was used as a control. 24 hours after incubation with indicated compounds, cells were evaluated by flow cytometry for activation. 
     As shown in  FIG. 26 , 960K03 (DAPA) C31 conjugate induced downregulation of DC-SIGN on monocyte dendritic cells, indicating target engagement ( FIG. 26A ). 960K03 (DAPA) C31 induced monocyte dendritic cell activation (as measured by CD86 upregulation) with less payload than the isotype control (DAPA) C31 conjugate or unconjugated T1-1 ( FIG. 26B ). 960K03 (DAPA) C31 also induced IP-10 secretion into the culture supernatant at a higher concentration with less payload than the isotype control (DAPA) C31 conjugate or unconjugated T1-1 ( FIG. 26C ). 
     Example 8: DC-SIGN Immunoconjugates Induce DC Activation and Cytokine Production in Tg+ Mice 
     Transgenic mice expressing human DC-SIGN gene (Tg+) or DC-SIGN negative control littermates (Tg−) were treated intravenously with 1 mg/kg of Hz 2B2 (DAPA) conjugated to the following payloads: C1, C2, C31, C23a/b, C36a/b or C28. Blood was collected at 6 hours post dose to analyze plasma cytokine and chemokine levels and spleens were analyzed at 24 hours post dose to look at dendritic cell activation. 
     As shown in  FIG. 4 , in the transgenic mouse model used here, all Hz 2B2 (DAPA) immunoconjugates except for C2 induced proinflammatory cytokine release at 6 hours post dose including IL-6 ( FIG. 4C ), TNFα ( FIG. 4D ) and IP-10 ( FIG. 4B ). All Hz 2B2 (DAPA) immunoconjugates except for C2 induced dendritic cell maturation as measured by CD86 upregulation at 24 hours post dose ( FIG. 4A ). 
     Transgenic mice expressing human DC-SIGN gene (Tg+) or transgene-negative littermate control (Tg−) mice were treated with Hz 2B2 (DAPA), 2B2 (DAPA)-C1, or isotype control (DAPA) C1 at 1 milligram per kilogram body weight (mpk) intravenously (i.v.). Mice were bled 6 hours after dosing to collect plasma for analysis of circulating cytokine levels. 
     As shown in  FIG. 5 , Tg+ mice showed a robust increase in circulating plasma IP-10 ( FIG. 5A ), IFN ( FIG. 5B ), IL-6 ( FIG. 5C ), TNFα ( FIG. 5D ) and IL-12p70 ( FIG. 5E ). 
     Spleens were harvested 24 hours post dose and analyzed by flow cytometry to look at CD11c+ dendritic cells. 
     As shown in  FIG. 6 , DC-SIGN levels were significantly reduced in Tg+ mice treated with humanized 2B2 (DAPA)-C1 ( FIG. 6A ), indicating target engagement. Both CD80 and CD86 were highly upregulated in CD8+ and CD11b+ DCs from mice treated with humanized 2B2 (DAPA)-C1 ( FIGS. 6B-6E ), demonstrating dendritic cell activation. 
     Transgenic mice expressing human DC-SIGN gene (Tg+) or transgene-negative littermate control (Tg−) mice were treated intravenously (i.v.) with 1 mg/kg of the indicated anti-DC-SIGN antibodies (DAPA format) conjugated to C1. Spleens were harvested 24 hours post dose and analyzed by flow cytometry to look at CD11c+ dendritic cells. 
     As shown in  FIG. 7 , Tg+ mice treated with anti-DC-SIGN (DAPA) C1 conjugates had a significant downregulation of surface DC-SIGN ( FIGS. 7A and 7C ), indicating target engagement. Tg+ mice treated with anti-DC-SIGN (DAPA) C1 conjugates also had a robust upregulation of CD86 on the surface of dendritic cells indicative of DC activation ( FIGS. 7B and 7D ). 
     Transgenic mice expressing human DC-SIGN gene (Tg+) or transgene-negative littermate control (Tg−) mice were treated intravenously (i.v.) with 1 mg/kg of the indicated anti-DC-SIGN antibodies (DAPA format) conjugated to C1. Mice were bled 6 hours after dosing to collect plasma for analysis of circulating cytokine levels. 
     As shown in  FIG. 8 , Tg+ mice treated with anti-DC-SIGN (DAPA) C1 conjugates showed robust increases in plasma IP-10 ( FIGS. 8A and 8C ) and TNFα levels ( FIGS. 8B and 8D ) indicative of activation. 
     Transgenic mice expressing human DC-SIGN gene (Tg+) or transgene-negative littermate control (Tg−) mice were treated with 960K03 (DAPA) DAR4 C31 at 0.01, 0.03, 0.1, 0.3 or 1 milligram per kilogram body weight (mpk) intravenously (i.v.). Mice were bled 6 hours after dosing to collect plasma for analysis of circulating cytokine levels. 
     As shown in  FIG. 24 , Tg+ mice showed a robust increase in circulating plasma IP-10 ( FIG. 24A ) and TNFα ( FIG. 24B ). 
     Transgenic mice expressing human DC-SIGN gene (Tg+) or transgene-negative littermate control (Tg−) mice were treated with 960K03 (DAPA) DAR4 C31 at 0.01, 0.03, 0.1, 0.3 or 1 milligram per kilogram body weight (mpk) intravenously (i.v.). Spleens were harvested 24 hours post dose and analyzed by flow cytometry to look at CD11c+ dendritic cells. 
     As shown in  FIG. 25 , DC-SIGN levels were significantly reduced in Tg+ mice treated with 960K03(DAPA) DAR4 C31 ( FIG. 25A ), indicating target engagement. CD86 was highly upregulated on CD11c+ dendritic cells in a dose dependent manner in Tg+ mice treatment with 960K03(DAPA) DAR4 C31 ( FIG. 25B ), demonstrating dendritic cell activation 
     Example 9: WT, Fc Silent, Fab2 and Fab Versions of 2B2 C1 Immunoconjugates Induce Cytokine Production and DC Activation in Tg+ Mice 
     Transgenic mice expressing human DC-SIGN gene (Tg+) and Tg− controls were treated intravenously with 1 mg/kg of Hz 2B2 (DAPA) C1, 1 mg/kg of 2B2 C1 (WT Fc), 1.33 mg/kg 2B2 Fab2 DAR2 C1, 1.3 mg/kg 2B2 Fab DAR1 C1 or 1 mg/kg of isotype control (DAPA) C1 conjugates. Blood was collected at 6 hours post dose to analyze plasma IP-10 and IL-12p70 levels. Spleens were analyzed at 24 hours post dose to look at dendritic cell activation. 
     As shown in  FIG. 9 , DAPA and VVT Fc formats as well as Fab2 and Fab C1 conjugates induced IP-10 production ( FIG. 9A ). DAPA, VVT and Fab2 formats induced IL-12p70 production in Tg+ mice in a target dependent manner ( FIG. 9B ). 
     As shown in  FIG. 10 , DAPA and VVT Fc formats as well as Fab2 and Fab versions of 2B2 C1 conjugates induced DC-SIGN downregulation ( FIG. 10A ), indicative of target engagement and CD86 upregulation on DCs ( FIG. 10B ), indicative of DC activation in Tg+ mice. 
     The activity on human monocyte derived DCs was tested for the WT and Fc silent formats of the 2B2 C1 immunoconjugate. Primary human monocytes were isolated from a leukapheresis using magnetic bead selection and frozen for storage in liquid nitrogen. For monocyte DC (moDC) differentiation, cells were thawed and incubated in media containing GM-CSF and IL-4 for 7 days. After the differentiation process, media was washed off and replaced with fresh media containing isotype control (DAPA), humanized 2B2 (DAPA), isotype control (WT) or 2B2 (WT) conjugated to C1. Free T1-1 compound was used as a control. 24 hours after incubation with indicated compounds, cells were evaluated by flow cytometry for activation. 
     As shown in  FIG. 11 , both WT and DAPA 2B2 C1 conjugates induced downregulation of DC-SIGN on monocyte dendritic cells, indicating target engagement ( FIG. 11A ). Both VVT and DAPA 2B2 C1 conjugates induced monocyte dendritic cell activation as measured by CD86 upregulation ( FIG. 11B ). 
     Transgenic mice expressing human DC-SIGN gene (Tg+) and Tg− controls were treated intravenously with 5 mg/kg of Hz 2B2 (DAPA)-C1 immunoconjugates, 2B2 (Fc silent) C1 immunoconjugates or saline as a control. Blood was collected at 6 hours post dose to analyze plasma IP-10 and TNFα levels. 
     As shown in  FIG. 12 , both DAPA and Fc silent versions of 2B2 C1 Immunoconjugates induced high levels of circulating IP-10 ( FIG. 12A ) and TNFα ( FIG. 12B ). Spleens were analyzed at 24 hours post dose to look at dendritic cell activation. Both DAPA and Fc silent versions of 2B2 C1 conjugates induced DC-SIGN downregulation ( FIG. 12C ) indicative of target engagement and CD86 upregulation on DCs ( FIG. 12D ) indicative of DC activation in Tg+ mice. 
     Example 10: DC-SIGN Immunoconjugates Induce Cytokine Production and DC Activation in a Target Dependent Manner 
     The induction of cytokine production and dendritic cell activation by DC-SIGN immunoconjugates and by free payload was compared. Transgenic mice expressing human DC-SIGN gene (Tg+) were treated intravenously with 1 mg/kg of 2B2 (DAPA) C1 conjugate (approximately equivalent to 0.5 micrograms (μg) of T1-1 compound), 10 μg or 100 μg of free T1-1 compound. Mice were bled 6 hours after dosing and plasma was collected for circulating cytokine analysis. 
     As shown in  FIG. 13 , Tg+ mice dosed with 1 mg/kg of 2B2 (DAPA) C1 or 100 μg free T1-1 had increased circulating plasma IL-12p70 ( FIG. 13C ), TNFα ( FIG. 13B ) and IP-10 ( FIG. 13A ) levels compared to the untreated Tg+ mice and compared to mice treated with 10 μg of free T1-1 compound. 
     Transgenic mice expressing human DC-SIGN gene (Tg+) were treated intravenously with 1 mg/kg of 2B2 (DAPA)-C1 immunoconjugates (approximately equivalent to 0.5 micrograms (μg) of T1-1 compound), 10 μg or 100 μg of free T1-1 compound. Mice were sacrificed 24 hours post dosing and spleens were analyzed for CD11c+DC activation by flow cytometry. 
     As shown in  FIG. 14 , DC-SIGN levels were significantly reduced in Tg+ mice treated with humanized 2B2 (DAPA)-C1 ( FIG. 14A ), indicating target engagement. CD80 and CD86 were significantly upregulated on the surface of DCs from mice treated with 2B2 (DAPA) C1 and to a greater extent than was observed in animals treated with free T1-1 ( FIGS. 14B and 14C ). 
     Example 11: DC-SIGN Immunoconjugates with Different Anti-DC-SIGN Antibodies and in DAR2 Format Induce Cytokine Production and DC Activation 
     Another DC-SIGN immunoconjugate was evaluated for its activity to induce cytokine production and DC activation. Transgenic mice expressing human DC-SIGN gene (Tg+) or transgene-negative littermate control (Tg−) mice were treated with parental 1G12 (DAPA) C1 (mlgG2a isotype) at 1 milligram per kilogram body weight (mpk) intravenously (i.v.). Mice were bled 6 hours after dosing to collect plasma for analysis of circulating cytokine levels. Spleens were harvested 24 hours post dose and analyzed by flow cytometry to look at CD11c+ dendritic cells. 
     As shown in  FIG. 15 , Tg+ mice treated with 1G12 (DAPA) C1 had a significant downregulation of surface DC-SIGN ( FIG. 15A ), indicating target engagement. Tg+ mice treated with 1G12 (DAPA) C1 also had a significant upregulation of CD86 on the surface of dendritic cells indicating activation ( FIG. 15B ). IP-10 ( FIG. 15D ) and IL-12p70 ( FIG. 15C ) plasma levels were significantly increased in Tg+ mice treated with 1G12 (DAPA) C1 at 6 hours post dose, indicative of on target activation through DC-SIGN. 
     The induction of dendritic cell activation by DAR4 and DAR2 versions of DC-SIGN immunoconjugates was compared. Transgenic mice expressing human DC-SIGN gene (Tg+) were treated intravenously with 1 mg/kg of Hz 2B2 (DAPA) C1 immunoconjugates, 2 mg/kg of Hz 2B2 (DAPA) DAR2 C1 immunoconjugates (dosed to deliver equivalent T1-1 payload as 1 mg/kg dose of 2B2 (DAPA) C1), 1 mg/kg of Hz 2B2 (DAPA) DAR2 C1 immunoconjugates (dosed at the equivalent antibody dose as 1 mg/kg dose of 2B2 (DAPA) C1) or 1 mg/kg of isotype control (DAPA) C1. Blood was collected at 6 hours post dose to analyze plasma IP-10 and IL-12p70 levels and spleens were analyzed at 24 hours post dose to look at dendritic cell activation. 
     As shown in  FIG. 16 , both antibody and payload matched doses of 2B2 (DAPA) DAR2-C1 induced DC activation as measured by CD86 upregulation ( FIG. 16A ) as well as IL-12p70 secretion ( FIG. 16C ) and IP-10 secretion ( FIG. 16B ) in a target dependent manner. 
     Example 12: DC-SIGN Immunoconjugate Enhances Antibody Responses to DNP-KLH and Promotes Isotype Switching in Tg+ Mice 
     Transgenic mice expressing human DC-SIGN gene (Tg+) were immunized with DNP-KLH formulated in alum or PBS in alum as a control. One day after immunization, some mice received 1 mg/kg of Hz 2B2 (DAPA) C1 or isotype control (DAPA) C1 intravenously. 10 days post dose, blood plasma was collected and analyzed for DNP binding antibodies by ELISA. 
     As shown in  FIG. 17 , mice treated with 2B2 (DAPA) C1 show a significant increase in total DNP binding IgG ( FIG. 17A ) and also in IgG2a ( FIG. 17C ) and IgG3 ( FIG. 17D ) subclasses of DNP binding antibodies but not IgG1 ( FIG. 17B ). 
     Example 13: DC-SIGN Immunoconjugates Delay Tumor Growth in Transgenic Mice Expressing DC-SIGN 
     Female transgenic mice expressing human DC-SIGN gene (Tg+) or Tg− animals were implanted with 2.5×10 5  MC38 tumor cells subcutaneously in the hind flank. Tumors were measured 3 times weekly throughout the course of the study. When tumors reached 100-200 cubic millimeters (mm 3 ), mice were treated with a single dose of 1 mg/kg 2B2 (DAPA) or 1 mg/kg 2B2 (DAPA)-C1. Mice were sacrificed 7 days after dosing. 
     As shown in  FIG. 18 , DC-SIGN Tg+ mice treated with 1mpk of 2B2 (DAPA) C1 conjugate had significantly delayed tumor growth kinetics, whereas Tg− mice did not show any impairment in tumor growth with either dose of the conjugate. 
     Spleens and tumors were analyzed 24 hours post dose by flow cytometry for PDL1 expression. As shown in  FIG. 19 , splenic CD11c high dendritic cells ( FIG. 19A ) and tumor resident dendritic cells and monocytic myeloid derived suppressor cells (mMDSCs) ( FIG. 19B ) showed a significant upregulation of surface PDL1 in Tg+ mice dosed with 1 mg/kg 2B2 (DAPA) C1. 
     The effect of DC-SIGN immunoconjugate on tumor T cell infiltration was also evaluated. Female transgenic mice expressing human DC-SIGN gene (Tg+) or Tg− animals were implanted with 2.5×10 5  MC38 tumor cells subcutaneously in the hind flank. Tumors were measured 3 times weekly throughout the course of the study. When tumors reached 100-200 cubic millimeters (mm 3 ), mice were treated with a single dose of vehicle control (PBS) or 1 mpk 2B2 (DAPA)-C1. Mice After the mice were sacrificed 7 days after dosing, tumors were analyzed for T cell infiltration and activation by flow cytometry. 
     As shown in  FIG. 20 , increased CD3+ T cells were observed 24 and 48 hours post dosing in Tg+ mice dosed with 2B2 (DAPA) C1 mice ( FIGS. 20A and 20B ). On day 7 post dose, a significant increase in CD8+ T cells ( FIG. 20C ) and a significant decrease in FoxP3+T regulatory cells ( FIG. 20D ) were observed in tumors from Tg+ mice dosed with 2B2 (DAPA) C1. Enhanced T cell activation as measured by CD69 upregulation was seen on CD4 and CD8 T cells in tumors from Tg+ mice dosed with 2B2 (DAPA) C1 24 hours post dose ( FIGS. 20E and 20F ). 
     Example 14: DC-SIGN Immunoconjugate has Enhanced Anti-Tumor Activity in Combination with Anti-PDL1 Therapy 
     Female transgenic mice expressing human DC-SIGN gene (Tg+) were implanted with 2.5×10 5  MC38 tumor cells subcutaneously in the hind flank. Tumors were measured 3 times weekly throughout the course of the study. When tumors reached 100-200 cubic millimeters (mm 3 ), mice were treated with a single dose of 1 mg/kg Isotype (DAPA) C1 or 1 mg/kg humanized 2B2 (DAPA) C1. Some groups were given 2 doses of anti-PDL1 clone 10F.9G2 from BioXcell at 10 mg/kg throughout the course of the study (every 3-4 days). 
     As shown in  FIG. 21 , mice treated with the combination of 2B2 (DAPA) C1 and anti-PDL1 clone 10F.9G2 showed enhanced reduction in tumor volume ( FIG. 21A ). 7 days after dosing with 2B2 (DAPA) C1 or Isotype (DAPA) C1, tumors were analyzed by flow cytometry for T cell infiltration. Mice treated with the combination of 2B2 (DAPA) C1 and anti-PDL1 clone 10F.9G2 showed enhanced infiltration of CD8 T cells in their tumors ( FIG. 21B ). 
     The effect of DAR2 version of DC-SIGN immunoconjugate was also evaluated. As shown in  FIG. 22 , mice treated with the combination of humanized 2B2 (DAPA) C1 and anti-PDL1 clone 10F.9G2 or humanized 2B2 (DAPA) DAR2 C1 and anti-PDL1 clone 10F.9G2 showed a reduction in tumor volume compared to isotype control treated animals ( FIG. 22A ). 7 days after dosing with immunoconjugates, tumors were analyzed by flow cytometry for T cell infiltration. Mice treated with the combination of humanized 2B2 (DAPA) C1 or humanized 2B2 (DAPA) DAR2 C1 and anti-PDL1 showed enhanced infiltration of CD8 T cells in their tumors compared to isotype control groups ( FIG. 22B ). 
     The effect of different payloads of DC-SIGN immunoconjugates were also evaluated. As shown in  FIG. 23 , Tg+ animals treated with 2B2 (DAPA) C31 in combination with an anti-PDL1 antibody had significantly smaller tumors than Tg− animals ( FIG. 23A ). Tg+ animals treated with both 2B2 (DAPA) C31 and 2B2 (DAPA) C18 at 0.3 mg/kg in combination with anti-PDL1 had significantly increased tumor CD8+ T cell infiltration compared to Tg− animals treated with the same regimen ( FIG. 23B ). 
     Female transgenic mice expressing human DC-SIGN gene (Tg+) or DC-SIGN negative littermate controls (Tg−) were implanted with 2.5×10 5  MC38 tumor cells subcutaneously in the hind flank. Tumors were measured 3 times weekly throughout the course of the study. When tumors reached 100-200 cubic millimeters (mm 3 ), mice were given a single treatment of 0.1, 0.3 or 1 mg/kg 960K03 (DAPA) DAR4 C31. A control group received no 960K03 (DAPA) DAR4 C31. All groups were given 2 doses of anti-PDL1 clone 10F.9G2 at 10 mg/kg throughout the course of the study (every 3-4 days). 7 days after dosing with 960K03 (DAPA) DAR4 C31, tumors were analyzed by flow cytometry for T cell infiltration. 
     As shown in  FIG. 27 , mice treated with the combination of 960K03 (DAPA) DAR4 C31 and anti-PDL1 showed enhanced reduction in tumor volume at both 0.3 mg/kg as well as the 1 mg/kg dose levels of 960K03 (DAPA) DAR4 C31 ( FIG. 27A ). Mice treated with the 960K03 (DAPA) DAR4 C31 and anti-PDL1 showed enhanced infiltration of CD8+ T cells in their tumors when compared to dose matched Tg− controls ( FIG. 27B ). 
     Materials and Methods Used in Examples 
     Mouse Tumor Experiments and Drug Antibody Conjugate Treatment. 
     MC38 cells were grown in 10% Dulbecco&#39;s Modified Eagle Medium (DMEM) at 80% confluence prior to implant. Cells growing in log phase were harvested and washed with Hank&#39;s Balanced Salt Solution (HBSS) prior to implant. 100 ul of 2.5×10e6 MC38 cells were implants subcutaneously in the hind flank of mice, using insulin syringes, gauge 31. Mice were anesthetized with isoflurane, shaved prior to implant and measured for body weight. Starting at day 5-7 post implant mice were measured using digital calipers using the formula V=(W(2)×L)/2 to determine tumor volume in mm 3  (W=tumor width, L=tumor length). Mice were measured every other day and monitored for signs of distress, body weight loss and possible ulcerations. Compounds were administered intravenously when tumors were between 100-200 mm 3  using a 1 ml syringe with a 27½ gauge needle. Retro-orbital intravenous injection of immunoconjugates (200 μl) and/or checkpoint blockade was administered under anesthesia. Unless otherwise stated, drug-antibody conjugate dosing was once and anti-PDL1 treatment was 2-3 times throughout the study with 3-4 days in between doses. Anti-PDL1 clone 10F.9G2 was purchased from BioXCell and used at 10 mg/kg where indicated. Where indicated, blood was collected at 6 and 24 hours post dose. Mice were sacrificed at indicated time points post dose and tumors, spleen and lymph nodes were harvested for analysis 
     DNP-KLH Immunization 
     Mice were anesthetized and shaved along the hind flank, and measured for baseline body weight. Day 0, mice were injected with either Phosphate Buffered Saline (PBS) in alum (Serve) or 100 μg of DNP-KLH (Calbiochem) in alum (Serve) (see preparation instructions below) intraperitoneally, 100 μl total volume. 24 hours later mice were given an intravenous dose (200p1) of either isotype control or DCSIGN antibody drug conjugate retro-orbitally under anesthesia. Mice were measured for body weight loss throughout the study. 10 days post immunization with DNP-KLH/alum mice were bled, and spleens removed for analysis. Blood was spun at 5000 rpm for 5 minutes, plasma was harvested and frozen at −20° C. until analysis by ELISA. Spleens were analyzed by flow cytometry. 
     DNP ELISA 
     0.05 mg/mL DNP-BSA (Thermo Fisher) in carbonate buffer was used to coat Nunc ELISA plates. Plates were washed with PBS Tween buffer and blocked with BSA in PBS. Plasma from animals were added in serial dilution and was tested at 1/1000, 1/10000, 1/100000, 1/1000000 dilutions. Plates were washed and secondary antibody was added as indicated (Goat anti-mouse IgG1-HRP, Goat anti-mouse IgG2a-HRP, Goat anti-mouse IgG3-HRP or Goat anti-mouse total H+L chain IgG-HRP). After washing, plates were developed with TMB substrate and the reaction was stopped after 5-30 minutes with the addition of 1N HCl. OD was determined at 450 nM using a plate reader. 
     Tumor and Spleen Processing and Flow Cytometry Protocol: 
     Tumors and/or spleens were extracted at the timepoints indicated from animals. Spleens were processed into a single cell suspension using glass slides and passed through a 100 micron mesh filter. Spleens were lysed in 1 mL of ACK lysis buffer (Life Technologies) for 5 minutes at room temperature. After lysis, cells were pelleted and resuspended in complete RMPI medium (RPMI Media 1640 with 10 percent fetal bovine serum (FBS), 0.05 mM 2-mercaptoethanol, 1 percent Penicillin-Streptomycin-Glutamine, 1 percent non-essential amino acids, 1 percent HEPES, 1 percent sodium pyruvate (all media reagents from Thermo Fisher). Tumors were extracted and put into digestion media in gentleMACS C tubes. Digestion media consists of Dulbecco&#39;s Modified Eagle Medium with 0.04 U/mL Dispase (StemCell Technologies), 0.1 mg/mL Collagenase P (Sigma) and 0.1 mg/mL DNase (Sigma). Tumors were incubated with in digestion media and then processed using the gentleMACS Dissociator (Miltenyi Biotec Inc, San Diego, Calif.) to obtain a single cell suspension. After processing, cells were filtered in 100 uM filters (Miltenyi Biotec Inc). 
     1-2 million cells for each sample were then stained with a cocktail of antibodies to determine impact of the treatments on dendritic cells, myeloid cells and T cells. For FACS analysis, cells were stained with a fixable, amine reactive dye to label dead cells (Zombie UV™ fixable viability kit, Biolegend) in PBS. For antibody staining, indicated antibodies (see table below) were diluted in PBS with 0.5% Bovine serum albumin (BSA, from Sigma). Samples were incubated at 4° C. for 30 minutes and then washed 2 times with PBS with 0.5% BSA. Cells were fixed with stabilizing fixative (BD). For intracellular analysis of FoxP3 to evaluate T regulatory cells, cells were fixed and permeabilized with the FoxP3 transcription factor kit according to manufacturer&#39;s recommendations (Thermo Fisher). Cells were then stained with FoxP3 clone FJK-16s (Thermo Fisher). After staining, cells were evaluated on the BD LSRFortessa™ cell analyzer (BD Biosciences, San Jose, Calif.). 
     T cells were identified as CD3+ MHCII− cells. CD8+ T cells and CD4+ T cells were further defined as CD8 and CD4 positive, respectively. Tregs were identified from CD4+ T cells as being FoxP3+. 
     Dendritic cells were identified as MHCII high CD11c high cells and further gated on expression of CD8 and CD11 b to identify CD8+DC subsets and CD11b+ DCs where noted. Monocytic myeloid derived suppressor cells were identified as CD45+ cells in tumors that express CD11b, MHCII, F4/80, Ly6C and are intermediate for Ly6G. 
     
       
         
           
               
             
               
                 TABLE 27 
               
             
            
               
                   
               
               
                 FACS antibodies 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                   
                   
                 Species 
               
               
                   
                 Marker 
                 Clone 
                 Vendor 
                 Reactvity 
               
               
                   
                   
               
               
                   
                 CD45 
                 30F11 
                 BD 
                 Mouse 
               
               
                   
                 CD8 
                 53-6.7 
                 BD 
                 Mouse 
               
               
                   
                 Ly6G 
                 1A8 
                 Biolegend 
                 Mouse 
               
               
                   
                 CD11b 
                 M1/70 
                 Biolegend 
                 Mouse 
               
               
                   
                 CD11c 
                 N418 
                 Biolegend 
                 Mouse 
               
               
                   
                 CD86 
                 GL-1 
                 Biolegend 
                 Mouse 
               
               
                   
                 PDL1 
                 10F.9G2 
                 Biolegend 
                 Mouse 
               
               
                   
                 Ly6C 
                 HK1.4 
                 Biolegend 
                 Mouse 
               
               
                   
                 MHCII 
                 M5.114 
                 Biolegend 
                 Mouse 
               
               
                   
                 CD4 
                 GK1.5 
                 Biolegend 
                 Mouse 
               
               
                   
                 CD44 
                 IM-7 
                 Biolegend 
                 Mouse 
               
               
                   
                 CD69 
                 H1.2F3 
                 Biolegend 
                 Mouse 
               
               
                   
                 CD62L 
                 MEL-14 
                 Biolegend 
                 Mouse 
               
               
                   
                 PD-1 
                 J43 
                 eBioscience/ 
                 Mouse 
               
               
                   
                   
                   
                 Thermo Fisher 
               
               
                   
                 F4/80 
                 BM8 
                 Biolegend 
                 Mouse 
               
               
                   
                 CD3 
                 17A2 
                 Biolegend 
                 Mouse 
               
               
                   
                 HLA-DR 
                 L243 
                 Biolegend 
                 Human 
               
               
                   
                 CD86 
                 IT2.2 
                 Biolegend 
                 Human 
               
               
                   
                 CD11c 
                 3.9 
                 Biolegend 
                 Human 
               
               
                   
                 DC-SIGN 
                 9E9A8 
                 Biolegend 
                 Human 
               
               
                   
                   
               
            
           
         
       
     
     Monocyte Isolation 
     Peripheral blood Leukopaks from normal human donors were obtained from HemaCare. Leukopaks were aliqouted into 50 mL conical tubes (BD Falcon) and centrifuged at 300 g to 30 minutes to pellet cells. Cells were resuspended in Phosphate Buffered Saline (PBS) containing 2% FBS and 1 mM EDTA to a final concentration of 10 8  per mL. EasySep Human CD14 Positive Selection Cocktail (StemCell Technologies) was added at 100 μL per mL of cells. CD14+ cells were obtained by positive magnetic selection by following manufactures recommended protocol. Following selection cells were pelleted by centrifugation at 300 g for 10 minutes and resuspended in Recovery™ Cell Culture freezing medium (Thermo Fisher) at 50-100 million cells per mL in cryovials. Cells were frozen in −80 degree C. freezer for at least one day and transferred to liquid nitrogen for storage. Cells were kept in liquid nitrogen until use. 
     moDC and M2 Macrophage Differentiation 
     Human CD14+ monocytes were isolated and frozen as described. On the day of differentiation, previously collected and frozen CD14+ monocytes were thawed in a 37 degree C. water bath until just thawed and added immediately to prewarmed complete RPMI medium (cRPMI). Cells were then spun at 1500 rotations per minute (rpm) for 5 minutes in a table top centrifuge to pellet cells. Medium was removed and cells were resuspended in fresh, prewarmed cRPMI medium. Cells were counted and plated at 40,000-80,000 cells per well in a 384 well flat bottom tissue culture plate (Greiner). 
     For monocyte dendritic cell (moDC) differentiation, cells were cultured in 40 μL final volume with 53 ng/mL of recombinant human GM-CSF (R4D Systems) and 20 ng/mL recombinant human IL-4 (R&amp;D Systems) for 7 days. Cells were washed and fresh, cRPMI was added prior to stimulation with compounds or antibody drug conjugates. 
     For M2 macrophage differentiation, cells were cultured in 40 μL final volume with a final concentration of 100 ng/mL of recombinant human MCSF. 6 days after differentiation, 20 ng/mL of IL-4 was added to polarize macrophages to an M2 phenotype. 24 hours after polarization, cells were washed and fresh, cRPMI was added prior to stimulation with compounds or antibody drug conjugates. 
     24 hours after activation with compounds, cells were evaluated by flow cytometry according to the described protocol using antibody clones described in flow cytometry protocol section. DC-SIGN+CD11c+ HLA-DR+ cells were identified and assessed for CD86 expression and levels of DC-SIGN. 
     IP-10 ELISA 
     Plasma was collected at indicated timepoints and analyzed with a Mouse IP-10 Platinum ELISA kit (eBioscience Affymetrix). Plasma was diluted 1:100 and the protocol was followed according to the manufacturer&#39;s recommendations. Data was collected using an Enspire spectro-photometer using 450 nM as the primary wavelength. 
     IFNβ ELISA 
     Plasma was collected at indicated timepoints and analyzed with a Mouse IFN-beta ELISA kit (R&amp;D Systems) according to the manufacturer&#39;s recommendations. Data was collected using an Enspire spectro-photometer using 450 nM as the primary wavelength. 
     MesoScale Discovery Cytokine Analysis (MSD) 
     Plasma was collected at indicated timepoints and analyzed with a mouse Proinflammatory Panel 1 (mouse) Kit V-PLEX™ 10 plex from MesoScale Discovery. 25 μL of plasma per sample was used and protocol was followed according to the manufacturer&#39;s recommendations. Data were collected and analyzed using a Sector Imager 6000. 
     Mouse Info and Breeding 
     Human DC-SIGN transgenic mice (Tg+) (Schaefer et al., J. Immunol. (2008) 180 (10) 6836-6845) were bred to Signr1 deficient mice (−/− or KO) (Orr et al., Glycobiology (2013) 23(3): 363-380). Human DC-SIGN expression was checked using PCR to genotype the mice. Human DC-SIGN Tg+ Signr1−/− mice or human DC-SIGN Tg− Signr1−/− mice were tested with compounds as indicated in the above examples. 
     Unless defined otherwise, the technical and scientific terms used herein have the same meaning as they usually understood by a specialist familiar with the field to which the disclosure belongs. 
     Unless indicated otherwise, all methods, steps, techniques and manipulations that are not specifically described in detail can be performed and have been performed in a manner known per se, as will be clear to the skilled person. Reference is for example again made to the standard handbooks and the general background art mentioned herein and to the further references cited therein. Unless indicated otherwise, each of the references cited herein is incorporated in its entirety by reference. 
     Claims to the invention are non-limiting and are provided below. 
     Although particular aspects and claims have been disclosed herein in detail, this has been done by way of example for purposes of illustration only, and is not intended to be limiting with respect to the scope of the appended claims, or the scope of subject matter of claims of any corresponding future application. In particular, it is contemplated by the inventors that various substitutions, alterations, and modifications may be made to the disclosure without departing from the spirit and scope of the disclosure as defined by the claims. The choice of nucleic acid starting material, clone of interest, or library type is believed to be a matter of routine for a person of ordinary skill in the art with knowledge of the aspects described herein. Other aspects, advantages, and modifications considered to be within the scope of the following claims. Those skilled in the art will recognize or be able to ascertain, using no more than routine experimentation, many equivalents of the specific aspects of the invention described herein. Such equivalents are intended to be encompassed by the following claims. Redrafting of claim scope in later filed corresponding applications may be due to limitations by the patent laws of various countries and should not be interpreted as giving up subject matter of the claims.