Patent Publication Number: US-2020291122-A1

Title: Treatment of cancer with anti-gitr agonist antibodies

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This application is a 35 U.S.C. 371 national stage filing of International Application No. PCT/US2018/032750, filed on May 15, 2018, which claims priority to U.S. Provisional Application Nos. 62/507,071, filed on May 16, 2017; 62/514,245, filed on Jun; 2, 2017; 62/514,312, filed on Jun. 2, 2017; and 62/573,494, filed on Oct. 17, 2017, respectively. The contents of the aforementioned applications are hereby incorporated by reference. 
    
    
     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 Nov. 12, 2019, is named MXI_559US_Sequence_Listing.txt and is 651,606 bytes in size. 
     BACKGROUND 
     The National Cancer Institute has estimated that in the United States alone, 1 in 3 people will be struck with cancer during their lifetime. Moreover, approximately 50% to 60% of people contracting cancer will eventually succumb to the disease. The widespread occurrence of this disease underscores the need for improved anticancer regimens for the treatment of malignancy. 
     Recently, several immune checkpoint pathway inhibitors have begun to provide new immunotherapeutic approaches for treating cancer, including the development of an antibody (Ab), ipilimumab (YERVOY®), that binds to and inhibits Cytotoxic T-Lymphocyte Antigen-4 (CTLA-4) for the treatment of patients with advanced melanoma and the development of Abs such as nivolumab and pembrolizumab (formerly lambrolizumab; USAN Council Statement, 2013) that bind specifically to the Programmed Death-1 (PD-1) receptor and block the inhibitory PD-1/PD-1 ligand pathway. 
     SUMMARY 
     Provided herein are methods of treatment of a subject having cancer, e.g., advanced solid tumors, by administering an anti-GITR agonist Ab in combination with an anti-PD-1 or anti-PD-L1 Ab. 
    
    
     
       BRIEF DESCRIPTION OF DRAWINGS 
         FIG. 1  shows the phase ½a study of 28F3.IgG1±nivolumab in patients with advanced solid tumors. DLT, dose-limiting toxicity; HCC, hepatocellular carcinoma; MAD, maximum administered dose; MTD, maximum tolerated dose; NSCLC, non-small cell lung cancer; PD, pharmacodynamics; PK, pharmacokinetics; SCCHN, squamous cell carcinoma of the head and neck; and Q2W, every 2 weeks. 
         FIG. 2  shows that GITR Ab and nivolumab demonstrate a linear PK and low immunogenicity. The concentration of GITR Ab is shown as a function of time and concentration of GITR Ab with or without nivolumab after administration of the first dose. The concentrations from bottom to top lines for the monotherapy are 10 mg, 30 mg, 100 mg, 240 mg and 800 mg. The concentrations from bottom to top lines for the GITR Ab and nivolumab are 30 mg, 100 mg, 240 mg and 800 mg (administered with 240 mg of nivolumab). 
         FIG. 3  shows that 28F3.IgG1+nivolumab increase proliferating (Ki67+) NK and CD8 cells in peripheral blood.  a Asterisk denotes outlier at 10.9.  b Asterisk denotes outlier at 7.8. 
         FIG. 4  shows that GITR Ab +nivolumab increases proliferation and activation of CD8 memory cells. The fold change over baseline of proliferation (measured with Ki67 marker) or activation (measured with HLA-DR marker) of effector memory CD8 cells is shown. The time of administration of the GITR Ab and nivolumab is shown with arrows. 
         FIG. 5  shows cross sections of tumors in a patient with cervical cancer, at baseline (before treatment) and during treatment (“April 2017” and “May 2017”) with a combination of 240 mg 28F3.IgG1 and 240 mg nivolumab. The changes in tumor size are shown with a circle. 
         FIG. 6  shows cross sections of tumors in a patient with adenocarcinoma of the ampulla of Vater, at baseline (before treatment) and during treatment (“December 2017”) with a combination of 240 mg 28F3.IgG1 and 240 mg nivolumab. The changes in tumor size are shown with a circle. 
         FIG. 7  shows cross sections of tumors in a patient with melanoma after progression on anti-PD-1 therapy, at baseline (before treatment) and during treatment (“December 2017”) with a combination of 100 mg 28F3.IgG1 and 240 mg nivolumab. The changes in tumor size are shown with a circle. 
         FIG. 8  shows cross sections of tumors in a patient with nasopharyngeal cancer after progression on anti-PD-1 therapy, at baseline (before treatment) and during treatment (“February 2017”) with a combination of 240 mg 28F3.IgG1 and 240 mg nivolumab. The changes in tumor size are shown with a circle. 
         FIG. 9  is a schematic of approaches for FIH safe starting dose selection for novel immunomodulatory protein therapeutics. 
         FIG. 10  is a schematic of the first-in-human dose selection strategy for 28F3.IgG1. 
         FIG. 11  is a schematic of the data analysis method for first-in-human dose selection. 
         FIG. 12  is a graph showing NK cell activation at the indicated concentrations of 28F3.IgG1. 
         FIG. 13  is a schematic of the dosing schedule of DTA1-mIgG2a in the CT26 mouse tumor model. 
         FIG. 14  is a graph showing the percentage of Ki67-positive cells among CD8+T cells at day 12 after cell implantation at the indicated doses of DTAmIgG2a. 
         FIG. 15  is a graph showing the CD8+T cell/Treg cell ratio in tumors of the CT26 mouse tumor model treated with the indicated doses of DTAmIgG2a. 
         FIG. 16  is a graph showing a time course of tumor-free mice at the indicated doses of DTAmIgG2a. 
         FIG. 17  is a graph showing projections of the human efficacious dose based on mouse efficacy data (tumor-free mice). 
     
    
    
     DETAILED DESCRIPTION 
     Provided herein are methods of treatment of cancer with anti-GITR agonist agents, e.g., antibodies, and anti-PD-1 or anti-PD-L1 (“PD-1/PD-L1 axis”) antagonist agents, e.g., antibodies. 
     Definitions 
     In order that the present description may be more readily understood, certain terms are first defined. Additional definitions are set forth throughout the detailed description. 
     The term “glucocorticoid-inducible TNF receptor” or “GITR” as used herein refers to a receptor that is a member of the TNF-receptor superfamily, which binds to GITR ligand (GITR-L). GITR is also referred to as tumor necrosis factor receptor superfamily, member 18 (TNFRSF18), AITR and CD357. The term “GITR” includes any variants or isoforms of GITR which are naturally expressed by cells. Accordingly, antibodies described herein may cross-react with GITR from species other than human (e.g., cynomolgus GITR). Alternatively, the antibodies may be specific for human GITR and may not exhibit any cross-reactivity with other species. GITR or any variants and isoforms thereof, may either be isolated from cells or tissues which naturally express them or be recombinantly produced using well-known techniques in the art and/or those described herein. 
     Three isoforms of human GITR have been identified, all of which share the same extracellular domain, except for its C-terminal portion. Variant 1 (Accession No. NP_004186; SEQ ID NO: 1) consists of 241 amino acids and represents the longest transcript. It contains an extra coding segment that leads to a frame shift, compared to variant 2. The resulting protein (isoform 1) contains a distinct and shorter C-terminus, as compared to isoform 2. Variant 2 (Accession No. NP_683699; SEQ ID NO: 2) encodes the longest protein (isoform 2), consisting of 255 amino acids, and is soluble. Variant 3 (Accession No. NP_683700; SEQ ID NO: 3) contains an extra coding segment that leads to a frame shift, compared to variant 2. The resulting protein (isoform 3) contains a distinct and shorter C-terminus, as compared to isoform 2, and consists of 234 amino acids. 
     Below are the amino acid sequences of the three known human GITR isoforms, cyno GITR and GITR-L. 
     
       
         
           
               
            
               
                 Human GITR isoform 1 (Accession No. NP_004186; 
               
               
                 SEQ ID NO: 1; encoded by the nucleotide sequence 
               
               
                 having Accession No. NM_004195.2): 
               
               
                 MAQHGAMGAFRALCGLALLCALSLGQRPTGGPGCGPGRLLLGTGTDARCC 
               
               
                   
               
               
                 RVHTTRCCRDYPGEECCSEWDCMCVQPEFHCGDPCCTTCRHHPCPPGQGV 
               
               
                   
               
               
                 QSQGKFSFGFQCIDCASGTFSGGHEGHCKPWTDCTQFGFLTVFPGNKTHN 
               
               
                   
               
               
                 AVCVPGSPPAEPLGWLTVVLLAVAACVLLLTSAQLGLHIWQLRSQCMWPR 
               
               
                   
               
               
                 ETQLLLEVPPSTEDARSCQFPEEERGERSAEEKGRLGDLWV 
               
               
                   
               
               
                 Human GITR isoform 2 (Accession No. NP_683699.1; 
               
               
                 SEQ ID NO: 2; encoded by the nucleotide sequence 
               
               
                 having Accession No. NM_148901.1): 
               
               
                 MAQHGAMGAFRALCGLALLCALSLGQRPTGGPGCGPGRLLLGTGTDARCC 
               
               
                   
               
               
                 RVHTTRCCRDYPGEECCSEWDCMCVQPEFHCGDPCCTTCRHHPCPPGQGV 
               
               
                   
               
               
                 QSQGKFSFGFQCIDCASGTFSGGHEGHCKPWTDCCWRCRRRPKTPEAASS 
               
               
                   
               
               
                 PRKSGASDRQRRRGGWETCGCEPGRPPGPPTAASPSPGAPQAAGALRSAL 
               
               
                   
               
               
                 GRALLPWQQKWVQEGGSDQRPGPCSSAAAAGPCRRERETQSWPPSSLAGP 
               
               
                   
               
               
                 DGVGS 
               
               
                   
               
               
                 Human GITR isoform 3 (Accession No. NP_683700.1; 
               
               
                 SEQ ID NO: 3; encoded by the nucleotide sequence 
               
               
                 having Accession No. NM_148902.1): 
               
               
                 MAQHGAMGAFRALCGLALLCALSLGQRPTGGPGCGPGRLLLGTGTDARCC 
               
               
                   
               
               
                 RVHTTRCCRDYPGEECCSEWDCMCVQPEFHCGDPCCTTCRHHPCPPGQGV 
               
               
                   
               
               
                 QSQGKFSFGFQCIDCASGTFSGGHEGHCKPWTDCTQFGFLTVFPGNKTHN 
               
               
                   
               
               
                 AVCVPGSPPAEPLGWLTVVLLAVAACVLLLTSAQLGLHIWQLRKTQLLLE 
               
               
                   
               
               
                 VPPSTEDARSCQFPEEERGERSAEEKGRLGDLWV 
               
            
           
         
       
     
     The signal sequence of isoforms 1-3 corresponds to amino acids 1-25. Thus, the mature isoforms 1, 2 and 3 consist of amino acids 26 to 241, 255 or 234, respectively. The extracellular domain of mature GITR consists of amino acids 26-162 and has the amino acid sequence: 
     
       
         
           
               
            
               
                 (SEQ ID NO: 4) 
               
               
                 QRPTGGPGCGPGRLLLGTGTDARCCRVHTTRCCRDYPGEECCSEWDCMCV 
               
               
                 QPEFHCGDPCCTTCRHHPCPPGQGVQSQGKFSFGFQCIDCASGTFSGGHE 
               
               
                 GHCKPWTDCTQFGFLTVFPGNKTHNAVCVPGSPPAEP 
               
               
                   
               
               
                 Cynomolgus GITR protein sequence (SEQ ID NO: 5): 
               
               
                 MCASGTLCCLALLCAASLGQRPTGGPGCGPGRLLLGTGKDARCCRVHPTR 
               
               
                   
               
               
                 CCRDYQGEECCSEWDCVCVQPEFHCGNPCCTTCQHHPCPSGQGVQPQGKF 
               
               
                   
               
               
                 SFGFRCVDCALGTFSRGHDGHCKPWTDCTQFGFLTVFPGNKTHNAVCVPG 
               
               
                   
               
               
                 SPPAEPPGWLTIILLAVAACVLLLTSAQLGLHIWQLRSQPTGPRETQLLL 
               
               
                   
               
               
                 EVPPSTEDASSCQFPEEERGERLAEEKGRLGDLWV 
               
               
                   
               
               
                 Human GITR-L protein sequence (Accession No. NP_ 
               
               
                 005083.2; SEQ ID NO: 6): 
               
               
                 MTLHPSPITCEFLFSTALISPKMCLSHLENMPLSHSRTQGAQRSSWKLWL 
               
               
                   
               
               
                 FCSIVMLLFLCSFSWLIFIFLQLETAKEPCMAKFGPLPSKWQMASSEPPC 
               
               
                   
               
               
                 VNKVSDWKLEILQNGLYLIYGQVAPNANYNDVAPFEVRLYKNKDMIQTLT 
               
               
                   
               
               
                 NKSKIQNVGGTYELHVGDTIDLIFNSEHQVLKNNTYWGIILLANPQFIS 
               
            
           
         
       
     
     The term “antibody” as used to herein includes whole antibodies and any antigen binding fragments (i.e., “antigen-binding portions”) or single chains thereof. An “antibody” refers, in one embodiment, to a glycoprotein comprising at least two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds, or an antigen binding portion thereof. Each heavy chain is comprised of a heavy chain variable region (abbreviated herein as V H ) and a heavy chain constant region. In certain naturally occurring antibodies, the heavy chain constant region is comprised of three domains, CH1, CH2 and CH3. In certain naturally occurring antibodies, each light chain is comprised of a light chain variable region (abbreviated herein as V L ) and a light chain constant region. The light chain constant region is comprised of one domain, CL. The V H  and V L  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 V H  and V L  is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-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 (Clq) of the classical complement system. 
     Antibodies typically bind specifically to their cognate antigen with high affinity, reflected by a dissociation constant (K D ) of 10 −5  to 10 −11  M or less. Any K D  greater than about 10 −4  M is generally considered to indicate nonspecific binding. As used herein, an antibody that “binds specifically” to an antigen refers to an antibody that binds to the antigen and substantially identical antigens with high affinity, which means having a K D  of 10 −7  M or less, preferably 10 −8  M or less, even more preferably 5×10 M or less, and most preferably between 10 −8  M and 10 −10  M or less, but does not bind with high affinity to unrelated antigens. An antigen is “substantially identical” to a given antigen if it exhibits a high degree of sequence identity to the given antigen, for example, if it exhibits at least 80%, at least 90%, preferably at least 95%, more preferably at least 97%, or even more preferably at least 99% sequence identity to the sequence of the given antigen. By way of example, an antibody that binds specifically to human GITR may also have cross-reactivity with GITR antigens from certain primate species (e.g., cynomolgus GITR), but may not cross-react with GITR antigens from other species or with an antigen other than GITR. 
     An immunoglobulin may be from any of the commonly known isotypes, including but not limited to IgA, secretory IgA, IgG and IgM. The IgG isotype is divided in subclasses in certain species: IgG1, IgG2, IgG3 and IgG4 in humans, and IgG1, IgG2a, IgG2b and IgG3 in mice. In certain embodiments, the anti-GITR antibodies described herein are of the IgG1 or IgG2 subtype. Immunoglobulins, e.g., IgG1, exist in several allotypes, which differ from each other in at most a few amino acids. “Antibody” includes, by way of example, both naturally occurring and non-naturally occurring antibodies; monoclonal and polyclonal antibodies; chimeric and humanized antibodies; human and nonhuman antibodies; wholly synthetic antibodies; and single chain antibodies. An antibody can be part of an antibody multimer (or multimeric antibody), e.g., dimer, trimer, tetramer, pentamer and hexamer. 
     The term “monoclonal antibody,” as used herein, refers to an antibody that displays a single binding specificity and affinity for a particular epitope or a composition of antibodies in which all antibodies display a single binding specificity and affinity for a particular epitope. 
     Accordingly, the term “human monoclonal antibody” refers to an antibody or antibody composition that display(s) a single binding specificity and which has variable and optional constant regions derived from human germline immunoglobulin sequences. In one embodiment, human monoclonal antibodies are produced by a hybridoma which includes a B cell obtained from a transgenic non-human animal, e.g., a transgenic mouse, having a genome comprising a human heavy chain transgene and a light chain transgene fused to an immortalized cell. 
     A “human” antibody (HuMAb) refers to an antibody having variable regions in which both the framework and CDR regions are derived from human germline immunoglobulin sequences. Furthermore, if the antibody contains a constant region, the constant region also is derived from human germline immunoglobulin sequences. The antibodies described herein may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo). 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 terms “human” antibodies and “fully human” antibodies are used synonymously. 
     A “humanized” antibody refers to an antibody in which some, most or all of the amino acids outside the CDR domains of a non-human antibody are replaced with corresponding amino acids derived from human immunoglobulins. In one embodiment of a humanized form of an antibody, some, most or all of the amino acids outside the CDR domains have been replaced with amino acids from human immunoglobulins, whereas some, most or all amino acids within one or more CDR regions are unchanged. Small additions, deletions, insertions, substitutions or modifications of amino acids are permissible as long as they do not abrogate the ability of the antibody to bind to a particular antigen. A “humanized” antibody retains an antigenic specificity similar to that of the original antibody. 
     A “chimeric antibody” refers to an antibody in which the variable regions are derived from one species and the constant regions are derived from another species, such as an antibody in which the variable regions are derived from a mouse antibody and the constant regions are derived from a human antibody. As used herein, “isotype” refers to the antibody class (e.g., IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgD, and IgE antibody) that is encoded by the heavy chain constant region genes. 
     “Allotype” refers to naturally occurring variants within a specific isotype group, which variants differ in a few amino acids (see, e.g., Jefferis et al. (2009) mAbs 1:1). Antibodies described herein may be of any allotype. As used herein, antibodies referred to as “IgGlf” or “IgG1.1f” isotype are IgG1 and effectorless IgG1.1 antibodies, respectively, of the allotype “f,” i.e., having 214R, 356E and 358M according to the EU index as in Kabat, as shown, e.g., in SEQ ID NO: 7 (see underlined residues in SEQ ID NO: 7 of Table 2). 
     The phrases “an antibody recognizing an antigen” and “an antibody specific for an antigen” are used interchangeably herein with the term “an antibody which binds specifically to an antigen.” 
     An “isolated antibody,” as used herein, is intended to refer to an antibody which is substantially free of other antibodies having different antigenic specificities (e.g., an isolated antibody that specifically binds to GITR is substantially free of antibodies that specifically bind antigens other than GITR). An isolated antibody that specifically binds to an epitope of GITR may, however, have cross-reactivity to other GITR proteins from different species. 
     “Programmed Death-1 (PD-1)” refers to an immunoinhibitory receptor belonging to the CD28 family. PD-1 is expressed predominantly on previously activated T cells in vivo, and binds to two ligands, PD-L1 and PD-L2. The term “PD-1” as used herein includes human PD-1 (hPD-1), variants, isoforms, and species homologs of hPD-1, and analogs having at least one common epitope with hPD-1. The complete hPD-1 sequence can be found under GenBank Accession No. U64863. 
     “Programmed Death Ligand-1 (PD-L1)” is one of two cell surface glycoprotein ligands for PD-1 (the other being PD-L2) that down-regulate T cell activation and cytokine secretion upon binding to PD-1. The term “PD-L1” as used herein includes human PD-L1 (hPD-L1), variants, isoforms, and species homologs of hPD-L1, and analogs having at least one common epitope with hPD-L1. The complete hPD-L1 sequence can be found under GenBank Accession No. Q9NZQ7. 
     An “Fc region” (fragment crystallizable region) or “Fc domain” or “Fc” refers to the C-terminal region of the heavy chain of an antibody that mediates the binding of the immunoglobulin to host tissues or factors, including binding to Fc receptors located on various cells of the immune system (e.g., effector cells) or to the first component (C1q) of the classical complement system. Thus, an Fc region comprises the constant region of an antibody excluding the first constant region immunoglobulin domain (e.g., CH1 or CL). In IgG, IgA and IgD antibody isotypes, the Fc region comprises two identical protein fragments, derived from the second (C H2 ) and third (C H3 ) constant domains of the antibody&#39;s two heavy chains; IgM and IgE Fc regions comprise three heavy chain constant domains (C H  domains 2-4) in each polypeptide chain. For IgG, the Fc region comprises immunoglobulin domains Cy2 and Cy3 and the hinge between Cy1 and Cy2. Although the boundaries of the Fc region of an immunoglobulin heavy chain might vary, the human IgG heavy chain Fc region is usually defined to stretch from an amino acid residue at position C226 or P230 (or amino acid between these two amino acids) to the carboxy-terminus of the heavy chain, wherein the numbering is according to the EU index as in Kabat. The C H2  domain of a human IgG Fc region extends from about amino acid 231 to about amino acid 340, whereas the C H3  domain is positioned on C-terminal side of a C H2  domain in an Fc region, i.e., it extends from about amino acid 341 to about amino acid 447 of an IgG. As used herein, the Fc region may be a native sequence Fc, including any allotypic variant, or a variant Fc (e.g., a non-naturally occurring Fc). Fc may also refer to this region in isolation or in the context of an Fc-comprising protein polypeptide such as a “binding protein comprising an Fc region,” also referred to as an “Fc fusion protein” (e.g., an antibody or immunoadhesin). 
     A “native sequence Fc region” or “native sequence Fc” comprises an amino acid sequence that is identical to the amino acid sequence of an Fc region found in nature. Native sequence human Fc regions include a native sequence human IgG1 Fc region; native sequence human IgG2 Fc region; native sequence human IgG3 Fc region; and native sequence human IgG4 Fc region as well as naturally occurring variants thereof. Native sequence Fc include the various allotypes of Fcs (see, e.g., Jefferis et al. (2009) mAbs 1:1). 
     A “hinge”, “hinge domain” or “hinge region” or “antibody hinge region” refers to the domain of a heavy chain constant region that joins the CH1 domain to the CH2 domain and includes the upper, middle, and lower portions of the hinge (Roux et al. J. Immunol. 1998 161:4083). The hinge provides varying levels of flexibility between the binding and effector regions of an antibody and also provides sites for intermolecular disulfide bonding between the two heavy chain constant regions. As used herein, a hinge starts at Glu216 and ends at Gly237 for all IgG isotypes (Roux et al., 1998 J Immunol 161:4083). The sequences of wildtype IgG1, IgG2, IgG3 and IgG4 hinges are show in Tables 1 and 2. 
     
       
         
           
               
             
               
                 TABLE 1 
               
             
            
               
                   
               
               
                 Hinge region amino acid sequences 
               
            
           
           
               
               
               
               
               
            
               
                 Ig Type 
                 C-terminal CH1* 
                 Upper Hinge 
                 Middle Hinge 
                 Lower Hinge 
               
               
                   
               
               
                 IgG1 
                 VDKRV 
                 EPKSCDKTHT 
                 CPPCP 
                 APELLGG 
               
               
                   
                 (SEQ ID NO: 299) 
                 (SEQ ID NO: 301) 
                 (SEQ ID NO: 305) 
                 (SEQ ID NO: 313) 
               
               
                   
               
               
                 IgG2 
                 VDKTV 
                 ERK 
                 CCVECPPCP 
                 APPVAG 
               
               
                   
                 (SEQ ID NO: 300) 
                   
                 (SEQ ID NO: 306) 
                 (SEQ ID NO: 314) 
               
               
                   
               
               
                 IgG3 (17-15- 
                 VDKRV 
                 ELKTPLGDTTHT 
                 CPRCP 
                 APELLGG 
               
               
                 15-15) 
                 (SEQ ID NO: 299) 
                 (SEQ ID NO: 302) 
                 (EPKSCDTPPPCPRCP) 3   
                 (SEQ ID NO: 313) 
               
               
                   
                   
                   
                 (SEQ ID NO: 307) 
                   
               
               
                   
               
               
                 IgG3 (17-15- 
                 VDKRV 
                 ELKTPLGDTTHT 
                 CPRCP 
                 APELLGG 
               
               
                 15) 
                 (SEQ ID NO: 299) 
                 (SEQ ID NO: 302) 
                 (EPKSCDTPPPCPRCP) 2   
                 (SEQ ID NO: 313) 
               
               
                   
                   
                   
                 (SEQ ID NO: 308) 
                   
               
               
                   
               
               
                 IgG3 (17-15) 
                 VDKRV 
                 ELKTPLGDTTHT 
                 CPRCP 
                 APELLGG 
               
               
                   
                 (SEQ ID NO: 299) 
                 (SEQ ID NO: 302) 
                 (EPKSCDTPPPCPRCP) 1   
                 (SEQ ID NO: 313) 
               
               
                   
                   
                   
                 (SEQ ID NO: 309) 
                   
               
               
                   
               
               
                 IgG3 (15-15- 
                 VDKRV 
                 EPKS 
                 CDTPPPCPRCP 
                 APELLGG 
               
               
                 15) 
                 (SEQ ID NO: 299) 
                 (SEQ ID NO: 303) 
                 (EPKSCDTPPPCPRCP) 2   
                 (SEQ ID NO: 313) 
               
               
                   
                   
                   
                 (SEQ ID NO: 310) 
                   
               
               
                   
               
               
                 IgG3 (15) 
                 VDKRV 
                 EPKS 
                 CDTPPPCPRCP 
                 APELLGG 
               
               
                   
                 (SEQ ID NO: 299) 
                 (SEQ ID NO: 303) 
                 (SEQ ID NO: 311) 
                 (SEQ ID NO: 313) 
               
               
                   
               
               
                 IgG4 
                 VDKRV 
                 ESKYGPP 
                 CPSCP 
                 APEFLGG 
               
               
                   
                 (SEQ ID NO: 299) 
                 (SEQ ID NO: 304) 
                 (SEQ ID NO: 312) 
                 (SEQ ID NO: 313) 
               
               
                   
               
               
                 *C-terminal amino acid sequences of the CH1 domains. 
               
            
           
         
       
     
     The term “hinge” includes wildtype hinges (such as those set forth in Table 1 or 2), as well as variants thereof (e.g., non-naturally-occurring hinges or modified hinges). For example, the term “IgG2 hinge” includes wildtype IgG2 hinge, as shown in Table 1 or 2, and variants having 1, 2, 3, 4, 5, 1-3, 1-5, 3-5 and/or at most 5, 4, 3, 2, or 1 mutations, e.g., substitutions, deletions or additions. Exemplary IgG2 hinge variants include IgG2 hinges in which 1, 2, 3 or all 4 cysteines (C219, C220, C226 and C229) are changed to another amino acid. In a specific embodiment, an IgG2 comprises a C219S substitution. In certain embodiments, a hinge is a hybrid hinge that comprises sequences from at least two isotypes. For example, a hinge may comprise the upper, middle or lower hinge from one isotype and the remainder of the hinge from one or more other isotypes. For example, a hinge can be an IgG2/IgG1 hinge, and may comprise, e.g., the upper and middle hinges of IgG2 and the lower hinge of IgG1. A hinge may have effector function or be deprived of effector function. For example, the lower hinge of wildtype IgG1 provides effector function. 
     The term “CH1 domain” refers to the heavy chain constant region linking the variable domain to the hinge in a heavy chain constant domain. As used herein, a CH1 domain starts at A118 and ends at V215. The term “CH1 domain” includes wildtype CH1 domains (such as having SEQ ID NO: 278 for IgG1 and SEQ ID NO: 279 for IgG2; Table 2), as well as variants thereof (e.g., non-naturally-occurring CH1 domains or modified CH1 domains). For example, the term “CH1 domain” includes wildtype CH1 domains and variants having 1, 2, 3, 4, 5, 1-3, 1-5, 3-5 and/or at most 5, 4, 3, 2, or 1 mutations, e.g., substitutions, deletions or additions. Exemplary CH1 domains include CH1 domains with mutations that modify a biological activity of an antibody, such as ADCC, CDC or half-life. Modifications to the CH1 domain that affect a biological activity of an antibody are provided herein. 
     The term “CH2 domain” refers to the heavy chain constant region linking the hinge to the CH3 domain in a heavy chain constant domain. As used herein, a CH2 domain starts at P238 and ends at K340. The term “CH2 domain” includes wildtype CH2 domains (such as having SEQ ID NO: 280 for IgG1 and SEQ ID NO: 297 for IgG2; Table 2), as well as variants thereof (e.g., non-naturally-occurring CH2 domains or modified CH2 domains). For example, the term “CH2 domain” includes wildtype CH2 domains and variants having 1, 2, 3, 4, 5, 1-3, 1-5, 3-5 and/or at most 5, 4, 3, 2, or 1 mutations, e.g., substitutions, deletions or additions. Exemplary CH2 domains include CH2 domains with mutations that modify a biological activity of an antibody, such as ADCC, CDC or half-life. In certain embodiments, a CH2 domain comprises the substitutions A330S/P331S that reduce effector function. Other modifications to the CH2 domain that affect a biological activity of an antibody are provided herein. 
     The term “CH3 domain” refers to the heavy chain constant region that is C-terminal to the CH2 domain in a heavy chain constant domain. As used herein, a CH3 domain starts at G341 and ends at K447. The term “CH3 domain” includes wildtype CH3 domains (such as having SEQ ID NO: 282 for IgG1 and SEQ ID NO: 298 for IgG2; Table 2), as well as variants thereof (e.g., non-naturally-occurring CH3 domains or modified CH3 domains). For example, the term “CH3 domain” includes wildtype CH3 domains and variants having 1, 2, 3, 4, 5, 1-3, 1-5, 3-5 and/or at most 5, 4, 3, 2, or 1 mutations, e.g., substitutions, deletions or additions. Exemplary CH3 domains include CH3 domains with mutations that modify a biological activity of an antibody, such as ADCC, CDC or half-life. Modifications to the CH3 domain that affect a biological activity of an antibody are provided herein. 
     A “native sequence Fc region” or “native sequence Fc” comprises an amino acid sequence that is identical to the amino acid sequence of an Fc region found in nature. Native sequence human Fc regions include a native sequence human IgG1 Fc region; native sequence human IgG2 Fc region; native sequence human IgG3 Fc region; and native sequence human IgG4 Fc region as well as naturally occurring variants thereof. Native sequence Fc includes the various allotypes of Fcs (see, e.g., Jefferis et al. (2009) mAbs 1:1). 
     The term “epitope” or “antigenic determinant” refers to a site on an antigen (e.g., GITR) to which an immunoglobulin or antibody specifically binds. Epitopes can be formed both from contiguous amino acids (usually a linear epitope) or noncontiguous amino acids juxtaposed by tertiary folding of a protein (usually a conformational epitope). Epitopes formed from contiguous amino acids are typically, but not always, retained on exposure to denaturing solvents, whereas epitopes formed by tertiary folding are typically lost on treatment with denaturing solvents. An epitope typically includes at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acids in a unique spatial conformation. Methods for determining what epitopes are bound by a given antibody (i.e., epitope mapping) are well known in the art and include, for example, immunoblotting and immunoprecipitation assays, wherein overlapping or contiguous peptides from (e.g., from GITR) are tested for reactivity with a given antibody (e.g., anti-GITR antibody). Methods of determining spatial conformation of epitopes include techniques in the art and those described herein, for example, x-ray crystallography, 2-dimensional nuclear magnetic resonance and HDX-MS (see, e.g.,  Epitope Mapping Protocols in Methods in Molecular Biology,  Vol. 66, G. E. Morris, Ed. (1996)). 
     The term “epitope mapping” refers to the process of identification of the molecular determinants for antibody-antigen recognition. 
     The term “binds to the same epitope” with reference to two or more antibodies means that the antibodies bind to the same segment of amino acid residues, as determined by a given method. Techniques for determining whether antibodies bind to the “same epitope on GITR” with the antibodies described herein include, for example, epitope mapping methods, such as, x-ray analyses of crystals of antigen:antibody complexes which provides atomic resolution of the epitope and hydrogen/deuterium exchange mass spectrometry (HDX-MS). Other methods monitor the binding of the antibody to antigen fragments or mutated variations of the antigen where loss of binding due to a modification of an amino acid residue within the antigen sequence is often considered an indication of an epitope component. In addition, computational combinatorial methods for epitope mapping can also be used. These methods rely on the ability of the antibody of interest to affinity isolate specific short peptides from combinatorial phage display peptide libraries. Antibodies having the same VH and VL or the same CDR1, 2 and 3 sequences are expected to bind to the same epitope. 
     Antibodies that “compete with another antibody for binding to a target” refer to antibodies that inhibit (partially or completely) the binding of the other antibody to the target. Whether two antibodies compete with each other for binding to a target, i.e., whether and to what extent one antibody inhibits the binding of the other antibody to a target, may be determined using known competition experiments. In certain embodiments, an antibody competes with, and inhibits binding of another antibody to a target by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100%. The level of inhibition or competition may be different depending on which antibody is the “blocking antibody” (i.e., the cold antibody that is incubated first with the target). Competition assays can be conducted as described, for example, in Ed Harlow and David Lane, Cold Spring Harb Protoc; 2006; doi:10.1101/pdb.prot4277 or in Chapter 11 of “Using Antibodies” by Ed Harlow and David Lane, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., USA 1999. Competing antibodies bind to the same epitope, an overlapping epitope or to adjacent epitopes (e.g., as evidenced by steric hindrance). 
     Other competitive binding assays include: solid phase direct or indirect radioimmunoassay (RIA), solid phase direct or indirect enzyme immunoassay (EIA), sandwich competition assay (see Stahli et al.,  Methods in Enzymology  9:242 (1983)); solid phase direct biotin-avidin EIA (see Kirkland et  al., J. Immunol.  137:3614 (1986)); solid phase direct labeled assay, solid phase direct labeled sandwich assay (see Harlow and Lane,  Antibodies: A Laboratory Manual,  Cold Spring Harbor Press (1988)); solid phase direct label RIA using 1-125 label (see Morel et al.,  Mol. Immunol.  25(1):7 (1988)); solid phase direct biotin-avidin EIA (Cheung et al.,  Virology  176:546 (1990)); and direct labeled RIA. (Moldenhauer et al.,  Scand. J. Immunol.  32:77 (1990)). 
     As used herein, the terms “specific binding,” “selective binding,” “selectively binds,” and “specifically binds,” refer to antibody binding to an epitope on a predetermined antigen. Typically, the antibody (i) binds with an equilibrium dissociation constant (K D ) of approximately less than 10 −7  M, such as approximately less than 10  −8  M, 10 −9  M or 10 −10  M or even lower when determined by, e.g., surface plasmon resonance (SPR) technology in a BIACORE 2000 instrument using the predetermined antigen, e.g., recombinant human GITR, as the analyte and the antibody as the ligand, or Scatchard analysis of binding of the antibody to antigen positive cells, and (ii) binds to the predetermined antigen with an affinity that is at least two-fold greater than its affinity for binding to a non-specific antigen (e.g., BSA, casein) other than the predetermined antigen or a closely-related antigen. Accordingly, an antibody that “specifically binds to human GITR” refers to an antibody that binds to soluble or cell bound human GITR with a K D  of 10 −7  M or less, such as approximately less than 10  −8  M, 10 −9  M or 10 −10  M or even lower. An antibody that “cross-reacts with cynomolgus GITR” refers to an antibody that binds to cynomolgus GITR with a K D  of 10 −7  M or less, such as approximately less than 10  −8  M, 10 −9  M or 10 −10  M or even lower. In certain embodiments, such antibodies that do not cross-react with GITR from a non-human species exhibit essentially undetectable binding against these proteins in standard binding assays. 
     The term “naturally-occurring” as used herein as applied to an object refers to the fact that an object can be found in nature. For example, a polypeptide or polynucleotide sequence that is present in an organism (including viruses) that can be isolated from a source in nature and which has not been intentionally modified by man in the laboratory is naturally-occurring. 
     A “polypeptide” refers to a chain comprising at least two consecutively linked amino acid residues, with no upper limit on the length of the chain. One or more amino acid residues in the polypeptide may contain a modification such as, but not limited to, glycosylation, phosphorylation or disulfide bond formation. A “protein” may comprise one or more polypeptides. 
     The term “nucleic acid molecule,” as used herein, is intended to include DNA molecules and RNA molecules. A nucleic acid molecule may be single-stranded or double-stranded, and may be cDNA. 
     Also provided are “conservative sequence modifications” of the sequences set forth herein, e.g., in Table 2, such as in SEQ ID NOs: 13-191, i.e., nucleotide and amino acid sequence modifications which do not abrogate the binding of the antibody encoded by the nucleotide sequence or containing the amino acid sequence, to the antigen. Such conservative sequence modifications include conservative nucleotide and amino acid substitutions, as well as, nucleotide and amino acid additions and deletions. For example, modifications can be introduced into a sequence in Table 2, e.g., SEQ ID NOs: 13-191, by standard techniques known in the art, such as site-directed mutagenesis and PCR-mediated mutagenesis. Conservative amino acid substitutions include 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, a predicted nonessential amino acid residue in an anti-GITR antibody is preferably replaced with another amino acid residue from the same side chain family. Methods of identifying nucleotide and amino acid conservative substitutions which do not eliminate antigen binding are well-known in the art (see, e.g., Brummell et al.,  Biochem.  32:1180-1187 (1993); Kobayashi et al.  Protein Eng.  12(10):879-884 (1999); and Burks et al.  Proc. Natl. Acad. Sci. USA  94:412-417 (1997)). Alternatively, in certain embodiments, mutations can be introduced randomly along all or part of an anti-GITR antibody coding sequence, such as by saturation mutagenesis, and the resulting modified anti-GITR antibodies can be screened for binding activity. 
     For polypeptides, the term “substantial homology” indicates that two polypeptides, or designated sequences thereof, when optimally aligned and compared, are identical, with appropriate amino acid insertions or deletions, in at least about 80% of the amino acids, usually at least about 90% to 95%, and more preferably at least about 98% to 99.5% of the amino acids. The percent identity between two sequences is a function of the number of identical positions shared by the sequences (i.e., % homology=# of identical positions/total # of positions×100), 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, as described in the non-limiting examples below. 
     The percent identity between two nucleotide or amino acid sequences can also be determined using the algorithm of E. Meyers and W. Miller (CABIOS, 4:11-17 (1989)) 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. In addition, the percent identity between two amino acid sequences can be determined using the Needleman and Wunsch ( J. Mol. Biol . (48):444-453 (1970)) algorithm which has been incorporated into the GAP program in the GCG software package (available at http://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. 
     The nucleic acid and protein sequences described herein can further be used as a “query sequence” to perform a search against public databases to, for example, identify 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 the nucleic acid molecules described herein. BLAST protein searches can be performed with the XBLAST program, score=50, wordlength=3 to obtain amino acid sequences homologous to the protein molecules described herein. To obtain gapped alignments for comparison purposes, Gapped BLAST can be utilized as described in Altschul et al., (1997)  Nucleic Acids Res.  25(17):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. 
     An “immune response” refers to a biological response within a vertebrate against foreign agents, which response protects the organism against these agents and diseases caused by them. An immune response is mediated by the action of a cell of the immune system (for example, a T lymphocyte, B lymphocyte, natural killer (NK) cell, macrophage, eosinophil, mast cell, dendritic cell or neutrophil) and soluble macromolecules produced by any of these cells or the liver (including antibodies, cytokines, and complement) that results in selective targeting, binding to, damage to, destruction of, and/or elimination from the vertebrate&#39;s body of invading pathogens, cells or tissues infected with pathogens, cancerous or other abnormal cells, or, in cases of autoimmunity or pathological inflammation, normal human cells or tissues. An immune reaction includes, e.g., activation or inhibition of a T cell, e.g., an effector T cell or a Th cell, such as a CD4+ or CD8+ T cell, or the inhibition of a Treg cell. 
     An “immunomodulator” or “immunoregulator” refers to an agent, e.g., a component of a signaling pathway, that may be involved in modulating, regulating, or modifying an immune response. “Modulating,” “regulating,” or “modifying” an immune response refers to any alteration in a cell of the immune system or in the activity of such cell (e.g., an effector T cell). Such modulation includes stimulation or suppression of the immune system which may be manifested by an increase or decrease in the number of various cell types, an increase or decrease in the activity of these cells, or any other changes which can occur within the immune system. Both inhibitory and stimulatory immunomodulators have been identified, some of which may have enhanced function in a tumor microenvironment. In preferred embodiments, the immunomodulator is located on the surface of a T cell. An “immunomodulatory target” or “immunoregulatory target” is an immunomodulator that is targeted for binding by, and whose activity is altered by the binding of, a substance, agent, moiety, compound or molecule. Immunomodulatory targets include, for example, receptors on the surface of a cell (“immunomodulatory receptors”) and receptor ligands (“immunomodulatory ligands”). 
     “Immunotherapy” refers to the treatment of a subject afflicted with, or at risk of contracting or suffering a recurrence of, a disease by a method comprising inducing, enhancing, suppressing or otherwise modifying an immune response. 
     “Immunostimulating therapy” or “immunostimulatory therapy” refers to a therapy that results in increasing (inducing or enhancing) an immune response in a subject for, e.g., treating cancer. 
     “Potentiating an endogenous immune response” means increasing the effectiveness or potency of an existing immune response in a subject. This increase in effectiveness and potency may be achieved, for example, by overcoming mechanisms that suppress the endogenous host immune response or by stimulating mechanisms that enhance the endogenous host immune response. 
     “T effector” (“T eff ”) cells refers to T cells (e.g., CD4+ and CD8+ T cells) with cytolytic activities as well as T helper (Th) cells, which secrete cytokines and activate and direct other immune cells, but does not include regulatory T cells (Treg cells). Anti-GITR antibodies described herein activate T eff  cells, e.g., CD4+ and CD8+ T eff  cells. 
     An increased ability to stimulate an immune response or the immune system, can result from an enhanced agonist activity of T cell costimulatory receptors and/or an enhanced antagonist activity of inhibitory receptors. An increased ability to stimulate an immune response or the immune system may be reflected by a fold increase of the EC 50  or maximal level of activity in an assay that measures an immune response, e.g., an assay that measures changes in cytokine or chemokine release, cytolytic activity (determined directly on target cells or indirectly via detecting CD107a or granzymes) and proliferation. The ability to stimulate an immune response or the immune system activity may be enhanced by at least 10%, 30%, 50%, 75%, 2 fold, 3 fold, 5 fold or more. 
     An agonist activity of an antibody can be determined, e.g., by measuring the level of IFN-γ or IL-2 secretion from T cells that are contacted with the antibody. The agonist activity of one agonist agent, e.g., an antibody, may be higher by at least 10%, 30%, 50%, 75%, 2 fold, 3 fold, 5 fold or more relative to another agonist agent, as defined by increased cytokine release or increased proliferation in effector T cells; reduced T regulatory cell activity if engagement on Tregs reduces Treg function; or increased depletion of Tregs. For example, the amount of IFN-γ or IL-2 secreted from T cells stimulated with a first agonist agent, e.g., antibody, may be at least 10%, 30%, 50%, 75%, 2 fold, 3 fold, 5 fold or more higher than that of T cells simulated with the a second agonist agent, e.g., antibody. 
     An “agonist” of a ligand or receptor is an agent that mirrors the activity of the natural ligand/receptor interaction. 28F3.IgG1 is an exemplary GITR agonist antibody. 
     An “antagonist” of a ligand or receptor is an agent that inhibits the interaction between the ligand and the receptor. Nivolumab is an exemplary PD-1 antagonist antibody. 
     As used herein, the term “linked” refers to the association of two or more molecules. The linkage can be covalent or non-covalent. The linkage also can be genetic (i.e., recombinantly fused). Such linkages can be achieved using a wide variety of art recognized techniques, such as chemical conjugation and recombinant protein production. 
     As used herein, “administering” refers to the physical introduction of a composition comprising a therapeutic agent to a subject, using any of the various methods and delivery systems known to those skilled in the art, e.g., intravenous. Routes of administration for antibodies described herein include intravenous, intraperitoneal, intramuscular, subcutaneous, spinal or other parenteral routes of administration, for example by injection or infusion. The phrase “parenteral administration” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intraperitoneal, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion, as well as in vivo electroporation. Alternatively, an antibody described herein can be administered via a non-parenteral route, such as a topical, epidermal or mucosal route of administration, for example, intranasally, orally, vaginally, rectally, sublingually or topically. Administering can also be performed, for example, once, a plurality of times, and/or over one or more extended periods. 
     As used herein, the term “T cell-mediated response” refers to a response mediated by T cells, including effector T cells (e.g., CD8 +  cells) and helper T cells (e.g., CD4 +  cells). T cell mediated responses include, for example, T cell cytotoxicity and proliferation. 
     As used herein, the term “cytotoxic T lymphocyte (CTL) response” refers to an immune response induced by cytotoxic T cells. CTL responses are mediated primarily by CD8 +  T cells. 
     As used herein, the terms “inhibits” or “blocks” (e.g., referring to inhibition/blocking of binding of GITR-L to GITR on cells or PD-1 to PD-L1 or PD-L2 on cells) are used interchangeably and encompass both partial and complete inhibition/blocking. In some embodiments, the anti-GITR antibody inhibits binding of GITR-L to GITR by at least about 50%, for example, about 60%, 70%, 80%, 90%, 95%, 99%, or 100%, determined, e.g., as further described herein. In some embodiments, the anti-GITR antibody inhibits binding of GITR-L to GITR by no more than 50%, for example, by about 40%, 30%, 20%, 10%, 5% or 1%, determined, e.g., as further described herein. 
     As used herein, the term “inhibits growth” of a tumor includes any measurable decrease in the growth of a tumor, e.g., the inhibition of growth of a tumor by at least about 10%, for example, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 99%, or 100%. 
     As used herein, “cancer” refers a broad group of diseases characterized by the uncontrolled growth of abnormal cells in the body. Unregulated cell division may result in the formation of malignant tumors or cells that invade neighboring tissues and may metastasize to distant parts of the body through the lymphatic system or bloodstream. 
     The terms “treat,” “treating,” and “treatment,” as used herein, refer to any type of intervention or process performed on, or administering an active agent to, the subject with the objective of reversing, alleviating, ameliorating, inhibiting, or slowing down or preventing the progression, development, severity or recurrence of a symptom, complication, condition or biochemical indicia associated with a disease. Treatment can be of a subject having a disease or a subject who does not have a disease (e.g., for prophylaxis). 
     A “hematological malignancy” includes a lymphoma, leukemia, myeloma or a lymphoid malignancy, as well as a cancer of the spleen and the lymph nodes. Exemplary lymphomas include both B cell lymphomas (a B-cell hematological cancer) and T cell lymphomas. B-cell lymphomas include both Hodgkin&#39;s lymphomas and most non-Hodgkin&#39;s lymphomas. Non-limiting examples of B cell lymphomas include diffuse large B-cell lymphoma, follicular lymphoma, mucosa-associated lymphatic tissue lymphoma, small cell lymphocytic lymphoma (overlaps with chronic lymphocytic leukemia), mantle cell lymphoma (MCL), Burkitt&#39;s lymphoma, mediastinal large B cell lymphoma, Waldenström macroglobulinemia, nodal marginal zone B cell lymphoma, splenic marginal zone lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, lymphomatoid granulomatosis. Non-limiting examples of T cell lymphomas include extranodal T cell lymphoma, cutaneous T cell lymphomas, anaplastic large cell lymphoma, and angioimmunoblastic T cell lymphoma. Hematological malignancies also include leukemia, such as, but not limited to, secondary leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, and acute lymphoblastic leukemia. Hematological malignancies further include myelomas, such as, but not limited to, multiple myeloma and smoldering multiple myeloma. Other hematological and/or B cell- or T-cell-associated cancers are encompassed by the term hematological malignancy. 
     The term “effective dose” or “effective dosage” is defined as an amount sufficient to achieve or at least partially achieve a desired effect. A “therapeutically effective amount” or “therapeutically effective dosage” of a drug or therapeutic agent is any amount of the drug that, when used alone or in combination with another therapeutic agent, promotes disease regression evidenced by a decrease in severity of disease symptoms, an increase in frequency and duration of disease symptom-free periods, or a prevention of impairment or disability due to the disease affliction. A therapeutically effective amount or dosage of a drug includes a “prophylactically effective amount” or a “prophylactically effective dosage”, which is any amount of the drug that, when administered alone or in combination with another therapeutic agent to a subject at risk of developing a disease or of suffering a recurrence of disease, inhibits the development or recurrence of the disease. The ability of a therapeutic agent to promote disease regression or inhibit the development or recurrence of the disease can be evaluated using a variety of methods known to the skilled practitioner, such as in human subjects during clinical trials, in animal model systems predictive of efficacy in humans, or by assaying the activity of the agent in in vitro assays. 
     By way of example, an anti-cancer agent is a drug that promotes cancer regression in a subject. In preferred embodiments, a therapeutically effective amount of the drug promotes cancer regression to the point of eliminating the cancer. “Promoting cancer regression” means that administering an effective amount of the drug, alone or in combination with an anti-neoplastic agent, results in a reduction in tumor growth or size, necrosis of the tumor, a decrease in severity of at least one disease symptom, an increase in frequency and duration of disease symptom-free periods, a prevention of impairment or disability due to the disease affliction, or otherwise amelioration of disease symptoms in the patient. In addition, the terms “effective” and “effectiveness” with regard to a treatment includes both pharmacological effectiveness and physiological safety. Pharmacological effectiveness refers to the ability of the drug to promote cancer regression in the patient. Physiological safety refers to the level of toxicity, or other adverse physiological effects at the cellular, organ and/or organism level (adverse effects) resulting from administration of the drug. 
     By way of example for the treatment of tumors, a therapeutically effective amount or dosage of the drug preferably inhibits cell growth or tumor growth by at least about 20%, more preferably by at least about 40%, even more preferably by at least about 60%, and still more preferably by at least about 80% relative to untreated subjects. In the most preferred embodiments, a therapeutically effective amount or dosage of the drug completely inhibits cell growth or tumor growth, i.e., preferably inhibits cell growth or tumor growth by 100%. The ability of a compound to inhibit tumor growth can be evaluated using the assays described infra. Alternatively, this property of a composition can be evaluated by examining the ability of the compound to inhibit cell growth, such inhibition can be measured in vitro by assays known to the skilled practitioner. In other preferred embodiments described herein, tumor regression may be observed and continue for a period of at least about 20 days, more preferably at least about 40 days, or even more preferably at least about 60 days. 
     The term “patient” includes human and other mammalian subjects that receive either prophylactic or therapeutic treatment. 
     As used herein, the term “subject” includes any human or non-human animal. For example, the methods and compositions described herein can be used to treat a subject having cancer. 
     “Therapeutic synergy” refers to a phenomenon where treatment of patients with a combination of therapeutic agents manifests a therapeutically superior outcome to the outcome achieved by each individual constituent of the combination used at its optimum dose (Corbett, T. H. et al.,  Cancer Treatment Reports,  66:1187 (1982)). For example, a therapeutically superior outcome is one in which the patients either a) exhibit fewer incidences of adverse events while receiving a therapeutic benefit that is equal to or greater than that where individual constituents of the combination are each administered as monotherapy at the same dose as in the combination, or b) do not exhibit dose-limiting toxicities while receiving a therapeutic benefit that is greater than that of treatment with each individual constituent of the combination when each constituent is administered in at the same doses in the combination(s) as is administered as individual components. 
     Methods of Treating Cancer 
     An anti-GITR agonist agent, such as an anti-GITR agonist Ab, may be administered to a subject having cancer, e.g., an advanced solid tumor, at a flat dose of 3 mg, 10 mg, 30 mg, 100 mg, 240 mg, 480 mg, 600 mg, 800 mg or 1000 mg of an anti-GITR agonist agent, e.g., an Ab, once every week, once every two weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, once every 6 weeks, once every 7 weeks or once every 8 weeks. The treatment may be administered in 8 week cycles, e.g., one 8 week cycle, two 8 week cycles, three 8 week cycles, four 8 week cycles, five 8 week cycles, six 8 week cycles, or more. Once cycle may comprise 8, 7, 6, 5, 4, 3, 2 or 1 administration of the anti-GITR agonist agent, such as an antibody. One cycle preferably comprises 4 administrations with one administration every two weeks. The treatment may be a monotherapy or part of a combination therapy. 
     An anti-GITR agonist agent, e.g., Ab, may be administered to a subject having cancer, e.g., an advanced solid tumor, as a combination therapy with an anti-PD-1 or anti-PD-L1 antagonist agent, e.g., Ab, at a flat dose of 3 mg, 10 mg, 30 mg, 100 mg, 200 mg, 240 mg, 250 mg, 300 mg, 400 mg, 480 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg or 1000 mg (e.g., 30 mg to 1000 mg; 30 mg to 800 mg; 100 mg to 800 mg; 100 mg to 600 mg) of an anti-GITR agonist agent, e.g., an Ab, once every week, once every two weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, once every 6 weeks, once every 7 weeks or once every 8 weeks. The treatment may be administered in 8 week cycles, e.g., one 8 week cycle, two 8 week cycles, three 8 week cycles, four 8 week cycles, five 8 week cycles, six 8 week cycles, or more. The anti-PD-1 or anti-PD-L1 antagonist, e.g., antibody, may be administered at a flat dose of, e.g., 100-500 mg, 200 mg-500 mg, 100-300 mg, such as, 200-300 mg, 220-260 mg, 230-250 mg, 120 mg, 240 mg or 480 mg. 
     An anti-GITR agonist agent, e.g., Ab, as monotherapy or combination therapy (a “first therapy”) may be administered to a subject having cancer, e.g., an advanced solid tumor, for 1-6 cycles, followed by a rest period (a “follow-up period”) and then retreatment with an anti-GITR agonist agent, e.g., Ab, as monotherapy or combination therapy (a “second therapy”). The first dose of the re-treatment (i.e., second therapy) may be administered within 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or more months after the last dose of the first therapy. In certain embodiments, the first dose of the retreatment occurs within 12 months of the last dose of the first therapy. 
     Exemplary combination therapies comprise an anti-GITR agonist agent, e.g., Ab, and an anti-PD-1 or anti-PD-L1 antagonist agent, e.g., an antagonist Ab. In certain embodiments, an anti-GITR agonist agent, e.g., Ab, is infused first, followed by an infusion of a PD-1 or PD-L1 antagonist agent. For example, an anti-GITR agent, e.g., Ab, may be administered by infusion for a period of 30-60 minutes, followed by an infusion of an anti-PD-1 or anti-PD-L1 agent over a period of 30-60 minutes. In certain embodiments, an anti-PD-1 or anti-PD-L1 agent is administered by infusion for a period of 30-60 minutes, followed by an infusion of an anti-GITR agonist agent, e.g., Ab, over a period of 30-60 minutes. In certain embodiments, the two infusions are separated by a time period, e.g., 10 minutes, 30 minutes, 60 minutes, 2 hours, 3 hours, 6 hours, 12 hours, 24 hours, 10 minutes to 12 hours, 10 minutes to 6 hours, 10 minutes to 3 hours, or 20 minutes to 2 hours. 
     An anti-GITR agonist agent, e.g., Ab, and an anti-PD-1 or anti-PD-L1 antagonist agent, e.g., Ab, may be administered at the same time, and may be coformulated. An exemplary combination therapy comprises administering an anti-GITR agonist agent, e.g., Ab, in combination with the anti-PD-1 Ab nivolumab. Nivolumab may be administered at a flat dose of 240 mg every two weeks. 
     An anti-GITR agonist agent, e.g., Ab, may be administered via infusion, e.g., an infusion over a period of at least 30 minutes, e.g., 30-60 or 30-90 minutes. For example, an anti-GITR agonist agent, e.g., Ab, may be administered by infusion over a period of 30 minutes or a period of 60 minutes. An anti-GITR agent, e.g., Ab, e.g., for administration by infusion, may be provided as a formulation of 1 mg/ml, 2 mg/ml, 3 mg/ml, 4 mg/ml, 5 mg/ml, 6 mg/ml, 7 mg/ml, 8 mg/ml, 9 mg/ml, 10 mg/ml, 20 mg/ml or more. 
     An exemplary treatment, e.g., monotherapy, comprises administering to a subject having an advanced solid tumor a 1 mg flat dose of an anti-GITR agonist agent, e.g., Ab, administered as an IV infusion, e.g., over 60 minutes, every 2 weeks. A treatment may comprise administering to a subject having an advanced solid tumor a 3 mg flat dose of an anti-GITR agonist agent, e.g., Ab, administered as an IV infusion, e.g., over 60 minutes, every 2 weeks. A treatment may comprise administering to a subject having an advanced solid tumor a 10 mg flat dose of an anti-GITR agonist agent, e.g., Ab, administered as an IV infusion, e.g., over 60 minutes, every 2 weeks. A treatment may comprise administering to a subject having an advanced solid tumor a 30 mg flat dose of an anti-GITR agonist agent, e.g., Ab, administered as an IV infusion, e.g., over 60 minutes, every 2 weeks. A treatment may comprise administering to a subject having an advanced solid tumor a 100 mg flat dose of an anti-GITR agonist agent, e.g., Ab, administered as an IV infusion, e.g., over 60 minutes, every 2 weeks. A treatment may comprise administering to a subject having an advanced solid tumor a 240 mg flat dose of an anti-GITR agonist agent, e.g., Ab, administered as an IV infusion, e.g., over 800 minutes, every 2 weeks. A treatment may comprise administering to a subject having an advanced solid tumor a 800 mg flat dose of an anti-GITR agonist agent, e.g., Ab, administered as an IV infusion, e.g., over 800 minutes, every 2 weeks. 
     An exemplary combination treatment comprises administering to a subject having an advanced solid tumor a 1 mg flat dose of an anti-GITR agonist agent, e.g., Ab, and an anti-PD-1 or anti-PD-L1 antagonist agent, e.g., nivolumab, at a flat dose of 240 mg, administered together or separately, as one or two IV infusions, e.g., over 30-60 minutes each, every 2 weeks. A treatment may comprise administering to a subject having an advanced solid tumor a 3 mg flat dose of an anti-GITR agonist agent, e.g., Ab, and an anti-PD-1 or anti-PD-L1 antagonist agent, e.g., nivolumab, at a flat dose of 240 mg, both administered together or separately, as one or two IV infusions, e.g., over 30-60 minutes each, every 2 weeks. A treatment may comprise administering to a subject having an advanced solid tumor a 10 mg flat dose of an anti-GITR agonist agent, e.g., Ab, and an anti-PD-1 or anti-PD-L1 antagonist agent, e.g., nivolumab, at a flat dose of 240 mg, both administered together or separately, as one or two IV infusions, e.g., over 30-60 minutes each, every 2 weeks. A treatment may comprise administering to a subject having an advanced solid tumor a 30 mg flat dose of an anti-GITR agonist agent, e.g., Ab, and an anti-PD-1 or anti-PD-L1 antagonist agent, e.g., nivolumab, at a flat dose of 240 mg, both administered together or separately, as one or two IV infusions, e.g., over 30-60 minutes each, every 2 weeks. A treatment may comprise administering to a subject having an advanced solid tumor a 100 mg flat dose of an anti-GITR agonist agent, e.g., Ab, and an anti-PD-1 or anti-PD-L1 antagonist agent, e.g., nivolumab, at a flat dose of 240 mg, both administered together or separately, as one or two IV infusions, e.g., over 30-60 minutes each, every 2 weeks. A treatment may comprise administering to a subject having an advanced solid tumor a 240 mg flat dose of an anti-GITR agonist agent, e.g., Ab, and an anti-PD-1 or anti-PD-L1 antagonist agent, e.g., nivolumab, at a flat dose of 240 mg, both administered together or separately, as one or two IV infusions, e.g., over 30-60 minutes each, every 2 weeks. A treatment may comprise administering to a subject having an advanced solid tumor a 800 mg flat dose of an anti-GITR agonist agent, e.g., Ab, and an anti-PD-1 or anti-PD-L1 antagonist agent, e.g., nivolumab, at a flat dose of 240 mg, both administered together or separately, as one or two IV infusions, e.g., over 30-60 minutes each, every 2 weeks. A combination treatment may exhibit a therapeutic synergy. 
     An exemplary combination treatment comprises administering to a subject having an advanced solid tumor a 1 mg flat dose of an anti-GITR agonist agent, e.g., Ab, and an anti-PD-1 or anti-PD-L1 antagonist agent, e.g., nivolumab, at a flat dose of 120 mg, administered together or separately, as one or two IV infusions, e.g., over 30-60 minutes each, every week. A treatment may comprise administering to a subject having an advanced solid tumor a 3 mg flat dose of an anti-GITR agonist agent, e.g., Ab, and an anti-PD-1 or anti-PD-L1 antagonist agent, e.g., nivolumab, at a flat dose of 120 mg, administered together or separately, as one or two IV infusions, e.g., over 30-60 minutes each, every week. A treatment may comprise administering to a subject having an advanced solid tumor a 10 mg flat dose of an anti-GITR agonist agent, e.g., Ab, and an anti-PD-1 or anti-PD-L1 antagonist agent, e.g., nivolumab, at a flat dose of 120 mg, administered together or separately, as one or two IV infusions, e.g., over 30-60 minutes each, every week. A treatment may comprise administering to a subject having an advanced solid tumor a 30 mg flat dose of an anti-GITR agonist agent, e.g., Ab, and an anti-PD-1 or anti-PD-L1 antagonist agent, e.g., nivolumab, at a flat dose of 120 mg, administered together or separately, as one or two IV infusions, e.g., over 30-60 minutes each, every week. A treatment may comprise administering to a subject having an advanced solid tumor a 100 mg flat dose of an anti-GITR agonist agent, e.g., Ab, and an anti-PD-1 or anti-PD-L1 antagonist agent, e.g., nivolumab, at a flat dose of 120 mg, administered together or separately, as one or two IV infusions, e.g., over 30-60 minutes each, every week. A treatment may comprise administering to a subject having an advanced solid tumor a 240 mg flat dose of an anti-GITR agonist agent, e.g., Ab, and an anti-PD-1 or anti-PD-L1 antagonist agent, e.g., nivolumab, at a flat dose of 120 mg, administered together or separately, as one or two IV infusions, e.g., over 30-60 minutes each, every week. A treatment may comprise administering to a subject having an advanced solid tumor a 800 mg flat dose of an anti-GITR agonist agent, e.g., Ab, and an anti-PD-1 or anti-PD-L1 antagonist agent, e.g., nivolumab, at a flat dose of 120 mg, administered together or separately, as one or two IV infusions, e.g., over 30-60 minutes each, every week. A combination treatment may exhibit a therapeutic synergy. 
     An exemplary combination treatment comprises administering to a subject having an advanced solid tumor a 1 mg flat dose of an anti-GITR agonist agent, e.g., Ab, and an anti-PD-1 or anti-PD-L1 antagonist agent, e.g., nivolumab, at a flat dose of 360 mg, administered together or separately, as one or two IV infusions, e.g., over 30-60 minutes each, every 3 weeks. A treatment may comprise administering to a subject having an advanced solid tumor a 3 mg flat dose of an anti-GITR agonist agent, e.g., Ab, and an anti-PD-1 or anti-PD-L1 antagonist agent, e.g., nivolumab, at a flat dose of 360 mg, administered together or separately, as one or two IV infusions, e.g., over 30-60 minutes each, every 3 weeks. A treatment may comprise administering to a subject having an advanced solid tumor a 10 mg flat dose of an anti-GITR agonist agent, e.g., Ab, and an anti-PD-1 or anti-PD-L1 antagonist agent, e.g., nivolumab, at a flat dose of 360 mg, administered together or separately, as one or two IV infusions, e.g., over 30-60 minutes each, every 3 weeks. A treatment may comprise administering to a subject having an advanced solid tumor a 30 mg flat dose of an anti-GITR agonist agent, e.g., Ab, and an anti-PD-1 or anti-PD-L1 antagonist agent, e.g., nivolumab, at a flat dose of 360 mg, administered together or separately, as one or two IV infusions, e.g., over 30-60 minutes each, every 3 weeks. 
     A treatment may comprise administering to a subject having an advanced solid tumor a 100 mg flat dose of an anti-GITR agonist agent, e.g., Ab, and an anti-PD-1 or anti-PD-L1 antagonist agent, e.g., nivolumab, at a flat dose of 360 mg, administered together or separately, as one or two IV infusions, e.g., over 30-60 minutes each, every 3 weeks. A treatment may comprise administering to a subject having an advanced solid tumor a 240 mg flat dose of an anti-GITR agonist agent, e.g., Ab, and an anti-PD-1 or anti-PD-L1 antagonist agent, e.g., nivolumab, at a flat dose of 360 mg, administered together or separately, as one or two IV infusions, e.g., over 30-60 minutes each, every 3 weeks. A treatment may comprise administering to a subject having an advanced solid tumor a 360 mg flat dose of an anti-GITR agonist agent, e.g., Ab, and an anti-PD-1 or anti-PD-L1 antagonist agent, e.g., nivolumab, at a flat dose of 360 mg, administered together or separately, as one or two IV infusions, e.g., over 30-60 minutes each, every 3 weeks. A treatment may comprise administering to a subject having an advanced solid tumor a 460 mg flat dose of an anti-GITR agonist agent, e.g., Ab, and an anti-PD-1 or anti-PD-L1 antagonist agent, e.g., nivolumab, at a flat dose of 360 mg, administered together or separately, as one or two IV infusions, e.g., over 30-60 minutes each, every 3 weeks. A treatment may comprise administering to a subject having an advanced solid tumor a 600 mg flat dose of an anti-GITR agonist agent, e.g., Ab, and an anti-PD-1 or anti-PD-L1 antagonist agent, e.g., nivolumab, at a flat dose of 360 mg, administered together or separately, as one or two IV infusions, e.g., over 30-60 minutes each, every 3 weeks. A treatment may comprise administering to a subject having an advanced solid tumor a 800 mg flat dose of an anti-GITR agonist agent, e.g., Ab, and an anti-PD-1 or anti-PD-L1 antagonist agent, e.g., nivolumab, at a flat dose of 360 mg, administered together or separately, as one or two IV infusions, e.g., over 30-60 minutes each, every 3 weeks. A combination treatment may exhibit a therapeutic synergy. 
     An exemplary combination treatment comprises administering to a subject having an advanced solid tumor a 1 mg flat dose of an anti-GITR agonist agent, e.g., Ab, and an anti-PD-1 or anti-PD-L1 antagonist agent, e.g., nivolumab, at a flat dose of 480 mg, administered together or separately, as one or two IV infusions, e.g., over 30-60 minutes each, every 4 weeks. A treatment may comprise administering to a subject having an advanced solid tumor a 3 mg flat dose of an anti-GITR agonist agent, e.g., Ab, and an anti-PD-1 or anti-PD-L1 antagonist agent, e.g., nivolumab, at a flat dose of 480 mg, administered together or separately, as one or two IV infusions, e.g., over 30-60 minutes each, every 4 weeks. A treatment may comprise administering to a subject having an advanced solid tumor a 10 mg flat dose of an anti-GITR agonist agent, e.g., Ab, and an anti-PD-1 or anti-PD-L1 antagonist agent, e.g., nivolumab, at a flat dose of 480 mg, administered together or separately, as one or two IV infusions, e.g., over 30-60 minutes each, every 4 weeks. A treatment may comprise administering to a subject having an advanced solid tumor a 30 mg flat dose of an anti-GITR agonist agent, e.g., Ab, and an anti-PD-1 or anti-PD-L1 antagonist agent, e.g., nivolumab, at a flat dose of 480 mg, administered together or separately, as one or two IV infusions, e.g., over 30-60 minutes each, every 4 weeks. A treatment may comprise administering to a subject having an advanced solid tumor a 100 mg flat dose of an anti-GITR agonist agent, e.g., Ab, and an anti-PD-1 or anti-PD-L1 antagonist agent, e.g., nivolumab, at a flat dose of 480 mg, administered together or separately, as one or two IV infusions, e.g., over 30-60 minutes each, every 4 weeks. A treatment may comprise administering to a subject having an advanced solid tumor a 240 mg flat dose of an anti-GITR agonist agent, e.g., Ab, and an anti-PD-1 or anti-PD-L1 antagonist agent, e.g., nivolumab, at a flat dose of 480 mg, administered together or separately, as one or two IV infusions, e.g., over 30-60 minutes each, every 4 weeks. A treatment may comprise administering to a subject having an advanced solid tumor a 360 mg flat dose of an anti-GITR agonist agent, e.g., Ab, and an anti-PD-1 or anti-PD-L1 antagonist agent, e.g., nivolumab, at a flat dose of 480 mg, administered together or separately, as one or two IV infusions, e.g., over 30-60 minutes each, every 4 weeks. A treatment may comprise administering to a subject having an advanced solid tumor a 480 mg flat dose of an anti-GITR agonist agent, e.g., Ab, and an anti-PD-1 or anti-PD-L1 antagonist agent, e.g., nivolumab, at a flat dose of 480 mg, administered together or separately, as one or two IV infusions, e.g., over 30-60 minutes each, every 4 weeks. A treatment may comprise administering to a subject having an advanced solid tumor a 600 mg flat dose of an anti-GITR agonist agent, e.g., Ab, and an anti-PD-1 or anti-PD-L1 antagonist agent, e.g., nivolumab, at a flat dose of 480 mg, administered together or separately, as one or two IV infusions, e.g., over 30-60 minutes each, every 4 weeks. A treatment may comprise administering to a subject having an advanced solid tumor a 800 mg flat dose of an anti-GITR agonist agent, e.g., Ab, and an anti-PD-1 or anti-PD-L1 antagonist agent, e.g., nivolumab, at a flat dose of 480 mg, administered together or separately, as one or two IV infusions, e.g., over 30-60 minutes each, every 4 weeks. A combination treatment may exhibit a therapeutic synergy. 
     An anti-GITR agonist agent, e.g., Ab, may be administered to patients who have lung cancer, such as non-small cell lung cancer (NSCLC), e.g., NSCLC subjects with progressive or recurrent disease during or after prior platinum doublet-based chemotherapy, followed by recurrent or progressive disease (per RECIST v1.1) during or after subsequent anti-PD-1 or anti-PD-L1 therapy. An anti-GITR agonist agent, e.g., Ab, may be administered to patients who have cervical cancer, such as persistent, recurrent or metastatic cervical cancer. 
     An anti-GITR agonist agent, e.g., Ab, may be administered in combination with an anti-PD-1 or anti-PD-L1 agent, e.g., nivolumab, in the following types of subjects (i) NSCLC subjects with progressive or recurrent disease during or after prior platinum doublet-based chemotherapy followed by progressive or recurrent disease (per RECIST v1.1) during or after subsequent anti-PD-1 or anti-PD-L1 therapy (ii) NSCLC subjects with progressive or recurrent disease during or after platinum doublet-based chemotherapy with no prior anti-PD-1 or anti-PD-L1 therapy, and (iii) persistent, recurrent or metastatic cervical cancer. Treatment, e.g., monotherapy, may consists of up to three, 8-week treatment cycles, wherein, e.g., each treatment cycle comprises 4 doses of an anti-GITR agonist agent, e.g., Ab administered every 2 weeks on Days 1, 15, 29, and 43 of the treatment cycle. For combination treatments, each treatment cycle may comprise 4 doses of an anti-GITR agonist agent, e.g., Ab, (administered on Days 1, 15, 29 and 43) in combination with 4 doses of an anti-PD-1 or anti-PD-L1 agent, e.g., nivolumab, administered on Days 1, 15, 29, and 43 of the treatment cycle. When an anti-GITR agonist agent, e.g., Ab, and anti-PD-1 or an anti-PD-L1 agent are given, the anti-PD-1 or an anti-PD-L1 agent may be given first followed by the anti-GITR agonist agent, e.g., Ab, at least 30 minutes (e.g., 30 minutes to 3, 4, or 5 hours) after completion of the infusion of the anti-PD-1 or an anti-PD-Ll agent. 
     Subjects completing approximately 24 weeks (e.g., 6 months) of treatment with ongoing disease control (complete remission (CR), partial remission (PR) or stable disease (SD) or unconfirmed progressive disease (PD)) may receive an additional 3 cycles of monotherapy or combination therapy beyond the initial 24 weeks. 
     Cancer may be monitored by radiologic (e.g., tumor scans) and clinical tumor assessments, e.g., every 12 weeks or every six months. 
     Patients receiving an anti-GITR agonist agent, e.g., Ab, as monotherapy or as part of a combination therapy may have post-chemotherapy NSCLC or advanced/metastatic cervical cancer. 
     Following each treatment cycle, the decision to treat a subject with additional cycles of anti-GITR agonist agent, e.g., Ab, as monotherapy or combination therapy, may be based on tumor assessment (e.g., evaluation performed between Days 49 and 56 of each cycle and completed before the first dose in the next cycle). Tumor progression or response endpoints may be assessed using RECIST v1.1 criteria for solid tumors. 
     In certain embodiments in which subjects having NSCLC are treated with an anti-GITR agonist agent, e.g., Ab, as monotherapy or combination therapy, the subjects had progressive or recurrent disease during or after platinum doublet-based chemotherapy; the subjects with non-squamous histology have a known EGFR and ALK status; the subjects with an activating EGFR mutation have received an EGFR tyrosine kinase inhibitor; and/or the subjects with an ALK translocation have received an ALK inhibitor. 
     In certain embodiments in which subjects having a solid tumor, e.g., advanced solid tumor, such as cervical cancer, are treated with an anti-GITR agonist agent, e.g., Ab, as monotherapy or combination therapy, the subjects have persistent, recurrent or metastatic cervical cancer with documented disease progression; the subject have squamous, adenosquamous or adenocarcinoma histology; the subjects have had one prior systemic chemotherapeutic regimen (e.g. paclitaxel/cisplatin, paclitaxel/cisplatin/bevacizumab) for persistent, recurrent, or metastatic disease; the subjects had chemotherapy administered concurrently with primary radiation (e.g. weekly cisplatin), adjuvant chemotherapy given following completion of radiation therapy or as concurrent chemotherapy and radiation therapy (e.g. paclitaxel and carboplatin for up to 4 cycles); the subjects are HPV positive or negative; the subjects have ECOG performance status of &lt;1; the subjects have at least one lesion with measurable disease as defined by RECIST v1.1 for solid tumors and/or the lesion(s) have demonstrated clear progression and can be measured accurately; the subjects had prior exposure to therapy with any agent specifically targeting checkpoint pathway inhibition (such as anti-PD-1, anti-PD-L1, anti-PDL-2, anti-LAG-3, antiCTLA-4 antibody), preferably with a washout period of any time greater than 4 weeks from the last treatment; the subjects experienced prior Grade 1 to 2 checkpoint therapy-related immune-mediated adverse events, which subjects may or not have confirmed recovery from these events at the time of the beginning of the anti-GITR agonist agent, e.g., Ab, therapy, other than endocrinopathies treated with supplementation, as documented by resolution of all related clinical symptoms, abnormal findings on physical examination, and/or associated laboratory abnormalities; and/or subjects had prior ≥Grade 3 checkpoint therapy-related immune adverse events; the subjects had prior therapy with any agent specifically targeting T-cell co-stimulation pathways, such as anti- CD137, anti-OX40 antibody, preferably with a washout period of any time greater than 4 weeks from the last treatment; the subjects had prior palliative radiotherapy that was completed, e.g., at least 2 weeks prior to first dose of the anti-GITR agonist agent, e.g., Ab, therapy; the subjects have symptomatic tumor lesions at baseline; the subjects had palliative radiotherapy within 4 weeks of first dose of the anti-GITR agonist agent, e.g., Ab, therapy; and/or the subjects have adequate organ function for subjects with solid tumor histologies as defined by the following: 1) WBC≥2000/μL (stable off any growth factor within 4 weeks of first administration); 2) Neutrophils≥1500/μL (stable off any growth factor within 4 weeks of first administration); 3) Platelets≥100×103/μL (transfusion to achieve this level is not permitted within 2 weeks of first administration); 4) Hemoglobin≥8.5 g/dL; 5) ALT and AST≤3×ULN; 6) Total bilirubin≤1.5×ULN (except subjects with Gilbert&#39;s Syndrome who must have normal direct bilirubin); 7) Normal thyroid function, subclinical hypothyroidism (TSH&lt;10 mIU/mL) or have controlled hypothyroidism on appropriate thyroid supplementation; 8) Serum creatinine≤1.5×ULN or creatinine clearance (CrCl)≥40 ml/min (measured using the Cockcroft-Gault formula below): Female CrCl=(140−age in years)×weight in kg×0.85 72×serum creatinine in mg/dL Male CrCl=(140−age in years)×weight in kg×1.00 72×serum creatinine in mg/dL. 
     A patient receiving a treatment described herein may be a patient having one or more of the inclusion criteria set forth in Example 1, or not having one or more of the exclusion criteria set forth in Example 1. 
     In certain embodiments in which subjects having a solid tumor, e.g., advanced solid tumor, such as cervical cancer, are treated with an anti-GITR agonist agent, e.g., Ab, as monotherapy or combination therapy, the subjects have no known or suspected central nervous system (CNS) metastases, untreated CNS metastases, or have the CNS as the only site of disease, except that the subject may have controlled brain metastases (i.e., no radiographic progression for at least 4 weeks following radiation and/or surgical treatment (or 4 weeks of observation if no intervention is clinically indicated), and off of steroids for at least 2 weeks, and no new or progressive neurological signs and symptoms; the subjects have no known carcinomatous meningitis. 
     In certain embodiments, a method of treatment with an anti-GITR agonist Ab comprises administering the anti-GITR agonist agent, e.g., Ab, into one or more tumors, e.g., solid tumors, of the subject. Administration into a tumor can be via injection into the tumor. In certain embodiments, the anti-GITR agent, e.g., Ab, is administered both parenterally (e.g., intravenously or subcutaneously) and directly into one or more tumors (i.e., intratumorally). Any of the doses recited herein for administering the Ab may be used for intratumoral administration. Alternatively, half of a dose described herein is administered parenterally and half of the dose is administered intratumorally. In certain embodiments, 0.01-10 mg of an anti-GITR agent, e.g., Ab, is administered intratumorally in a subject as a single dose, or alternatively, every week, every 2 weeks, every 3 weeks, or once a month, e.g., until tumor shrinkage. For example, 0.01 mg, 0.05 mg, 0.1 mg, 0.5 mg, 1 mg, 2 mg, 5 mg, 7 mg or 10 mg of an anti-GITR agent, e.g., Ab, is administered intratumorally as a single dose, every week, every 2 weeks, every 3 weeks, or once a month, e.g., until tumor shrinkage. In certain embodiments, lower amounts of the agent, e.g., Ab, may be administered, e.g., 1 μg, 3 μg, 5 μg, 10 μg, 25 μg, 50 μg, or 100 μg. 
     An anti-PD-1 or PD-L1 antagonist Ab may be co-administered with an anti-GITR agonist agent, e.g., Ab, into one or more tumors in a subject. The anti-PD-1 or PD-L1 Ab may be administered at the same time, before, or after administration of the anti-GITR agent, e.g., Ab. For example, the anti-PD-1 or PD-L1 Ab may be injected into a tumor at the same time as the anti-GITR agent, e.g., Ab, is injected into the tumor. In certain embodiments, the two agents are co-formulated prior to administration into a tumor. In certain embodiments, one agent is administered parenterally and one agent is administered directly into one or more tumors. For example, an anti-PD-1 agent, e.g., Ab, or PD-L1 agent, e.g., Ab, is administered parenterally and an anti-GITR agent, e.g., Ab, is administered intratumorally. 
     Anti-tumor activity of an anti-GITR agonist agent, e.g., Ab, alone or in combination with an anti-PD-1 or anti-PD-L1 antagonist agent, e.g., Ab, e.g., nivolumab, may be evidenced by an increase in overall survival, e.g., by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 16, 24 months or more, relative to a subject treated with a placebo. Efficacy of treatment may be determined by measurement of the objective response rate (ORR). ORR and corresponding 2-sided exact 95% exact confidence interval by the Clopper and Pearson method may be determined. Median duration of response and corresponding two-sided 95% confidence interval may be determined. Duration of response may be analyzed using the Kaplan-Meier method. Progression free survival rate (PFSR), the probability of a subject remaining progression free or surviving to 24 weeks, may be estimated by the Kaplan-Meier methodology. The corresponding 90% confidence interval may be derived based on Greenwood formula. Overall survival may be plotted using the Kaplan-Meier method. 
     GITR Agonist Agents 
     A GITR agonist agent is an agent that enhances the activity that normally results from the interaction between GITR and GITRL. In certain embodiments, a GITR agonist agent is an antibody or a variant thereof, such as a multimer thereof, or single chain or antigen binding fragment or bi-specific agent. In certain embodiments, a GITR agonist agent is human GITRL or a variant thereof, such as a fragment thereof, a fusion protein (comprising full length or a GITR binding fragment of GITRL) or a multimer of the full length or a GITR binding fragment of GITRL). Exemplary GITR agonist agents include the following antibodies or multimers thereof or GITRL based molecules: 
     TRX518; MK-4166; MK-1248; Medi 1873; AMG 228; LKZ-145; GWN-323; INCAGN01876; iNBRX-110 (FPA-154); CK-302; OMP-336B11; Regeneron/Sanofi anti-GITR antibody; HERA-GITR-ligands; or a GITR agonist agent described in any one of the following publications: WO06/105021; WO2011/028683; JP2008278814; US20140072566; US20140072565; US20140065152; WO2015/031667; WO/2015/116178; WO2015/184099; WO/2016/054638; WO2016/057841; WO2016/057846; CN105669867; WO/2016/126781; WO/2017/015623; WO/2017/025610; WO/2017/068185; and WO/2017/068186, each of which is specifically incorporated by reference herein. 
     Anti-GITR Abs 
     Anti-GITR agonist Abs for use in the methods described herein may be monoclonal antibodies, in particular human monoclonal antibodies that specifically bind GITR and have desirable functional properties, e.g., high affinity binding to human GITR and the ability to stimulate antigen-specific T cell responses. Antigen binding fragments of such Abs may also be used. 
     In one aspect, anti-GITR agonist Abs, or antigen binding portions thereof, which bind to GITR may exhibit at least one of the following properties: 
     (a) bind to soluble human GITR; 
     (b) bind to membrane bound human GITR; 
     (c) bind to membrane bound cynomolgus GITR; 
     (d) induce or enhance T cell activation, e.g., antigen specific T cell activation; 
     (e) inhibit the binding of GITR ligand to GITR on 3A9-hGITR cells; 
     (f) at most partially inhibits the binding of GITR ligand to GITR on activated T cells; 
     (g) bind to a conformational epitope on mature human GITR (SEQ ID NO: 4); 
     (h) bind to both O-linked and N-glycosylated and unglycosylated human GITR; 
     (i) have agonist activity in the absence of binding to an Fc receptor, but wherein binding to an Fc receptor further enhances the agonist activity; and 
     (j) compete in either direction or both directions for binding to human GITR with one or more of antibodies 28F3, 3C3-1, 3C3-2, 2G6, 8A6, 9G7-1, 9G7-2, 14E3, 19H8-1, 19H8-2, 19D3, 18E10, and 6G10. 
     In certain embodiments, the anti-GITR agonist antibodies, or antigen binding portions thereof, described herein stimulate an anti-tumor immune response, for example, an antigen-specific T cell response. In certain embodiments, the anti-GITR agonist antibodies, or antigen binding portions thereof, increase cytokine production (e.g., IL-2 and/or IFN-γ) in GITR-expressing T cells and/or increase T cell proliferation. 
     In certain embodiments, the anti-GITR agonist antibodies, or antigen binding portions thereof, do not bind to Fc receptors. In certain embodiments, the anti-GITR agonist antibodies, or antigen binding portions thereof, bind to one or more FcγRs, e.g., activating or inhibitory, FcγRs. 
     In certain embodiments, the anti-GITR agonist antibodies, or antigen binding portions thereof, bind to soluble human GITR with a K D  of 100 nM or less as measured by Biacore, bind to membrane bound human GITR with a K D  of 10 nM or less as measured by Scatchard, bind to membrane bound human GITR with an EC 50  of 1 nM or less as measured by FACS, bind to membrane bound cynomolgus GITR with an EC 50  of 10 nM or less as measured by FACS, induce or enhance T cell, e.g, T eff  cell, activation without requiring multivalent cross-linking, inhibit the binding of GITR ligand to GITR with an EC 50  of 1 μg/mL or less as measured by FACS, and/or bind within the regions PTGGPGCGPGRLLLGTGT (SEQ ID NO: 217) and CRDYPGEE (SEQ ID NO: 218) of mature human GITR (SEQ ID NO: 4). 
     Provided herein are isolated anti-GITR agonist monoclonal antibodies, or antigen binding portions thereof, which specifically bind to GITR and comprise the three variable heavy chain CDRs and the three variable light chain CDRs that are in the variable heavy chain and variable light chain pairs selected from: 
     (a) SEQ ID NOs: 13 and 14; 
     (b) SEQ ID NOs: 26 and 27; 
     (c) SEQ ID NOs: 39 and 40; 
     (d) SEQ ID NOs: 52 and 53; 
     (e) SEQ ID NOs: 52 and 54; 
     (f) SEQ ID NOs: 71 and 72; 
     (g) SEQ ID NOs: 84 and 85; 
     (h) SEQ ID NOs: 97 and 98; 
     (i) SEQ ID NOs: 97 and 99; 
     (j) SEQ ID NOs: 115 and 116; 
     (k) SEQ ID NOs: 128 and 129; 
     (l) SEQ ID NOs: 128 and 130; and 
     (m) SEQ ID NOs: 335 and 336. 
     Provided herein are isolated anti-GITR agonist monoclonal antibodies, or antigen binding portions thereof, which bind to GITR and comprise: 
     (a) heavy chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 20, 21, and 22, respectively, and/or light chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 23, 24, and 25, respectively; 
     (b) heavy chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 33, 34, and 35, respectively, and/or light chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 36, 37, and 38, respectively; 
     (c) heavy chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 46, 47, and 48, respectively, and/or light chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 49, 50, and 51, respectively; 
     (d) heavy chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 62, 63, and 64, respectively, and/or light chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 65, 66, and 67, respectively; 
     (e) heavy chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 62, 63, and 64, respectively, and/or light chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 68, 69, and 70, respectively; 
     (f) heavy chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 78, 79, and 80, respectively, and/or light chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 81, 82, and 83, respectively; 
     (g) heavy chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 91, 92, and 93, respectively, and/or light chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 94, 95, and 96, respectively; 
     (h) heavy chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 106, 107, and 108, respectively, and/or light chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 109, 110, and 111, respectively; 
     (i) heavy chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 106, 107, and 108, respectively, and/or light chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 112, 113, and 114, respectively; 
     (j) heavy chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 122, 123, and 124, respectively, and/or light chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 125, 126, and 127, respectively; 
     (k) heavy chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 138, 139, and 140, respectively, and/or light chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 141, 142, and 143, respectively; 
     (l) heavy chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 138, 139, and 140, respectively, and/or light chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 144, 145, and 146, respectively; or 
     (m) heavy chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 342, 343, and 344, respectively, and/or light chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 345, 346, and 347, respectively. 
     Provided herein are isolated anti-GITR agonist monoclonal antibodies, or antigen binding portions thereof, which bind to GITR and comprise heavy and light chain variable regions, wherein the heavy chain variable region comprises an amino acid sequence which is at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence selected from the group consisting of SEQ ID NOs: 13, 26, 39, 52, 71, 84, 97, 115, 128, and 335. 
     Provided herein are isolated anti-GITR agonist monoclonal antibodies, or antigen binding portions thereof, which bind to GITR and comprise heavy and light chain variable regions, wherein the light chain variable region comprises an amino acid sequence which is at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence selected from the group consisting of SEQ ID NOs: 14, 27, 40, 53, 54, 72, 85, 98, 99, 116, 129, 130, and 336. 
     Provided herein are isolated anti-GITR agonist antibodies, e.g., monoclonal antibodies, or antigen binding portions thereof, which bind to GITR and comprise heavy and light chain variable region sequences at least 85% identical, for example, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical, to the amino acid sequences selected from the group consisting of: 
     (a) SEQ ID NOs: 13 and 14, respectively; 
     (b) SEQ ID NOs: 26 and 27, respectively; 
     (c) SEQ ID NOs: 39 and 40, respectively; 
     (d) SEQ ID NOs: 52 and 53, respectively; 
     (e) SEQ ID NOs: 52 and 54, respectively; 
     (f) SEQ ID NOs: 71 and 72, respectively; 
     (g) SEQ ID NOs: 84 and 85, respectively; 
     (h) SEQ ID NOs: 97 and 98, respectively; 
     (i) SEQ ID NOs: 97 and 99, respectively; 
     (j) SEQ ID NOs: 115 and 116, respectively; 
     (k) SEQ ID NOs: 128 and 129, respectively; 
     (l) SEQ ID NOs: 128 and 130, respectively; and 
     (m) SEQ ID NOs: 335 and 336, respectively. 
     Provided herein are isolated anti-GITR agonist antibodies, e.g., monoclonal antibodies, or antigen binding portions thereof, which bind to GITR and comprise heavy chain and light chain sequences at least 80%, 85%, 90%, 95%, 96%, 97%, 98% 99%, or 100% identical to the amino acid sequences selected from the group consisting of: 
     (a) SEQ ID NOs: 15 and 16, respectively; 
     (b) SEQ ID NOs: 17 and 19, respectively; 
     (c) SEQ ID NOs: 18 and 19, respectively; 
     (d) SEQ ID NOs: 28 and 29, respectively; 
     (e) SEQ ID NOs: 30 and 32, respectively; 
     (f) SEQ ID NOs: 31 and 32, respectively; 
     (g) SEQ ID NOs: 41 and 42, respectively; 
     (h) SEQ ID NOs: 43 and 45, respectively; 
     (i) SEQ ID NOs: 44 and 45, respectively; 
     (j) SEQ ID NOs: 55 and 56, respectively; 
     (k) SEQ ID NOs: 55 and 57, respectively; 
     (l) SEQ ID NOs: 58 and 60, respectively; 
     (m) SEQ ID NOs: 59 and 60, respectively; 
     (n) SEQ ID NOs: 58 and 61, respectively; 
     (o) SEQ ID NOs: 59 and 61, respectively; 
     (p) SEQ ID NOs: 73 and 74, respectively; 
     (q) SEQ ID NOs: 75 and 77, respectively; 
     (r) SEQ ID NOs: 76 and 77, respectively; 
     (s) SEQ ID NOs: 86 and 87, respectively; 
     (t) SEQ ID NOs: 88 and 90, respectively; 
     (u) SEQ ID NOs: 89 and 90, respectively; 
     (v) SEQ ID NOs: 102 and 104, respectively; 
     (w) SEQ ID NOs: 103 and 104, respectively; 
     (x) SEQ ID NOs: 100 and 101, respectively; 
     (y) SEQ ID NOs: 100 and 371, respectively; 
     (z) SEQ ID NOs: 102 and 105, respectively; 
     (za) SEQ ID NOs: 103 and 105, respectively; 
     (zb) SEQ ID NOs: 117 and 118, respectively; 
     (zc) SEQ ID NOs: 119 and 121, respectively; 
     (zd) SEQ ID NOs: 120 and 121, respectively; 
     (ze) SEQ ID NOs: 131 and 132, respectively; 
     (zf) SEQ ID NOs: 134 and 136, respectively; 
     (zg) SEQ ID NOs: 135 and 136, respectively; 
     (zh) SEQ ID NOs: 131 and 133, respectively; 
     (zi) SEQ ID NOs: 134 and 137, respectively; 
     (zj) SEQ ID NOs: 135 and 137, respectively 
     (zk) SEQ ID NOs: 337 and 338, respectively; 
     (zl) SEQ ID NOs: 339 and 341, respectively; and 
     (zm) SEQ ID NOs: 340 and 341, respectively. 
     Also provided are anti-GITR agonist antibodies comprising a VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and/or VLCDR3 that differs from the corresponding CDR of 28F3, 3C3-1, 3C3-2, 2G6, 8A6, 9G7-1, 9G7-2, 14E3, 19H8-1, 19H8-2, 19D3, 18E10, and/or 6G10, in 1, 2, 3, 4, 5, 1-2, 1-3, 1-4, or 1-5 amino acid changes (i.e., amino acid substitutions, additions or deletions). In certain embodiments, an anti-GITR antibody comprises 1-5 amino acid changes in each of 1, 2, 3, 4, 5 or 6 of the CDRs relative to the corresponding sequence in 28F3, 3C3-1, 3C3-2, 2G6, 8A6, 9G7-1, 9G7-2, 14E3, 19H8-1, 19H8-2, 19D3, 18E10, and/or 6G10. In certain embodiments, an anti-GITR antibody comprises at total of 1-5 amino acid changes across all CDRs relative to the CDRs in 28F3, 3C3-1, 3C3-2, 2G6, 8A6, 9G7-1, 9G7-2, 14E3, 19H8-1, 19H8-2, 19D3, 18E10, and/or 6G10. 
     In certain embodiments, an anti-GITR antibody comprises VH and VL CDRs consisting of those of 28F3, wherein one or more of the amino acids in one or more CDRs are those of one of the other anti-GITR agonist antibodies disclosed herein. 
     For example, in certain embodiments, an anti-GITR agonist antibody comprises a VHCDR1 comprising one or more amino acid modifications relative to SYGMH (SEQ ID NO: 20), and may comprise, e.g., one of the following degenerate sequences: 
     SYGXH (SEQ ID NO: 372), wherein X is any amino acid, e.g., M or F; 
     X 1 YGX 2 H, wherein X 1  is any amino acid, e.g., S,N or D; and X 2  is any amino acid, e.g., M or F; and 
     X 1 YGX 2 X 3 , wherein X 1  is any amino acid, e.g., S,N or D; X 2  is any amino acid, e.g., M or F, and X3 is any amino acid, e.g., H or Q. 
     In certain embodiments, an anti-GITR agonist antibody comprises a VHCDR2 comprising one or more amino acid modifications relative to VIWYEGSNKYYADSVKG (SEQ ID NO: 21), and may comprise one of the following degenerate sequences: 
     VIWYX 1 GSNKX 2 YADSVKG (SEQ ID NO: 373), wherein X 1  is any amino acid, e.g., E or A; and X 2  is any amino acid, e.g., Y or F; and 
     VIWYX 1 GSNKX 2 YX 3 DSVKG (SEQ ID NO: 374), wherein X 1  is any amino acid, e.g., E, A, G or D; X 2  is any amino acid, e.g., Y or F; and X 3  is any amino acid, e.g., A or V. 
     In certain embodiments, an anti-GITR agonist antibody comprises a VHCDR3 comprising one or more amino acid modifications relative to GGSMVRGDYYYGMDV(SEQ ID NO: 22), and may comprise, e.g., one of the following degenerate sequences: 
     GGSX 1 VRGDYYYGMDV (SEQ ID NO: 375), wherein X 1  is any amino acid, e.g., M or V, L, I or A. 
     GGSX 1 VRGX 2 YYYGMDV (SEQ ID NO: 376), wherein X 1  is any amino acid, e.g., M or V, L, I or A; and X 2  is any amino acid, e.g., D or E. Particular combinations of X 1  and X 2  are set forth in the Examples. 
     GG (6-7aa) MDVWYYX1MDVW (SEQ ID NO: 377), wherein X 1  is any amino acid, e.g., G, S or V. In certain embodiments, the 6-7 amino acids correspond to the amino acids at that position in a VHCDR3 sequence of an anti-GITR antibody disclosed herein. 
     In certain embodiments, an anti-GITR agonist antibody comprises a VLCDR1 comprising one or more amino acid modifications relative to RASQGISSALA (SEQ ID NO: 23), and may comprise, e.g., one of the following degenerate sequences: 
     RASQGISSXLA (SEQ ID NO: 378), wherein X is any amino acid, e.g., A or W (or A, W or Y); and 
     RASQG (2-3 aa) SX 1 LA (SEQ ID NO: 379), wherein X 1  is any amino acid, e.g., W, Y or A and the 2-3 amino acids are any amino acids, e.g., GI, SVS or SVT. 
     In certain embodiments, an anti-GITR agonist antibody comprises a VLCDR2 comprising one or more amino acid modifications relative to DASSLES (SEQ ID NO: 24), and may comprise, e.g., one of the following degenerate sequences: 
     DASSLXS (SEQ ID NO: 380), wherein X is any amino acid, e.g., E or Q; and 
     X 1 ASSX 2 X 3 X 4 , wherein X 1  is any amino acid, e.g., A, D or G; X 4  is any amino acid, e.g., L or R; X 3  is any amino acid, e.g., Q, E or A; and X 4  is any amino acid, e.g., S or T. 
     In certain embodiments, an anti-GITR agonist antibody comprises a VLCDR3 comprising one or more amino acid modifications relative to QQFNSYPYT (SEQ ID NO: 25), and may comprise, e.g., one of the following degenerate sequences: 
     QQXNSYPYT (SEQ ID NO: 381), wherein X is any amino acid, e.g., F or Y; and 
     QQX 1 X 2 SX 3 PX 4 T (SEQ ID NO: 382), wherein X 1  is any amino acid, e.g., F or Y; X 2  is any amino acid, e.g., N or G; X 3  is any amino acid, e.g., Y or S; and X 4  is any amino acid, e.g., Y, W, I, P or Q. 
     In certain embodiments, the isolated monoclonal antibodies, or antigen binding portions thereof, (a) bind to the same epitope on GITR as 28F3, 19D3, 18E10, 3C3-1, 3C3-2, 2G6, 9G7-1, 9G7-2, 14E3, 19H8-1, 19H8-2 and/or 6G10, and/or (b) inhibit binding of 28F3, 19D3, 18E10, 3C3-1, 3C3-2, 2G6, 9G7-1, 9G7-2, 14E3, 19H8-1, 19H8-2, and/or 6G10 to GITR on activated T cells by at least 50%, 60%, 70%, 80% or 90% as measured by, e.g., FACS. 
     In certain embodiments, the anti-GITR agonist antibodies, or antigen binding portions thereof, bind within the regions PTGGPGCGPGRLLLGTGT (SEQ ID NO: 217) and CRDYPGEE (SEQ ID NO: 218) of mature human GITR (SEQ ID NO: 4). In some embodiments, the anti-GITR agonist antibodies, or antigen binding portions thereof, described herein, bind to both human and cynomolgus GITR. 
     In certain embodiments, the anti-GITR agonist antibodies, or antigen-binding portions thereof, are IgG1, IgG2, IgG3, or IgG4 antibodies, or variants thereof. In certain embodiments, the anti-GITR agonist antibodies, or antigen-binding portions thereof, comprise an effectorless IgG1 Fc, for example, an effectorless IgG1 Fc with the following mutations: L234A, L235E, G237A, A330S and P331S. In certain embodiments, the anti-GITR agonist antibodies, or antigen-binding portions thereof, comprise an Fc binding to, or having enhanced binding to, an activating FcγR, e.g., relative to a wild-type IgG1 Fc. In certain embodiments, methionine residues in the CDR regions of the anti-GITR agonist antibodies, or antigen-binding portions thereof, are substituted for amino acid residues that do not undergo oxidation. In certain embodiments, the anti-GITR agonist antibodies, or antigen-binding portions thereof, are human or humanized antibodies. 
     Anti-GITR agonist antibodies, or antigen binding portions thereof, may comprise a modified heavy chain constant region that comprises an IgG2 hinge and at least one of CH1, CH2 and CH3 that is not of an IgG2 isotype, wherein the anti-GITR agonist antibody has enhanced agonist activity relative to the same anti-GITR antibody but with a non-IgG2 hinge. 
     In certain embodiments, the modified heavy chain constant region comprises a heavy chain constant region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 223-226 and 283-290 or a heavy chain constant region that differs therefrom in at most 5 amino acids or is at least 95%, 96%, 97%, 98% or 99% identical to an amino acid sequence of SEQ ID NOs: 223-226 and 283-290. 
     In certain embodiments, the heavy chain comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 15, 17, 18, 28, 30, 31, 41, 43, 44, 55, 58, 59, 73, 75, 76, 86, 88, 89, 100, 102, 103, 117, 119, 120, 131, 134, 135, 227-275, 337, 339, 340, 348-352, 361, and 362, or a heavy chain that differs therefrom in at most 10 amino acids or is at least 95%, 96%, 97%, 98% or 99% identical to an amino acid sequence of SEQ ID NOs: 15, 17, 18, 28, 30, 31, 41, 43, 44, 55, 58, 59, 73, 75, 76, 86, 88, 89, 100, 102, 103, 117, 119, 120, 131, 134, 135, 227-275, 337, 339, 340, 348-352, 361, and 362. 
     In certain embodiments, the light chain comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 16, 19, 29, 32, 42, 45, 56, 57, 60, 61, 74, 87, 90, 101, 104, 105, 118, 121, 132, 133, 136, 137, 338, 341, and 371 or a light chain that differs therefrom in at most 10 amino acids or is at least 95%, 96%, 97%, 98% or 99% identical to an amino acid sequence of SEQ ID NOs: 16, 19, 29, 32, 42, 45, 56, 57, 60, 61, 74, 87, 90, 101, 104, 105, 118, 121, 132, 133, 136, 137, 338, 341, and 371. 
     When referring to % identity or amino acid substitutions in the context of Ab sequences, amino acid substitutions may be conservative amino acid substitutions. 
     Other anti-GITR agonist antibodies that may be administered as described herein include antibodies comprising the CDR sequences, VH and VL chains or heavy and light chains of (i) 
     TRX-518 or 6C8, as described, e.g., in W02006/105021 and Schaer et al.  Curr Opin Immunol.  (2012) April; 24(2): 217-224; (ii) an anti-GITR antibody described in WO2011/028683, e.g., MK4166; an anti-GITR antibody described in JP2008278814; or an anti-GITR antibody described in WO2015/031667. 
     In other embodiments, an anti-GITR agonist antibody is an antibody that cross-competes with TRX518, MK4166, MK-1248 or an anti-GITR antibody described in WO2015/031667. In some embodiments, an anti-GITR antibody for the present composition binds the same epitope as TRX518, MK4166 or an anti-GITR antibody described in WO2015/031667. In certain embodiments, an anti-GITR agonist antibody comprises six CDRs of TRX518, MK4166, MK-1248 or an anti-GITR antibody described in WO2015/031667. 
     The heavy chain of an anti-GITR Ab or other Ab described herein may or may not comprise the C-terminal lysine (K), as this amino acid is frequently cleaved off. 
     Anti-PD-1 and Anti-PD-L1 Abs 
     An anti-GITR agonist antibody may be administered with an anti-PD1 antibody or an anti-PD-L1 antibody. PD-1 is a key immune checkpoint receptor expressed by activated T and B cells and mediates immunosuppression. PD-1 is a member of the CD28 family of receptors, which includes CD28, CTLA-4, ICOS, PD-1, and BTLA. Two cell surface glycoprotein ligands for PD-1 have been identified, Programmed Death Ligand-1 (PD-L1) and Programmed Death Ligand-2 (PD-L2), that are expressed on antigen-presenting cells as well as many human cancers and have been shown to down regulate T cell activation and cytokine secretion upon binding to PD-1. Inhibition of the PD-1/PD-L1 interaction mediates potent antitumor activity in preclinical models. 
     HuMAbs that bind specifically to PD-1 with high affinity have been disclosed in U.S. Pat. Nos. 8,008,449 and 8,779,105. Other anti-PD-1 mAbs have been described in, for example, U.S. Pat. Nos. 6,808,710, 7,488,802, 8,168,757 and 8,354,509, and PCT Publication No. WO 2012/145493. Each of the anti-PD-1 HuMAbs disclosed in U.S. Pat. No. 8,008,449 has been demonstrated to exhibit one or more of the following characteristics: (a) binds to human PD-1 with a K D  of 1×10 −7  M or less, as determined by surface plasmon resonance using a Biacore biosensor system; (b) does not substantially bind to human CD28, CTLA-4 or ICOS; (c) increases T-cell proliferation in a Mixed Lymphocyte Reaction (MLR) assay; (d) increases interferon-γ production in an MLR assay; (e) increases IL-2 secretion in an MLR assay; (f) binds to human PD-1 and cynomolgus monkey PD-1; (g) inhibits the binding of PD-L1 and/or PD-L2 to PD-1; (h) stimulates antigen-specific memory responses; (i) stimulates Ab responses; and (j) inhibits tumor cell growth in vivo. Anti-PD-1 Abs useful for the present invention include mAbs that bind specifically to human PD-1 and exhibit at least one, preferably at least five, of the preceding characteristics. 
     In one embodiment, the anti-PD-1 Ab is nivolumab. Nivolumab (also known as “OPDIVO®”; formerly designated 5C4, BMS-936558, MDX-1106, or ONO-4538) is a fully human IgG4 (S228P) PD-1 immune checkpoint inhibitor Ab that selectively prevents interaction with PD-1 ligands (PD-L1 and PD-L2), thereby blocking the down-regulation of antitumor T-cell functions (U.S. Pat. No. 8,008,449; Wang et al., 2014  Cancer Immunol Res.  2(9):846-56). Nivolumab can also be referred to as BMS-936558, MDX-1106 ONO-4538, or by its CAS Registry No. 946414-94-4, and is disclosed as antibody 5C4 in WO 2006/121168, incorporated herein by reference in its entirety and for all purposes. Nivolumab is a human monoclonal antibody that specifically binds to PD1 and comprises a light chain variable region provided as SEQ ID NO: 397, and a heavy chain variable region provided as SEQ ID NO: 395. Nivolumab may also be described as an antibody comprising a light chain CDR1 having amino acids 24-34 of SEQ ID NO: 397, a light chain CDR2 having amino acids 50-56 of SEQ ID NO: 397, and a light chain CDR3 having amino acids 89-97 of SEQ ID NO: 397; and comprising a heavy chain CDR1 having amino acids 31-35 of SEQ ID NO: 395, a heavy chain CDR2 having amino acids 50-66 of SEQ ID NO: 395, and a heavy chain CDR3 having amino acids 99-102 of SEQ ID NO: 395. Pharmaceutical compositions of BMS-936558 include all pharmaceutically acceptable compositions comprising BMS-936558 and one or more diluents, vehicles and/or excipients. BMS-936558 may be administered by I.V. 
     
       
         
           
               
            
               
                 Light chain variable region for Nivolumab: 
               
               
                 (SEQ ID NO: 397) 
               
               
                 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIY 
               
               
                 DASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSSNWPRTF 
               
               
                 GQGTKVEIK 
               
               
                   
               
               
                 Heavy chain variable region for Nivolumab: 
               
               
                 (SEQ ID NO: 395) 
               
               
                 QVQLVESGGGVVQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGLEWVA 
               
               
                 VIWYDGSKRYYADSVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCAT 
               
               
                 NDDYWGQGTLVTVSS 
               
            
           
         
       
     
     In one embodiment, the anti-PD-1 Ab is pembrolizumab. Pembrolizumab (also known as “KEYTRUDA®”, lambrolizumab, and MK-3475) is a humanized monoclonal IgG4 antibody directed against human cell surface receptor PD-1 (programmed death-1 or programmed cell death-1). Pembrolizumab is described, for example, in U.S. Pat. Nos. 8,354,509 and 8,900,587; see also http://www.cancer.gov/drugdictionary?cdrid=695789 (last accessed: Dec. 14, 2014). Pembrolizumab has been approved by the FDA for the treatment of relapsed or refractory melanoma. 
     In other embodiments, the anti-PD-1 Ab is MEDI0608 (formerly AMP-514), which is a monoclonal antibody. MEDI0608 is described, for example, in U.S. Pat. No. 8,609,089B2 or in http://www.cancer.gov/drugdictionary?cdrid=756047 (last accessed Dec. 14, 2014). In some embodiments, the anti-PD-1 antibody is Pidilizumab (CT-011), which is a humanized monoclonal antibody. Pidilizumab is described in U.S. Pat. No. 8,686,119 B2 or WO 2013/014668 A1. The specificity of CT-011 for PD-1 binding has been questioned. 
     Anti-PD-1 Abs useful for the disclosed compositions also include isolated Abs that bind specifically to human PD-1 and compete or cross-compete for binding to human PD-1 with nivolumab (see, e.g., U.S. Pat. Nos. 8,008,449 and 8,779,105; WO 2013/173223) or other anti-PD-1 Ab. The ability of Abs to compete or cross-compete for binding to an antigen indicates that these Abs bind to the same or similar epitope region of the antigen and sterically hinder the binding of other competing or cross-competing Abs to that particular epitope region. These competing or cross-competing Abs are expected to have functional properties very similar to those of the antibody that they compete with, e.g., nivolumab, by virtue of their binding to the same or similar epitope region of PD-1. Competing or cross-competing Abs can be readily identified based on their ability to compete or cross-compete, respectively, with nivolumab (or other anti-PD-1 Ab) in standard PD-1 binding assays such as Biacore analysis, ELISA assays or flow cytometry (see, e.g., WO 2013/173223). “Cross-competing” refers to competing in both directions. 
     In certain embodiments, the Abs that compete or cross-compete for binding to human PD-1 with, or bind to the same or similar epitope region of human PD-1 as, e.g., nivolumab, are mAbs. For administration to human subjects, these competing or cross-competing Abs can be chimeric Abs, or humanized or human Abs. Such chimeric, humanized or human mAbs can be prepared and isolated by methods well known in the art. 
     Anti-PD-1 Abs useful for the compositions of the disclosed invention also include antigen-binding portions of the above Abs. It has been amply demonstrated that the antigen-binding function of an Ab can be performed by fragments of a full-length Ab. Examples of binding fragments encompassed within the term “antigen-binding portion” of an Ab include (i) a Fab fragment, a monovalent fragment consisting of the V L , V H , C L  and C H1  domains; (ii) a F(ab′) 2  fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Fd fragment consisting of the V H  and C H1  domains; and (iv) a Fv fragment consisting of the V L  and V H  domains of a single arm of an Ab. 
     Anti-PD-1 Abs suitable for use in the disclosed compositions are Abs that bind to PD-1 with high specificity and affinity, block the binding of PD-L1 and or PD-L2, and inhibit the immunosuppressive effect of the PD-1 signaling pathway. In any of the compositions or methods disclosed herein, an anti-PD-1 “antibody” includes an antigen-binding portion or fragment that binds to the PD-1 receptor and exhibits the functional properties similar to those of whole Abs in inhibiting ligand binding and upregulating the immune system. In certain embodiments, the anti-PD-1 Ab or antigen-binding portion thereof cross-competes with nivolumab for binding to human PD-1. In other embodiments, the anti-PD-1 Ab or antigen-binding portion thereof is a chimeric, humanized or human monoclonal Ab or a portion thereof. In certain embodiments, the Ab is a humanized Ab. In other embodiments, the Ab is a human Ab. Abs of an IgG1, IgG2, IgG3 or IgG4 isotype can be used. 
     In certain embodiments, the anti-PD-1 Ab or antigen-binding portion thereof comprises a heavy chain constant region which is of a human IgG1 or IgG4 isotype. In certain other embodiments, the sequence of the IgG4 heavy chain constant region of the anti-PD-1 Ab or antigen-binding portion thereof contains an S228P mutation which replaces a serine residue in the hinge region with the proline residue normally found at the corresponding position in IgG1 isotype antibodies. This mutation, which is present in nivolumab, prevents Fab arm exchange with endogenous IgG4 antibodies, while retaining the low affinity for activating Fc receptors associated with wild-type IgG4 antibodies (Wang et al., 2014). In yet other embodiments, the Ab comprises a light chain constant region which is a human kappa or lambda constant region. In other embodiments, the anti-PD-1 Ab or antigen-binding portion thereof is a mAb or an antigen-binding portion thereof. In certain embodiments of any of the therapeutic methods described herein comprising administration of an anti-PD-1 Ab, the anti-PD-1 Ab is nivolumab. In other embodiments, the anti-PD-1 Ab is pembrolizumab. In other embodiments, the anti-PD-1 Ab is chosen from the human antibodies 17D8, 2D3, 4H1, 4A11, 7D3 and 5F4 described in U.S. Pat. No. 8,008,449. In still other embodiments, the anti-PD-1 Ab is MEDI0608 (formerly AMP-514), AMP-224, or Pidilizumab (CT-011). 
     An exemplary anti-PD-1 antibody is 5C4 comprising heavy and light chains having the sequences shown in SEQ ID NOs: 393 and 394, respectively, or antigen binding fragments and variants thereof. In other embodiments, the antibody comprises the heavy and light chain CDRs or variable regions of 5C4. Accordingly, in one embodiment, the antibody comprises the CDR1, CDR2, and CDR3 domains of the VH of 5C4 having the sequence set forth in SEQ ID NO: 395, and the CDR1, CDR2 and CDR3 domains of the VL of 5C4 having the sequences set forth in SEQ ID NO: 397. In one embodiment, the antibody comprises VH CDR1, CDR2 and CDR3 domains having the sequences set forth in SEQ ID NOs: 399-401, respectively, and VL CDR1, CDR2 and CDR3 domains having the sequences set forth in SEQ ID NOs: 402-404, respectively. In one embodiment, the antibody comprises VH and/or VL regions having the amino acid sequences set forth in SEQ ID NO: 395 and/or SEQ ID NO: 397, respectively. In one embodiment, the antibody comprises the heavy chain variable (VH) and/or light chain variable (VL) regions encoded by the nucleic acid sequences set forth in SEQ ID NO: 396 and/or SEQ ID NO: 398, respectively. In one embodiment, the antibody competes for binding with and/or binds to the same epitope on PD-1 as the above-mentioned antibodies. In one embodiment, the antibody has at least about 90% variable region amino acid sequence identity with the above-mentioned antibodies (e.g., at least about 90%, 95% or 99% variable region identity with SEQ ID NO: 395 or SEQ ID NO: 397). 
     In certain embodiments, the PD1 antibodies exhibit one or more desirable functional properties, such as high affinity binding to PD-1, e.g., binding to human PD-1 with a K D  of 10 −7  M or less; lack of significant cross-reactivity to other CD28 family members, e.g., CD28, CTLA-4 and ICOS; the ability to stimulate T cell proliferation in a mixed lymphocyte reaction (MLR) assay; the ability to increase IFN-y and/or IL-2 secretion in an MLR; the ability to inhibit binding of one or more PD-1 ligands (e.g., PD-L1 and/or PD-L2) to PD-1; the ability to stimulate antigen-specific memory responses; the ability to stimulate antibody responses and/or the ability to inhibit growth of tumor cells in vivo. 
     In certain embodiments, the antibody to be administered with an anti-GITR Ab is an anti-PD-L1 antibody. Because anti-PD-1 and anti-PD-L1 target the same signaling pathway and have been shown in clinical trials to exhibit similar levels of efficacy in a variety of cancers, an anti-PD-L1 Ab can be substituted for the anti-PD-1 Ab in any of the therapeutic methods or compositions disclosed herein. In one embodiment, the anti-PD-L1 antibody is BMS-936559 (formerly 12A4 or MDX-1105) (see, e.g., U.S. Pat. No. 7,943,743; WO 2013/173223), or an antibody that comprises the CDRs or variable regions of 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7 and 13G4, which are described in PCT Publication WO 07/005874 and U.S. Pat. No. 7,943,743. In certain embodiment an anti-PD-L1 antibody is avelumab, durvalumab (MEDI4736 (also known as Anti-B7-H1)), MPDL3280A (also known as RG7446, atezolizumab and TECENTRIQ), MSB0010718C (WO2013/79174), or rHigM12B7. Any of the anti-PD-L1 antibodies disclosed in WO2013/173223, WO2011/066389, WO2012/145493, U.S. Pat. Nos. 7,635,757 and 8,217,149 and U.S. Publication No. 2009/145493 may also be used. Anti-PD-L1 antibodies that compete with and/or bind to the same epitope as that of any of these antibodies may also be used in the treatments described herein. 
     An exemplary anti-PD-L1 antibody is 12A4 (WO 2007/005874 and U.S. Pat. No. 7,943,743). In one embodiment, the antibody comprises the heavy and light chain CDRs or VRs of 12A4. Accordingly, in one embodiment, the antibody comprises the CDR1, CDR2, and CDR3 domains of the VH region of 12A4 having the sequence shown in SEQ ID NO: 383 and the CDR1, CDR2 and CDR3 domains of the VL region of 12A4 having the sequence shown in SEQ ID NO: 385. In one embodiment, the antibody comprises the heavy chain CDR1, CDR2 and CDR3 domains having the sequences set forth in SEQ ID NOs: 387-389, respectively, and the light chain CDR1, CDR2 and CDR3 domains having the sequences set forth in SEQ ID NOs: 390-392, respectively. In one embodiment, the antibody comprises VH and/or VL regions having the amino acid sequences set forth in SEQ ID NO: 383 and/or SEQ ID NO: 385, respectively. In one embodiment, the antibody comprises the heavy chain variable (VH) and/or light chain variable (VL) regions encoded by the nucleic acid sequences set forth in SEQ ID NO: 384 and/or SEQ ID NO: 386, respectively. In one embodiment, the antibody competes for binding with, and/or binds to the same epitope on PD-Ll as, the above-mentioned antibodies. In one embodiment, the antibody has at least about 90% variable region amino acid sequence identity with the above-mentioned antibodies (e.g., at least about 90% , 95% or 99% variable region identity with SEQ ID NO: 383 or SEQ ID NO: 385). 
     Thus, generally, a PD-1/PD-L1 antagonist agent that may be used in the methods described herein include nivolumab, pembrolizumab, atelozilumab, durvalumab, REGN2810, PDR001, AMP-514 (MEDI0608), AMP-224, BGB-A317 or a PD-1 or PD-L1 antagonist described in any one of the following publications: WO 2009/014708, WO 03/099196, WO 2009/114335 and WO 2011/161699. 
     Compositions 
     Further provided are compositions, e.g., a pharmaceutical compositions, containing anti-GITR agonist antibodies alone or in combination with antibodies to other targets, e.g., PD-1 or PD-L1, formulated together with a pharmaceutically acceptable carrier. As used herein, “pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible. Preferably, the carrier is suitable for intravenous, intramuscular, subcutaneous, parenteral, spinal or epidermal administration (e.g., by injection or infusion). 
     The pharmaceutical compounds described herein may include one or more pharmaceutically acceptable salts. A “pharmaceutically acceptable salt” refers to a salt that retains the desired biological activity of the parent compound and does not impart any undesired toxicological effects (see e.g., Berge, S. M., et al. (1977)  J. Pharm. Sci.  66:1-19). Examples of such salts include acid addition salts and base addition salts. Acid addition salts include those derived from nontoxic inorganic acids, such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, phosphorous and the like, as well as from nontoxic organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, aromatic acids, aliphatic and aromatic sulfonic acids and the like. Base addition salts include those derived from alkaline earth metals, such as sodium, potassium, magnesium, calcium and the like, as well as from nontoxic organic amines, such as N,N′-dibenzylethylenediamine, N-methylglucamine, chloroprocaine, choline, diethanolamine, ethylenediamine, procaine and the like. 
     A pharmaceutical composition described herein may also include a pharmaceutically acceptable anti-oxidant. Examples of pharmaceutically acceptable antioxidants include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like. 
     Examples of suitable aqueous and nonaqueous carriers that may be employed in the pharmaceutical compositions described herein include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. 
     These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of presence of microorganisms may be ensured both by sterilization procedures, supra, and by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin. 
     Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. The use of such media and agents for pharmaceutically active substances is known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the pharmaceutical compositions described herein is contemplated. A pharmaceutical composition may comprise a preservative or may be devoid of a preservative. Supplementary active compounds can be incorporated into the compositions. 
     Therapeutic compositions typically must be sterile and stable under the conditions of manufacture and storage. The composition can be formulated as a solution, microemulsion, liposome, or other ordered structure suitable to high drug concentration. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, monostearate salts and gelatin. 
     Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by sterilization microfiltration. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated herein. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying (lyophilization) that yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. 
     In certain embodiments, an anti-GITR agonist agent, e.g., Ab, is coformulated with an anti-PD-1 or PD-L1 antagonist agent, e.g., Ab. An exemplary pharmaceutical composition comprises an anti-PD-1 antibody, e.g., nivolumab (e.g., OPDIVO) or MK-3475 (pembrolizumab; KEYTRUDA), or other PD-1/PD-L1 axis antagonist (e.g., described herein) and an anti-GITR agonist agent (e.g., described herein), e.g., antibody, having the CDRs, variable regions or heavy and light chain sequences of 28F3.IgG1 or 28F3.IgG1.1 or other anti-GITR Ab described herein (e.g., TRX518, MK4166, MK-1248, or an Ab described in a reference cited herein, e.g., in WO2015/031667 or other described herein), wherein the ratio of the amount (e.g., concentration (e.g., mg/ml) or weight) of the anti-PD-1 agent, e.g., antibody, to the amount of the anti-GITR agent, e.g., antibody, (e.g., concentration (e.g., mg/ml) or weight, respectively) is from 1:1-20; 1:1-10; 1:1-5; 1:2-5; 1:2-3; 1:3-5; 1-20:1; 1-10:1; 1-5:1; 2-5:1; 2-3:1; or 3-5:1. The combination may be administered weekly, biweekly, once every three weeks, monthly once every 5 weeks or once every 6 weeks. For example, a flat dose of 10-1000, such as 100-400 mg, e.g., 200-300 mg or 240 mg or 250 mg of an anti-PD-1 agent, e.g., antibody, (e.g., nivolumab) or anti-PD-L1 antagonist agent, e.g., antibody, may be administered together, e.g., as a fixed dose combination, with a flat dose of 3 mg, 10 mg, 30 mg, 100 mg, 120 mg, 200 mg, 240 mg, 250 mg, 300 mg, 400 mg, 480 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg or 1000 mg of an anti-GITR agonist agent, e.g., Ab (e.g., 28F3.IgG1, 28F3.IgG1.1, TRX518, MK4166 or an Ab described in WO2015/031667 or other GITR agonist agent described herein), to a subject having cancer, e.g., advanced solid tumors, e.g., as an intravenous infusion over, e.g., 30, 30-60, 60 or 60-90 minutes every 1, 2, 3, 4, 5 or 6 weeks. In another example, about 3 mg/kg anti-PD-1 agent, e.g., antibody, e.g., nivolumab, may be administered together, e.g., as a fixed dose combination, with 0.1-10 mg/kg, 0.1-5 mg/kg, 0.5-10 mg/kg, 0.5-5 mg/kg, 0.5-2 mg/kg, 1-2 mg/kg or 2-5 mg/kg anti-GITR agent, e.g., antibody, e.g., 28F3.IgG1, 28F3.IgG1.1, TRX518, MK4166, MK-1248 or an Ab described in WO2015/031667 or elsewhere herein, e.g., as an intravenous infusion over, e.g., 30, 30-60, 60 or 60-90 minutes every 1, 2, 3, 4, 5 or 6 weeks. In certain embodiments, 2 mg/kg anti-PD-1 antibody, e.g., MK-3475, is administered together, e.g., as a fixed dose combination, with 0.1-10 mg/kg, 0.1-5 mg/kg, 0.5-10 mg/kg, 0.5-5 mg/kg, 0.5-2 mg/kg, 1-2 mg/kg or 2-5 mg/kg anti-GITR agent, e.g., antibody, e.g., MK4166 or MK-1248, e.g., as an intravenous infusion over, e.g., 30, 30-60 or 60 minutes every 1, 2, 3 or 4 weeks. The amount of antibodies in mg/kg can be calculated to determine the weight (mg) or the concentration (mg/ml) of the antibodies required for a fixed dosing ratio formulation. In certain embodiments, an anti-PD-1 agent, e.g., Ab, and an anti-GITR agent, e.g., Ab, are provided as a lyophilized composition, e.g., in a vial or a dual chamber syringe. A lyophilized composition can comprise, e.g., 50 mg of an anti-PD-1 agent, e.g., Ab, e.g., MK3475, and 5-250 mg, about 10-250, about 30-100 mg, about 30-70 mg or about 50 mg of an anti-GITR agent, e.g., Ab, e.g., 28F3.IgG1, 28F3.IgG1.1, TRX518, MK4166 or an Ab described in WO2015/031667 or other publications cited herein. The combination regimens described in WO/2016/196792 are specifically incorporated by reference herein, and may be applied to a GITR agent and a PD-1/PD-L1 axis antagonist. 
     Methods of Treatment 
     Provided herein are methods of treating cancer, e.g., by inhibiting growth of tumors, in a subject, comprising administering to the subject a therapeutically effective amount of an anti-GITR agonist agent, e.g., Ab, described herein, e.g., 28F3.IgG1 or 28F3.IgG1.1, or antigen-binding portion thereof. The antibody may be a human anti-GITR agent, e.g., Ab, (such as any of the human anti-human GITR antibodies described herein). Additionally or alternatively, the antibody can be a chimeric or humanized anti-GITR antibody, e.g., a chimeric or humanized anti-GITR antibody comprising sequences of 28F3 or other anti-GITR antibodies described herein. 
     Cancers whose growth may be inhibited using the antibodies of the invention include cancers typically responsive to immunotherapy and those that are not typically responsive to immunotherapy. Cancers may be cancers with solid tumors (e.g., advanced solid tumors) or blood malignancies (liquid tumors). Non-limiting examples of cancers for treatment include squamous cell carcinoma, small-cell lung cancer, non-small cell lung cancer, squamous non-small cell lung cancer (NSCLC), non-squamous NSCLC, glioma, gastrointestinal cancer, renal cancer (e.g. clear cell carcinoma), ovarian cancer, liver cancer, colorectal cancer, endometrial cancer, kidney cancer (e.g., renal cell carcinoma (RCC)), prostate cancer (e.g. hormone refractory prostate adenocarcinoma), thyroid cancer, neuroblastoma, pancreatic cancer, glioblastoma (glioblastoma multiforme), cervical cancer, stomach cancer, bladder cancer, hepatoma, breast cancer, colon carcinoma, and head and neck cancer (or carcinoma), gastric cancer, germ cell tumor, pediatric sarcoma, sinonasal natural killer, melanoma (e.g., metastatic malignant melanoma, such as cutaneous or intraocular malignant melanoma), bone cancer, skin cancer, uterine cancer, cancer of the anal region, testicular cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, solid tumors of childhood, cancer of the ureter, carcinoma of the renal pelvis, neoplasm of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axis tumor, brain cancer, brain stem glioma, pituitary adenoma, Kaposi&#39;s sarcoma, epidermoid cancer, squamous cell cancer, T-cell lymphoma, environmentally-induced cancers including those induced by asbestos, virus-related cancers or cancers of viral origin (e.g., human papilloma virus (HPV-related or -originating tumors)), and hematologic malignancies derived from either of the two major blood cell lineages, i.e., the myeloid cell line (which produces granulocytes, erythrocytes, thrombocytes, macrophages and mast cells) or lymphoid cell line (which produces B, T, NK and plasma cells), such as all types of leukemias, lymphomas, and myelomas, e.g., acute, chronic, lymphocytic and/or myelogenous leukemias, such as acute leukemia (ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), and chronic myelogenous leukemia (CML), undifferentiated AML (M0), myeloblastic leukemia (M1), myeloblastic leukemia (M2; with cell maturation), promyelocytic leukemia (M3 or M3 variant [M3V]), myelomonocytic leukemia (M4 or M4 variant with eosinophilia [M4E]), monocytic leukemia (M5), erythroleukemia (M6), megakaryoblastic leukemia (M7), isolated granulocytic sarcoma, and chloroma; lymphomas, such as Hodgkin&#39;s lymphoma (HL), non-Hodgkin&#39;s lymphoma (NHL), B cell hematologic malignancy, e.g., B-cell lymphomas, T-cell lymphomas, lymphoplasmacytoid lymphoma, monocytoid B-cell lymphoma, mucosa-associated lymphoid tissue (MALT) lymphoma, anaplastic (e.g., Ki 1+) large-cell lymphoma, adult T-cell lymphoma/leukemia, mantle cell lymphoma, angio immunoblastic T-cell lymphoma, angiocentric lymphoma, intestinal T-cell lymphoma, primary mediastinal B-cell lymphoma, precursor T-lymphoblastic lymphoma, T-lymphoblastic; and lymphoma/leukaemia (T-Lbly/T-ALL), peripheral T- cell lymphoma, lymphoblastic lymphoma, post-transplantation lymphoproliferative disorder, true histiocytic lymphoma, primary central nervous system lymphoma, primary effusion lymphoma, B cell lymphoma, lymphoblastic lymphoma (LBL), hematopoietic tumors of lymphoid lineage, acute lymphoblastic leukemia, diffuse large B-cell lymphoma, Burkitt&#39;s lymphoma, follicular lymphoma, diffuse histiocytic lymphoma (DHL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, cutaneous T-cell lymphoma (CTLC) (also called mycosis fungoides or Sezary syndrome), and lymphoplasmacytoid lymphoma (LPL) with Waldenstrom&#39;s macroglobulinemia; myelomas, such as IgG myeloma, light chain myeloma, nonsecretory myeloma, smoldering myeloma (also called indolent myeloma), solitary plasmocytoma, and multiple myelomas, chronic lymphocytic leukemia (CLL), hairy cell lymphoma; hematopoietic tumors of myeloid lineage, tumors of mesenchymal origin, including fibrosarcoma and rhabdomyoscarcoma; seminoma, teratocarcinoma, tumors of the central and peripheral nervous, including astrocytoma, schwannomas; tumors of mesenchymal origin, including fibrosarcoma, rhabdomyoscaroma, and osteosarcoma; and other tumors, including melanoma, xeroderma pigmentosum, keratoacanthoma, seminoma, thyroid follicular cancer and teratocarcinoma, hematopoietic tumors of lymphoid lineage, for example T-cell and B-cell tumors, including but not limited to T-cell disorders such as T-prolymphocytic leukemia (T-PLL), including of the small cell and cerebriform cell type; large granular lymphocyte leukemia (LGL) preferably of the T-cell type; a/d T-NHL hepatosplenic lymphoma; peripheral/post-thymic T cell lymphoma (pleomorphic and immunoblastic subtypes); angiocentric (nasal) T-cell lymphoma; cancer of the head or neck, renal cancer, rectal cancer, cancer of the thyroid gland; acute myeloid lymphoma, as well as any combinations of said cancers. The methods described herein may also be used for treatment of metastatic cancers, unresectable and/or refractory cancers (e.g., cancers refractory to previous immunotherapy, e.g., with a blocking CTLA-4 or PD-1 antibody), and recurrent cancers. The methods of treatment described herein may also be used to treat a subject who has progressed on an immuno therapy (e.g., immuno stimulating therapy), e.g., an anti-PD1 or anti-PD-L1 treatment. 
     In certain embodiments, an anti-GITR agent, e.g., Ab, is administered to patients having a cancer that exhibited an inadequate response to a prior treatment, e.g., a prior treatment with an immuno-oncology drug, or patients having a cancer that is refractory or resistant, either intrinsically refractory or resistant (e.g., refractory to a PD-1 pathway antagonist), or a wherein the resistance or refractory state is acquired. For example, subjects who are not responsive or not sufficiently responsive to a first therapy or who see disease progression following treatment, e.g., anti-PD-1 treatment, may be treated by administration of an anti-GITR agent, e.g., Ab, alone or in combination with another therapy (e.g., with an anti-PD-1 therapy). 
     In certain embodiments, an anti-GITR agent, e.g., Ab, is administered to patients who have not previously received (i.e., been treated with) an immuno-oncology agent, e.g., a PD-1 pathway antagonist (PD-1/PD-L1 axis antagonist or PD-1/PD-L1 antagonist). 
     An anti-GITR agent, e.g., Ab, and a PD-1/PD-L1 antagonist may be administered with a standard of care treatment. An anti-GITR agent, e.g., Ab, and/or PD-1/PD-L1 antagonist may be administered as a maintenance therapy, e.g., a therapy that is intended to prevent the occurrence or recurrence of tumors. 
     An anti-GITR agent, e.g., Ab, and a PD-1/PD-L1 antagonist may be administered with another treatment, e.g., radiation, surgery, or chemotherapy. An anti-GITR agent, e.g., Ab, a PD-1/PD-L1 antagonist adjunctive therapy may be administered when there is a risk that micrometastases may be present and/or in order to reduce the risk of a relapse. 
     Based at least on the finding that subjects treated with an GITR agonist agent and a PD-1/PD-L1 axis antagonist have an increased peripheral blood level (or number) of (1) proliferating CD8+ cells; (2) proliferating and activated CD4+ and CD8+ effector memory and central memory T cells and (3) proliferating NK cells 8 days after administration of a dose of the GITR agonist and the PD-1/PD-L1 axis antagonist, provided herein are methods for treating subjects having cancer with an immunostimulating therapy (e.g., GITR agonist and PD-1/PD-L1 antagonist), wherein the treatment increases the level or number of one or more of these populations of cells. In certain embodiment, administration of a single dose of the immunostimulating agent induces an elevation of the level of one or more of these cell populations by at least 1.5, 2, 3, 4 or 5 fold relative to their base level, e.g., level immediately prior to (e.g., less than 10, 5, 4, 3, 2, or 1 hour prior to) administration of the first dose of the therapy. Measurement of the level of these cell types in the peripheral blood of a subject can be done as described in the Examples. Accordingly, provided herein are methods of treating a subject having cancer with an immunostimulating therapy (e.g., an immuno-oncology drug, e.g., an PD-1/PD-L1 axis antagonist alone, or together with one or more immunostimulating agents, e.g., a GITR agonist agent), comprising administering to the subject a first dose of the immunostimulating therapy, wherein at about 5-12 days (e.g., 8 days) following the administration, the level (or number) of (1) proliferating CD8+cells; (2) proliferating and activated CD4+and CD8+effector memory and central memory T cells and/or (3) proliferating NK cells is higher by, e.g., 1.5 fold, 2, 3, 4 or 5 fold relative the level of the cell population before the administration. In certain embodiments, methods of treating a subject having cancer with an immunostimulating therapy (e.g., an immuno-oncology drug, e.g., an PD-1/PD-L1 axis antagonist alone, or together with one or more immunostimulating agents, e.g., a GITR agonist agent), comprising administering to the subject a first dose of the immunostimulating therapy, wherein at about 5-12 days (e.g., 8 days) following the administration, the level (or number) of (1) proliferating CD8+ cells; (2) proliferating and activated CD4+ and CD8+ effector memory and central memory T cells and (3) proliferating NK cells is higher by, e.g., 1.5 fold, 2, 3, 4 or 5 fold relative the level of the cell population before the administration. A method may comprise treating a subject having cancer with an immunostimulating therapy (e.g., an immuno-oncology drug, e.g., an PD-1/PD-L1 axis antagonist alone, or together with one or more immunostimulating agents, e.g., a GITR agonist agent), comprising administering to the subject a first dose of the immunostimulating therapy, wherein at about 5-12 days (e.g., 8 days) following the administration, the level (or number) of (i) proliferating CD8+effector memory cells; (ii) activated CD8+ effector memory cells; (iii) proliferating CD8+ central memory cells; and (iv) activated CD8+ central memory cells is higher by, e.g., 1.5 fold, 2, 3, 4 or 5 fold relative the level of the cell population before the administration. A method may comprise treating a subject having cancer with an immunostimulating therapy (e.g., an immuno-oncology drug, e.g., an PD-1/PD-L1 axis antagonist alone, or together with one or more immunostimulating agents, e.g., a GITR agonist agent), comprising administering to the subject a first dose of the immunostimulating therapy, wherein at about 5-12 days (e.g., 8 days) following the administration, the level (or number) of (i) proliferating CD4+ effector memory cells; (ii) activated CD4+ effector memory cells; (iii) proliferating CD4+ central memory cells; and (iv) activated CD4+ central memory cells is higher by, e.g., 1.5 fold, 2, 3, 4 or 5 fold relative the level of the cell population before the administration. A method may comprise treating a subject having cancer with an immunostimulating therapy (e.g., an immuno-oncology drug, e.g., an PD-1/PD-L1 axis antagonist alone, or together with one or more immunostimulating agents, e.g., a GITR agonist agent), comprising administering to the subject a first dose of the immunostimulating therapy, wherein at about 5-12 days (e.g., 8 days) following the administration, the level (or number) of (i) proliferating CD8+effector memory cells; (ii) activated CD8+ effector memory cells; (iii) proliferating CD8+ central memory cells; (iv) activated CD8+ central memory cells; (v) proliferating CD4+ effector memory cells; (vi) activated CD4+ effector memory cells; (vii) proliferating CD4+ central memory cells; and (viii) activated CD4+central memory cells is higher by, e.g., 1.5 fold, 2, 3, 4 or 5 fold relative the level of the cell population before the administration. 
     A method may comprise treating a subject having cancer with an immunostimulating therapy (e.g., an immuno-oncology drug, e.g., an PD-1/PD-L1 axis antagonist alone, or together with one or more immunostimulating agents, e.g., a GITR agonist agent), comprising administering to the subject a first dose of the immunostimulating therapy, wherein at about 5-12 days (e.g., 8 days) following the administration, the level (or number) of any one of (i) proliferating CD4+ central memory cells; (ii) proliferating CD8+ central memory cells; (iii) activated CD4+ central memory cells and (iv) activated CD8+ central memory cells, is higher by, e.g., 1.5 fold, 2, 3, 4 or 5 fold relative the level of the cell population before the administration. 
     A method may comprise treating a subject having cancer with an immunostimulating therapy (e.g., an immuno-oncology drug, e.g., an PD-1/PD-L1 axis antagonist alone, or together with one or more immunostimulating agents, e.g., a GITR agonist agent), comprising administering to the subject a first dose of the immunostimulating therapy, wherein at about 5-12 days (e.g., 8 days) following the administration, the level (or number) of (i) proliferating CD4+ central memory cells; (ii) proliferating CD8+ central memory cells; (iii) activated CD4+ central memory cells and (iv) activated CD8+ central memory cells, is higher by, e.g., 1.5 fold, 2, 3, 4 or 5 fold relative the level of the cell population before the administration. 
     A method may comprise treating a subject having cancer with an immunostimulating therapy (e.g., an immuno-oncology drug, e.g., an PD-1/PD-L1 axis antagonist alone, or together with one or more immunostimulating agents, e.g., a GITR agonist agent), comprising administering to the subject a first dose of the immunostimulating therapy, wherein at about 5-12 days (e.g., 8 days) following the administration, the level (or number) of any one of (i) proliferating CD4+ effector memory cells; (ii) proliferating CD8+ effector memory cells; (iii) activated CD4+ effector memory cells and (iv) activated CD8+ effector memory cells, is higher by, e.g., 1.5 fold, 2, 3, 4 or 5 fold relative the level of the cell population before the administration. 
     A method may comprise treating a subject having cancer with an immunostimulating therapy (e.g., an immuno-oncology drug, e.g., an PD-1/PD-L1 axis antagonist alone, or together with one or more immunostimulating agents, e.g., a GITR agonist agent), comprising administering to the subject a first dose of the immunostimulating therapy, wherein at about 5-12 days (e.g., 8 days) following the administration, the level (or number) of (i) proliferating CD4+ effector memory cells; (ii) proliferating CD8+ effector memory cells; (iii) activated CD4+ effector memory cells and (iv) activated CD8+ effector memory cells, is higher by, e.g., 1.5 fold, 2, 3, 4 or 5 fold relative the level of the cell population before the administration. 
     In any of these embodiments, proliferating CD4 effector memory cells are CD45+CD3+CD4+CD8-CD197-CD45RA-Ki67+ T cells (CD197 is CCR7); activated CD4 effector memory cells are CD45+CD3+CD4+CD8-CD197-CD45RA-HLA-DR+; proliferating CD4 central memory cells are CD45+CD3+CD4+CD8-CD197+CD45RA-Ki67+; and activated CD4 central memory cells are CD45+CD3+CD4+CD8-CD197+CD45RA-HLA-DR+; proliferating CD8 effector memory cells are CD45+CD3+CD4-CD8+CD197-CD45RA-Ki67+ cells; activated CD8 effector memory cells are CD45+CD3+CD4-CD8+CD197-CD45RA-HLA-DR+; proliferating CD8 central memory cells are CD45+CD3+CD4-CD8+CD197+CD45RA-Ki67+; and activated CD8 central memory cells are CD45+CD3+CD4-CD8+CD197+CD45RA-HLA-DR+, and the level of these cells is determined by flow cytometry, as described, e.g., in the Examples. 
     In certain embodiments, a dose, e.g., a first dose, of the immunostimulating therapy (e.g., GITR agonist agent and PD-1/PD-L1 antagonist agent) is administered to a subject having cancer, resulting in an elevation of the number of one or more populations of cells selected from (1) proliferating CD8+ cells; (2) proliferating and activated CD4+ and CD8+ effector memory and central memory T cells and (3) proliferating NK cells; and a second dose of the immunostimulating therapy is administered at a time when the proliferation or activation of one or more of these populations of cells, e.g., peripheral effector memory T cells and/or central memory T cells, are at or close to their respective baseline level that was present in the subject immediately prior to administration of the dose, e.g., first dose, of the immunostimulating therapy. In certain methods, a dose, e.g., a first dose, of an immunostimulating therapy (e.g., GITR agonist agent and PD-1/PD-L1 antagonist agent) is administered to a subject having cancer, resulting in an elevation of the level (or number) of (i) proliferating CD8+ effector memory cells; (ii) activated CD8+ effector memory cells; (iii) activated CD8+ effector memory cells; and/or (iv) activated CD8+ effector memory cells is higher by, e.g., 1.5 fold, 2, 3, 4 or 5 fold relative the level of the cell population before the administration; and a second dose of the immunostimulating therapy is administered at a time when the level (or number) of (i) proliferating CD8+ effector memory cells; (ii) activated CD8+ effector memory cells; (iii) proliferating CD8+ central memory cells; and/or (iv) activated CD8+ central memory cells are at or close (e.g., within 2 fold) to their respective baseline level that was present in the subject immediately prior to administration of the dose, e.g., first dose, of the immunostimulating therapy. In certain methods, a dose, e.g., a first dose, of an immunostimulating therapy (e.g., GITR agonist agent and PD-1/PD-L1 antagonist agent) is administered to a subject having cancer, resulting in an elevation of the level (or number) of (i) proliferating CD4+ effector memory cells; (ii) activated CD4+ effector memory cells; (iii) proliferating CD4+ central memory cells; and/or (iv) activated CD4+central memory cells is higher by, e.g., 1.5 fold, 2, 3, 4 or 5 fold relative the level of the cell population before the administration; and a second dose of the immunostimulating therapy is administered at a time when the level (or number) of (i) proliferating CD4+ effector memory cells; (ii) activated CD4+ effector memory cells; (iii) prolferating CD4+ central memory cells; and/or (iv) activated CD4+ central memory cells are at or close to (e.g., within 2 fold) their respective baseline level that was present in the subject immediately prior to administration of the dose, e.g., first dose, of the immunostimulating therapy. In certain methods, a dose, e.g., a first dose, of an immunostimulating therapy (e.g., GITR agonist agent and PD-1/PD-L1 antagonist agent) is administered to a subject having cancer, resulting in an elevation of the level (or number) of (i) proliferating CD8+ effector memory cells; (ii) activated CD8+ effector memory cells; (iii) proliferating CD8+ central memory cells; (iv) activated CD8+ central memory cells; (v) proliferating CD4+ effector memory cells; (vi) activated CD4+ effector memory cells; (vii) proliferating CD4+ central memory cells; and/or (viii) activated CD4+ central memory cells is higher by, e.g., 1.5 fold, 2, 3, 4 or 5 fold relative the level of the cell population before the administration; and a second dose of the immunostimulating therapy is administered at a time when the level (or number) of (i) proliferating CD8+ effector memory cells; (ii) activated CD8+ effector memory cells; (iii) proliferating CD8+ central memory cells; (iv) activated CD8+ central memory cells; (v) proliferating CD4+ effector memory cells; (vi) activated CD4+ effector memory cells; (vii) proliferating CD4+ central memory cells; and/or (viii) activated CD4+ central memory cells are at or close to (e.g., within 2 fold) their respective baseline level that was present in the subject immediately prior to administration of the dose, e.g., first dose, of the immunostimulating therapy. The subsequent doses may be administered at about the same time interval as that between the first and the second doses. In any of these embodiments, proliferating CD4 effector memory cells are CD45+CD3+CD4+CD8-CD197-CD45RA-Ki67+T cells (CD197 is CCR7); activated CD4 effector memory cells are CD45+CD3+CD4+CD8-CD197-CD45RA-HLA-DR+; proliferating CD4 central memory cells are CD45+CD3+CD4+CD8-CD197+CD45RA-Ki67+; and activated CD4 central memory cells are CD45+CD3+CD4+CD8-CD197+CD45RA-HLA-DR+; proliferating CD8 effector memory cells are CD45+CD3+CD4-CD8+CD197-CD45RA-Ki67+ cells; activated CD8 effector memory cells are CD45+CD3+CD4-CD8+CD197-CD45RA-HLA-DR+; proliferating CD8 central memory cells are CD45+CD3+CD4-CD8+CD197+CD45RA-Ki67+; and activated CD8 central memory cells are CD45+CD3+CD4-CD8+CD197+CD45RA-HLA-DR+, and the level of these cells is determined by flow cytometry, as described, e.g., in the Examples. 
     Also provided are methods for determining whether a subject is likely to respond to a given immunostimulating therapy, e.g., responding by the stabilization or shrinkage of the tumors. In one embodiment, a method comprises administering to a subject a dose of immunostimulating therapy (e.g., a GITR agonist agent and a PD-1/PD-L1 axis antagonist), and determining about 3-12 days later the level of one or one or more populations of cells selected from (1) proliferating CD8+ cells; (2) proliferating and activated CD4+ and CD8+ effector memory and central memory T cells and (3) proliferating NK cells, wherein an increase (by, 1.5, 2, 3, 4, or 5 or more fold) in one or more of these populations of cells relative to their respective level before administration of the therapy, indicates that the subject is likely to respond to the therapy, whereas the lack of increase in one or more of these cell populations indicates that the subject is not likely to respond to the treatment. A method may comprise administering to a subject a dose of immunostimulating therapy (e.g., a GITR agonist agent and a PD-1/PD-L1 axis antagonist), and determining about 3-12 days later the level of (i) proliferating CD8+ effector memory cells; (ii) activated CD8+ effector memory cells; (iii) proliferating CD8+central memory cells; and/or (iv) activated CD8+ central memory cells, wherein an increase (by, 1.5, 2, 3, 4, or 5 or more fold) in one or more (e.g., all) of these populations of cells relative to their respective level before administration of the therapy, indicates that the subject is likely to respond to the therapy, whereas the lack of increase in one or more (or all) of these cell populations indicates that the subject is not likely to respond to the treatment. A method may comprise administering to a subject a dose of immunostimulating therapy (e.g., a GITR agonist agent and a PD-1/PD-L1 axis antagonist), and determining about 3-12 days later the level of (i) proliferating CD4+ effector memory cells; (ii) activated CD4+ effector memory cells; (iii) proliferating CD4+ central memory cells; (iv) activated CD4+ central memory cells, wherein an increase (by, 1.5, 2, 3, 4, or 5 or more fold) in one or more (e.g., all) of these populations of cells relative to their respective level before administration of the therapy, indicates that the subject is likely to respond to the therapy, whereas the lack of increase in one or more (or all) of these cell populations indicates that the subject is not likely to respond to the treatment. A method may comprise administering to a subject a dose of immunostimulating therapy (e.g., a GITR agonist agent and a PD-1/PD-L1 axis antagonist), and determining about 3-12 days later the level of (i) proliferating CD8+ effector memory cells; (ii) activated CD8+ effector memory cells; (iii) proliferating CD8+ central memory cells; (iv) activated CD8+ central memory cells; (v) proliferating CD4+ effector memory cells; (vi) activated CD4+ effector memory cells; (vii) proliferating CD4+ central memory cells; and (viii) activated CD4+ central memory cells, wherein an increase (by, 1.5, 2, 3, 4, or 5 or more fold) in one or more (e.g., all) of these populations of cells relative to their respective level before administration of the therapy, indicates that the subject is likely to respond to the therapy, whereas the lack of increase in one or more (or all) of these cell populations indicates that the subject is not likely to respond to the treatment. In any of these embodiments, proliferating CD4 effector memory cells are CD45+CD3+CD4+CD8-CD197-CD45RA-Ki67+T cells (CD197 is CCR7); activated CD4 effector memory cells are CD45+CD3+CD4+CD8-CD197-CD45RA-HLA-DR+; proliferating CD4 central memory cells are CD45+CD3+CD4+CD8-CD197+CD45RA-Ki67+; and activated CD4 central memory cells are CD45+CD3+CD4+CD8-CD197+CD45RA-HLA-DR+; proliferating CD8 effector memory cells are CD45+CD3+CD4-CD8+CD197-CD45RA-Ki67+ cells; activated CD8 effector memory cells are CD45+CD3+CD4-CD8+CD197-CD45RA-HLA-DR+; proliferating CD8 central memory cells are CD45+CD3+CD4-CD8+CD197+CD45RA-Ki67+; and activated CD8 central memory cells are CD45+CD3+CD4-CD8+CD197+CD45RA-HLA-DR+, and the level of these cells is determined by flow cytometry, as described, e.g., in the Examples. 
     Kits 
     Also within the scope of the present invention are kits comprising an anti-GITR agonist agent, e.g., Ab, and optionally an anti-PD-1 or anti-PD-L1 antagonist agent, e.g., Ab, compositions and instructions for therapeutic uses. Kits typically include a label indicating the intended use of the contents of the kit and instructions for use. The term label includes any writing, or recorded material supplied on or with the kit, or which otherwise accompanies the kit. Accordingly, this disclosure provides a kit comprising: (a) an appropriate dosage of one or more compositions disclosed herein (e.g., an anti-GITR agonist agent, e.g., Ab, composition alone or with an anti-PD-1 or anti-PD-L1 antagonist composition or a composition comprising the two Abs) and (b) instructions for using the composition(s) in any of the methods disclosed herein. 
     Exemplary Embodiments 
     
         
         1. A method of treating a subject having cancer, comprising administering to a subject having cancer an anti-GITR agonist antibody (Ab) at a flat dose ranging from 1-800 mg once every 2-4 weeks. 
         2. The method of embodiment 1, wherein the anti-GITR agonist antibody is administered once every 2 weeks. 
         3. The method of embodiment 1, wherein the anti-GITR agonist antibody is administered once every 3 weeks. 
         4. The method of any one of embodiments 1-3, wherein the anti-GITR agonist antibody is administered at a flat dose ranging from 10-800 mg. 
         5. The method of embodiment 4, wherein the anti-GITR agonist antibody is administered at a flat dose ranging from 100-500 mg. 
         6. The method of any one of embodiments 1-5, wherein the anti-GITR agonist antibody is administered at a flat dose ranging from 100-500 mg once every 2-3 weeks. 
         7. The method of any one of embodiments 1-6, wherein the anti-GITR agonist antibody is administered for 1-5 cycles, wherein each cycle is 8 weeks long. 
         8. The method of embodiment 7, wherein the anti-GITR agonist antibody is administered for 3 cycles. 
         9. The method of any one of embodiments 1-8, wherein the cancer is a solid tumor cancer. 
         10. The method of any one of embodiments 1-8, wherein the cancer is an advanced cancer. 
         11. The method of embodiment 9, wherein the cancer is an advanced solid tumor cancer. 
         12. The method of any one of embodiments 1-8, wherein the cancer is a hematopoietic cancer. 
         13. The method of any one of embodiments 1-12, wherein the cancer comprises tumors expressing higher than normal GITR levels. 
         14. The method of embodiment 13, wherein the cancer comprises tumors having high levels of GITR positive Treg/Teff infiltration. 
         15. The method of any one of embodiments 1-14, wherein the GITR agonist antibody is administered as a monotherapy. 
         16. The method of any one of embodiments 1-14, wherein the GITR agonist antibody is administered as part of a combination therapy. 
         17. The method of embodiment 16, wherein the combination therapy is a fixed dose combination therapy. 
         18. The method of embodiment 16, wherein the combination therapy comprises administering an immuno-oncology agent other than the anti-GITR agonist Ab. 
         19. The method of embodiment 18, wherein the immuno-oncology agent is an anti-PD1 or anti-PD-L1 antagonist agent. 
         20. The method of embodiment 19, wherein the anti-PD1 or anti-PD-L1 antagonist agent is an antibody. 
         21. The method of embodiment 19 or 20, wherein the anti-PD1 or anti-PD-L1 antagonist agent is administered prior to administration of the anti-GITR agonist antibody. 
         22. The method of embodiment 21, wherein the anti-GITR agonist antibody and the anti-PD-1 or anti-PD-L1 antagonist agent are administered intravenously by infusion. 
         23. The method of embodiment 22, wherein the infusion of the anti-GITR agonist antibody is initiated 10-120 minutes after the termination of the infusion of the anti-PD1 or anti-PD-L1 antagonist agent. 
         24. The method of embodiment 23, wherein the infusion of the anti-GITR agonist antibody is initiated 30-60 minutes after the termination of the infusion of the anti-PD1 or anti-PD-L1 antagonist agent. 
         25. The method of embodiment 24, wherein the cancer is lung cancer or cervical cancer. 
         26. The method of embodiment 23, wherein the anti-GITR agonist antibody and the anti-PD-1 or anti-PD-L1 antagonist antibody are co-infused. 
         27. The method of any one of embodiments 1-26, wherein the subject has not been previously treated with an immuno-oncology agent. 
         28. The method of embodiment 27, wherein the subject has not been previously treated with an immuno-oncology agent within a year. 
         29. The method of any one of embodiments 1-26 and 28, wherein the subject is not responsive or is resistant to another immuno-oncology agent therapy. 
         30. The method of embodiment 29, wherein the other immuno-oncology agent therapy is a PD-1 or PD-L1 antagonist therapy. 
         31. The method of any one of embodiments 1-30, wherein the anti-GITR agonist Ab comprises the VH CDR1, CDR2, CDR3 and VL CDR1, CDR2, CDR3 of 28F3.IgG1. 
         32. The method of any one of embodiments 1-31, wherein the anti-GITR agonist Ab comprises a VH and VL chain that is at least 95%, 96%, 97%, 98% 99% or 100% identical to the VH and VL sequences of 28F3.IgG1, respectively. 
         33. The method of any one of embodiments 1-32, wherein the anti-GITR agonist Ab comprises a heavy chain (optionally without the C-terminal lysine of the heavy chain) and a light chain that are at least 95%, 96%, 97%, 98% 99% or 100% identical to the heavy and light chain sequences of 28F3.IgG1, respectively. 
         34. The method of any one of embodiments 1-33, which when it is a combination therapy, is administered with an anti-PD-1 Ab comprising the VH CDR1, CDR2, CDR3 and VL CDR1, CDR2, CDR3 of nivolumab. 
         35. The method of embodiment 34, wherein the anti-PD-1Ab comprises a VH and VL chain that is at least 95%, 96%, 97%, 98% 99% or 100% identical to the VH and VL sequences of nivolumab, respectively. 
         36. The method of embodiment 35, wherein the anti-PD-1Ab comprises a heavy chain (optionally without the C-terminal lysine of the heavy chain) and a light chain that are at least 95%, 96%, 97%, 98% 99% or 100% identical to the heavy and light chain sequences of nivolumab, respectively. 
         37. The method of any one of embodiments 1-33, which when it is a combination therapy, is administered with an anti-PD-L1 Ab comprising the VH CDR1, CDR2, CDR3 and VL CDR1, CDR2, CDR3 of 12A4. 
         38. The method of embodiment 34, wherein the anti- PD-Ll Ab comprises a VH and VL chain that is at least 95%, 96%, 97%, 98% 99% or 100% identical to the VH and VL sequences of 12A4, respectively. 
         39. The method of embodiment 35, wherein the anti- PD-Ll Ab comprises a heavy chain (optionally without the C-terminal lysine of the heavy chain) and a light chain that are at least 95%, 96%, 97%, 98% 99% or 100% identical to the heavy and light chain sequences of 12A4, respectively. 
         40. The method of any one of embodiments 1-39, wherein the subject has previously been treated for the same disease with a different therapeutic agent. 
         41. The method of embodiment 40, wherein the different therapeutic agent is not an immuno-oncology agent. 
       
    
     
       
         
           
               
             
               
                 TABLE 2 
               
             
            
               
                   
               
               
                 SEQUENCES 
               
            
           
           
               
               
               
            
               
                 SEQ 
                   
                   
               
               
                 ID 
                 Description 
                 Sequence 
               
               
                   
               
            
           
           
               
               
               
            
               
                 1 
                 Human GITR isoform 1 
                 MAQHGAMGAFRALCGLALLCALSLGQRPTGGPGCGPGR 
               
               
                   
                   
                 LLLGTGTDARCCRVHTTRCCRDYPGEECCSEWDCMCVQ 
               
               
                   
                   
                 PEFHCGDPCCTTCRHHPCPPGQGVQSQGKFSFGFQCID 
               
               
                   
                   
                 CASGTFSGGHEGHCKPWTDCTQFGFLTVFPGNKTHNAV 
               
               
                   
                   
                 CVPGSPPAEPLGWLTVVLLAVAACVLLLTSAQLGLHIW 
               
               
                   
                   
                 QLRSQCMWPRETQLLLEVPPSTEDARSCQFPEEERGER 
               
               
                   
                   
                 SAEEKGRLGDLWV 
               
               
                   
               
               
                 2 
                 Human GITR isoform 2 
                 MAQHGAMGAFRALCGLALLCALSLGQRPTGGPGCGPGR 
               
               
                   
                   
                 LLLGTGTDARCCRVHTTRCCRDYPGEECCSEWDCMCVQ 
               
               
                   
                   
                 PEFHCGDPCCTTCRHHPCPPGQGVQSQGKFSFGFQCID 
               
               
                   
                   
                 CASGTFSGGHEGHCKPWTDCCWRCRRRPKTPEAASSPR 
               
               
                   
                   
                 KSGASDRQRRRGGWETCGCEPGRPPGPPTAASPSPGAP 
               
               
                   
                   
                 QAAGALRSALGRALLPWQQKWVQEGGSDQRPGPCSSAA 
               
               
                   
                   
                 AAGPCRRERETQSWPPSSLAGPDGVGS 
               
               
                   
               
               
                 3 
                 Human GITR isoform 3 
                 MAQHGAMGAFRALCGLALLCALSLGQRPTGGPGCGPGR 
               
               
                   
                   
                 LLLGTGTDARCCRVHTTRCCRDYPGEECCSEWDCMCVQ 
               
               
                   
                   
                 PEFHCGDPCCTTCRHHPCPPGQGVQSQGKFSFGFQCID 
               
               
                   
                   
                 CASGTFSGGHEGHCKPWTDCTQFGFLTVFPGNKTHNAV 
               
               
                   
                   
                 CVPGSPPAEPLGWLTVVLLAVAACVLLLTSAQLGLHIW 
               
               
                   
                   
                 QLRKTQLLLEVPPSTEDARSCQFPEEERGERSAEEKGR 
               
               
                   
                   
                 LGDLWV 
               
               
                   
               
               
                 4 
                 Human GITR (mature) 
                 QRPTGGPGCGPGRLLLGTGTDARCCRVHTTRCCRDYPG 
               
               
                   
                   
                 EECCSEWDCMCVQPEFHCGDPCCTTCRHHPCPPGQGVQ 
               
               
                   
                   
                 SQGKFSFGFQCIDCASGTFSGGHEGHCKPWTDCTQFGF 
               
               
                   
                   
                 LTVFPGNKTHNAVCVPGSPPAEP 
               
               
                   
               
               
                 5 
                 Cynomolgus GITR 
                 MCASGTLCCLALLCAASLGQRPTGGPGCGPGRLLLGTG 
               
               
                   
                   
                 KDARCCRVHPTRCCRDYQGEECCSEWDCVCVQPEFHCG 
               
               
                   
                   
                 NPCCTTCQHHPCPSGQGVQPQGKFSFGFRCVDCALGTF 
               
               
                   
                   
                 SRGHDGHCKPWTDCTQFGFLTVFPGNKTHNAVCVPGSP 
               
               
                   
                   
                 PAEPPGWLTIILLAVAACVLLLTSAQLGLHIWQLRSQP 
               
               
                   
                   
                 TGPRETQLLLEVPPSTEDASSCQFPEEERGERLAEEKG 
               
               
                   
                   
                 RLGDLWV 
               
               
                   
               
               
                 6 
                 Human GITR-L 
                 MTLHPSPITCEFLFSTALISPKMCLSHLENMPLSHSRT 
               
               
                   
                   
                 QGAQRSSWKLWLFCSIVMLLFLCSFSWLIFIFLQLETA 
               
               
                   
                   
                 KEPCMAKFGPLPSKWQMASSEPPCVNKVSDWKLEILQN 
               
               
                   
                   
                 GLYLIYGQVAPNANYNDVAPFEVRLYKNKDMIQTLTNK 
               
               
                   
                   
                 SKIQNVGGTYELHVGDTIDLIFNSEHQVLKNNTYWGII 
               
               
                   
                   
                 LLANPQFIS 
               
               
                   
               
               
                 7 
                 Human IgG1 constant 
                 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT 
               
               
                   
                 domain 
                 VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL 
               
               
                   
                   
                 GTQTYICNVNHKPSNTKVDK R VEPKSCDKTHTCPPCPA 
               
               
                   
                   
                 PELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE 
               
               
                   
                   
                 DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLT 
               
               
                   
                   
                 VLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPRE 
               
               
                   
                   
                 PQVYTLPPSR E E M TKNQVSLTCLVKGFYPSDIAVEWES 
               
               
                   
                   
                 NGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN 
               
               
                   
                   
                 VFSCSVMHEALHNHYTQKSLSLSPG 
               
               
                   
               
               
                 8 
                 Human IgG1 constant 
                 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT 
               
               
                   
                 domain (allotypic variant) 
                 VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL 
               
               
                   
                   
                 GTQTYICNVNHKPSNTKVDK K VEPKSCDKTHTCPPCPA 
               
               
                   
                   
                 PELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE 
               
               
                   
                   
                 DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLT 
               
               
                   
                   
                 VLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPRE 
               
               
                   
                   
                 PQVYTLPPSR D E L TKNQVSLTCLVKGFYPSDIAVEWES 
               
               
                   
                   
                 NGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN 
               
               
                   
                   
                 VFSCSVMHEALHNHYTQKSLSLSPG 
               
               
                   
               
               
                 9 
                 Human IgGlconstant domain 
                 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT 
               
               
                   
                 with L234A, L235E, and 
                 VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL 
               
               
                   
                 G237A mutations 
                 GTQTYICNVNHKPSNTKVDK R VEPKSCDKTHTCPPCPA 
               
               
                   
                   
                 PEAEGAPSVFLF 
               
               
                   
                   
                 PPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDG 
               
               
                   
                   
                 VE 
               
               
                   
                   
                 VHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC 
               
               
                   
                   
                 KV 
               
               
                   
                   
                 SNKALPAPIEKTISKAKGQPREPQVYTLPPSR EEM TKN 
               
               
                   
                   
                 QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD 
               
               
                   
                   
                 SDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT 
               
               
                   
                   
                 QKSLSLSPG 
               
               
                   
               
               
                 10 
                 Human IgG1constant domain 
                 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT 
               
               
                   
                 with A330S and P331S 
                 VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL 
               
               
                   
                 mutations 
                 GTQTYICNVNHKPSNTKVDK R VEPKSCDKTHTCPPCPA 
               
               
                   
                   
                 PELLGGPSVFLF 
               
               
                   
                   
                 PPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDG 
               
               
                   
                   
                 VE 
               
               
                   
                   
                 VHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC 
               
               
                   
                   
                 KV 
               
               
                   
                   
                 SNKALPSSIEKTISKAKGQPREPQVYTLPPSR EEM TKN 
               
               
                   
                   
                 QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD 
               
               
                   
                   
                 SDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT 
               
               
                   
                   
                 QKSLSLSPG 
               
               
                   
               
               
                 11 
                 Human IgG1.1 constant 
                 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT 
               
               
                   
                 domain (L234A, L235E, 
                 VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL 
               
               
                   
                 G237A, A330S, and P331S 
                 GTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPA 
               
               
                   
                 mutations) 
                 PE AE G A PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE 
               
               
                   
                   
                 DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLT 
               
               
                   
                   
                 VLHQDWLNGKEYKCKVSNKALP SS IEKTISKAKGQPRE 
               
               
                   
                   
                 PQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWES 
               
               
                   
                   
                 NGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN 
               
               
                   
                   
                 VFSCSVMHEALHNHYTQKSLSLSPG 
               
               
                   
               
               
                 12 
                 Human IgG1 kappa light 
                 RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNA 
               
               
                   
                 chain constant region (CL) 
                 LQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQ 
               
               
                   
                   
                 GLSSPVTKSFNRGEC 
               
               
                   
               
               
                 13 
                 28F3 (VH) 
                 QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVR 
               
               
                   
                   
                 QAPGKGLEWVAVIWYEGSNKYYADSVKGRFTISRDNSK 
               
               
                   
                   
                 NTLYLQMNSLRAEDTAVYYCARGGSMVRGDYYYGMDVW 
               
               
                   
                   
                 GQGTTVTVSS 
               
               
                   
               
               
                 14 
                 28F3 (VL) 
                 AIQLTQSPSSLSASVGDRVTITCRASQGISSALAWYQQ 
               
               
                   
                   
                 KPGKAPKLLIYDASSLESGVPSRFSGSGSGTDFTLTIS 
               
               
                   
                   
                 SLQPEDFATYYCQQFNSYPYTFGQGTKLEIK 
               
               
                   
               
               
                 15 
                 28F3 (full length wild-type 
                 QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLE 
               
               
                   
                 heavy chain) 
                 WVAVIWYEGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTA 
               
               
                   
                 The constant region is 
                 VYYCARGGSMVRGDYYYGMDVWGQGTTVTVSS ASTKGPSVFPLAPC   
               
               
                   
                 underlined 
                 
                   SRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS 
                 
               
               
                   
                   
                 
                   GLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVEC 
                 
               
               
                   
                   
                 
                   PPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEV 
                 
               
               
                   
                   
                 
                   QFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEY 
                 
               
               
                   
                   
                 
                   KCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSL 
                 
               
               
                   
                   
                 
                   TCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLT 
                 
               
               
                   
                   
                 
                   VDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 
                 
               
               
                   
               
               
                 16 
                 28F3 (full length wild-type 
                 AIQLTQSPSSLSASVGDRVTITCRASQGISSALAWYQQKPGKAPKL 
               
               
                   
                 light chain) 
                 LIYDASSLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQFN 
               
               
                   
                 The constant region is 
                 SYPYTFGQGTKLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNN   
               
               
                   
                 underlined 
                 
                   FYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA 
                 
               
               
                   
                   
                 
                   DYEKHKVYACEVTHQGLSSPVTKSFNRGEC 
                 
               
               
                   
               
               
                 17 
                 28F3.IgG1 (VH + IgG1) 
                 QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLE 
               
               
                   
                   
                 WVAVIWYEGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTA 
               
               
                   
                   
                 VYYCARGGSMVRGDYYYGMDVWGQGTTVTVSSASTKGPSVFPLAPS 
               
               
                   
                   
                 SKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS 
               
               
                   
                   
                 GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKT 
               
               
                   
                   
                 HTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE 
               
               
                   
                   
                 DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLN 
               
               
                   
                   
                 GKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKN 
               
               
                   
                   
                 QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY 
               
               
                   
                   
                 SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 
               
               
                   
               
               
                 18 
                 28F3.IgG1.1 (VH + IgG1.1) 
                 QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLE 
               
               
                   
                   
                 WVAVIWYEGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTA 
               
               
                   
                   
                 VYYCARGGSMVRGDYYYGMDVWGQGTTVTVSSASTKGPSVFPLAPS 
               
               
                   
                   
                 SKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS 
               
               
                   
                   
                 GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKT 
               
               
                   
                   
                 HTCPPCPAPEAEGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE 
               
               
                   
                   
                 DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLN 
               
               
                   
                   
                 GKEYKCKVSNKALPSSIEKTISKAKGQPREPQVYTLPPSREEMTKN 
               
               
                   
                   
                 QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY 
               
               
                   
                   
                 SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 
               
               
                   
               
               
                 19 
                 28F3.IgG1 (VL + CL) 
                 AIQLTQSPSSLSASVGDRVTITCRASQGISSALAWYQQKPGKAPKL 
               
               
                   
                   
                 LIYDASSLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQFN 
               
               
                   
                   
                 SYPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNN 
               
               
                   
                   
                 FYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA 
               
               
                   
                   
                 DYEKHKVYACEVTHQGLSSPVTKSFNRGEC 
               
               
                   
               
               
                 20 
                 28F3 VH CDR1 
                 SYGMH 
               
               
                   
               
               
                 21 
                 28F3 VH CDR2 
                 VIWYEGSNKYYADSVKG 
               
               
                   
               
               
                 22 
                 28F3 VH CDR3 
                 GGSMVRGDYYYGMDV 
               
               
                   
               
               
                 23 
                 28F3 VL CDR1 
                 RASQGISSALA 
               
               
                   
               
               
                 24 
                 28F3 VL CDR2 
                 DASSLES 
               
               
                   
               
               
                 25 
                 28F3 VL CDR3 
                 QQFNSYPYT 
               
               
                   
               
               
                 26 
                 19D3 (VH) 
                 QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGFHWVR 
               
               
                   
                   
                 QAPGKGLEWVAVIWYAGSNKFYADSVKGRFTISRDNSK 
               
               
                   
                   
                 NTLYLQMNSLRAEDTAVYYCARGGQLDYYYYYVMDVWG 
               
               
                   
                   
                 QGTTVTVSS 
               
               
                   
               
               
                 27 
                 19D3 (VL) 
                 DIQMTQSPSSLSASVGDRVTITCRASQGISSWLAWYQQ 
               
               
                   
                   
                 KPEKAPKSLIYAASSLQSGVP 
               
               
                   
                   
                 SRFSGSGSGTDFTLTISSLQPEDFATYYCQQYNSYPYT 
               
               
                   
                   
                 FGQGTKLEIK 
               
               
                   
               
               
                 28 
                 19D3 (full length wild-type 
                 QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGFHWVR 
               
               
                   
                 heavy chain) 
                 QAPGKGLEWVAVIWYAGSNKFYADSVKGRFTISRDNSK 
               
               
                   
                 The constant region is 
                 NTLYLQMNSLRAEDTAVYYCARGGQLDYYYYYVMDVWG 
               
               
                   
                 underlined 
                 QGTTVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLV   
               
               
                   
                   
                 
                   KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSS 
                 
               
               
                   
                   
                 
                   VVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVE 
                 
               
               
                   
                   
                 
                   CPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVV 
                 
               
               
                   
                   
                 
                   DVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRV 
                 
               
               
                   
                   
                 
                   VSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTK 
                 
               
               
                   
                   
                 
                   GQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIA 
                 
               
               
                   
                   
                 
                   VEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSR 
                 
               
               
                   
                   
                 
                   WQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 
                 
               
               
                   
               
               
                 29 
                 19D3 (full length wild-type 
                 DIQMTQSPSSLSASVGDRVTITCRASQGISSWLAWYQQ 
               
               
                   
                 light chain) 
                 KPEKAPKSLIYAASSLQSGVPSRFSGSGSGTDFTLTIS 
               
               
                   
                   
                 SLQPEDFATYYCQQYNSYPYTFGQGTKLEIK RTVAAPS   
               
               
                   
                 The constant region is 
                 
                   VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDN 
                 
               
               
                   
                 underlined 
                 
                   ALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHK 
                 
               
               
                   
                   
                 
                   VYACEVTHQGLSSPVTKSFNRGEC 
                 
               
               
                   
               
               
                 30 
                 19D3.IgG1 (VH + IgG1) 
                 QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGFHWVR 
               
               
                   
                   
                 QAPGKGLEWVAVIWYAGSNKFYADSVKGRFTISRDNSK 
               
               
                   
                   
                 NTLYLQMNSLRAEDTAVYYCARGGQLDYYYYYVMDVWG 
               
               
                   
                   
                 QGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV 
               
               
                   
                   
                 KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSS 
               
               
                   
                   
                 VVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDK 
               
               
                   
                   
                 THTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVT 
               
               
                   
                   
                 CVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS 
               
               
                   
                   
                 TYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI 
               
               
                   
                   
                 SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP 
               
               
                   
                   
                 SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV 
               
               
                   
                   
                 DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 
               
               
                   
               
               
                 31 
                 19D3.IgG1.1 (VH + IgG1.1) 
                 QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGFHWVR 
               
               
                   
                   
                 QAPGKGLEWVAVIWYAGSNKFYADSVKGRFTISRDNSK 
               
               
                   
                   
                 NTLYLQMNSLRAEDTAVYYCARGGQLDYYYYYVMDVWG 
               
               
                   
                   
                 QGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV 
               
               
                   
                   
                 KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSS 
               
               
                   
                   
                 VVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDK 
               
               
                   
                   
                 THTCPPCPAPE AE G A PSVFLFPPKPKDTLMISRTPEVT 
               
               
                   
                   
                 CVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS 
               
               
                   
                   
                 TYRVVSVLTVLHQDWLNGKEYKCKVSNKALP SS IEKTI 
               
               
                   
                   
                 SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP 
               
               
                   
                   
                 SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV 
               
               
                   
                   
                 DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 
               
               
                   
               
               
                 32 
                 19D3.IgG1 (VL + CL) 
                 DIQMTQSPSSLSASVGDRVTITCRASQGISSWLAWYQQ 
               
               
                   
                   
                 KPEKAPKSLIYAASSLQSGVPSRFSGSGSGTDFTLTIS 
               
               
                   
                   
                 SLQPEDFATYYCQQYNSYPYTFGQGTKLEIKRTVAAPS 
               
               
                   
                   
                 VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDN 
               
               
                   
                   
                 ALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHK 
               
               
                   
                   
                 VYACEVTHQGLSSPVTKSFNRGEC 
               
               
                   
               
               
                 33 
                 19D3 VH CDR1 
                 SYGFH 
               
               
                   
               
               
                 34 
                 19D3 VH CDR2 
                 VIWYAGSNKFYADSVKG 
               
               
                   
               
               
                 35 
                 19D3 VH CDR3 
                 GGQLDYYYYYVMDV 
               
               
                   
               
               
                 36 
                 19D3 VL CDR1 
                 RASQGISSWLA 
               
               
                   
               
               
                 37 
                 19D3 VL CDR2 
                 AASSLQS 
               
               
                   
               
               
                 38 
                 19D3 VL CDR3 
                 QQYNSYPYT 
               
               
                   
               
               
                 39 
                 18E10 (VH) 
                 QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVR 
               
               
                   
                   
                 QAPGKGLEWVAVIWYAGSNKYYADSVKGRFTISRDNSK 
               
               
                   
                   
                 NTLYLQMNSLRAEDTAVYYCARGGRIAVAFYYSMDVWG 
               
               
                   
                   
                 QGTTVTVSS 
               
               
                   
               
               
                 40 
                 18E10 (VL) 
                 DIQMTQSPSSLSASVGDRVTITCRASQGISSWLAWYQQ 
               
               
                   
                   
                 KPEKAPKSLIYAASSLQSGVPSRFSGSGSGTDFTLTIS 
               
               
                   
                   
                 SLQPEDFATYYCQQYNSYPYTFGQGTKLEIK 
               
               
                   
               
               
                 41 
                 18E10 (full length wild-type 
                 QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVR 
               
               
                   
                 heavy chain) 
                 QAPGKGLEWVAVIWYAGSNKYYADSVKGRFTISRDNSK 
               
               
                   
                 The constant region is 
                 NTLYLQMNSLRAEDTAVYYCARGGRIAVAFYYSMDVWG 
               
               
                   
                 underlined 
                 QGTTVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLV   
               
               
                   
                   
                 
                   KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSS 
                 
               
               
                   
                   
                 
                   VVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVE 
                 
               
               
                   
                   
                 
                   CPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVV 
                 
               
               
                   
                   
                 
                   DVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRV 
                 
               
               
                   
                   
                 
                   VSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTK 
                 
               
               
                   
                   
                 
                   GQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIA 
                 
               
               
                   
                   
                 
                   VEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSR 
                 
               
               
                   
                   
                 
                   WQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 
                 
               
               
                   
               
               
                 42 
                 18E10 (full length wild-type 
                 DIQMTQSPSSLSASVGDRVTITCRASQGISSWLAWYQQ 
               
               
                   
                 light chain) 
                 KPEKAPKSLIYAASSLQSGVPSRFSGSGSGTDFTLTIS 
               
               
                   
                 The constant region is 
                 SLQPEDFATYYCQQYNSYPYTFGQGTKLEIK RTVAAPS   
               
               
                   
                 underlined 
                 
                   VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDN 
                 
               
               
                   
                   
                 ALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHK 
               
               
                   
                   
                 VYACEVTHQGLSSPVTKSFNRGEC 
               
               
                   
               
               
                 43 
                 18E10.IgG1 (VH + IgG1) 
                 QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVR 
               
               
                   
                   
                 QAPGKGLEWVAVIWYAGSNKYYADSVKGRFTISRDNSK 
               
               
                   
                   
                 NTLYLQMNSLRAEDTAVYYCARGGRIAVAFYYSMDVWG 
               
               
                   
                   
                 QGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV 
               
               
                   
                   
                 KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSS 
               
               
                   
                   
                 VVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDK 
               
               
                   
                   
                 THTCPPCPAPELLGGPSVFLF 
               
               
                   
                   
                 PPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDG 
               
               
                   
                   
                 VE 
               
               
                   
                   
                 VHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC 
               
               
                   
                   
                 KV 
               
               
                   
                   
                 SNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKN 
               
               
                   
                   
                 QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD 
               
               
                   
                   
                 SDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT 
               
               
                   
                   
                 QKSLSLSPG 
               
               
                   
               
               
                 44 
                 18E10.IgG1.1 (VH  
                 QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVR 
               
               
                   
                 IgG1.1) 
                 QAPGKGLEWVAVIWYAGSNKYYADSVKGRFTISRDNSK 
               
               
                   
                   
                 NTLYLQMNSLRAEDTAVYYCARGGRIAVAFYYSMDVWG 
               
               
                   
                   
                 QGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV 
               
               
                   
                   
                 KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSS 
               
               
                   
                   
                 VVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDK 
               
               
                   
                   
                 THTCPPCPAPE AE G A PSVFLFPPKPKDTLMISRTPEVT 
               
               
                   
                   
                 CVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS 
               
               
                   
                   
                 TYRVVSVLTVLHQDWLNGKEYKCKVSNKALP SS IEKTI 
               
               
                   
                   
                 SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP 
               
               
                   
                   
                 SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV 
               
               
                   
                   
                 DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 
               
               
                   
               
               
                 45 
                 18E10.IgG1 (VL + CL) 
                 DIQMTQSPSSLSASVGDRVTITCRASQGISSWLAWYQQ 
               
               
                   
                   
                 KPEKAPKSLIYAASSLQSGVPSRFSGSGSGTDFTLTIS 
               
               
                   
                   
                 SLQPEDFATYYCQQYNSYPYTFGQGTKLEIKRTVAAPS 
               
               
                   
                   
                 VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDN 
               
               
                   
                   
                 ALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHK 
               
               
                   
                   
                 VYACEVTHQGLSSPVTKSFNRGEC 
               
               
                   
               
               
                 46 
                 18E10 VH CDR1 
                 SYGMH 
               
               
                   
               
               
                 47 
                 18E10 VH CDR2 
                 VIWYAGSNKYYADSVKG 
               
               
                   
               
               
                 48 
                 18E10 VH CDR3 
                 GGRIAVAFYYSMDV 
               
               
                   
               
               
                 49 
                 18E10 VL CDR1 
                 RASQGISSWLA 
               
               
                   
               
               
                 50 
                 18E10 VL CDR2 
                 AASSLQS 
               
               
                   
               
               
                 51 
                 18E10 VL CDR3 
                 QQYNSYPYT 
               
               
                   
               
               
                 52 
                 3C3 (VH) 
                 QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWTWIR 
               
               
                   
                   
                 QPPGKGLEWIGKINHSGNTNYNPSLKSRVTISVDTSKN 
               
               
                   
                   
                 QFSLKLSSVTAADTAVYYCARLGAFDAFDIWGQGTMVT 
               
               
                   
                   
                 VSS 
               
               
                   
               
               
                 53 
                 3C3 (VL1) 
                 DIQMTQSPSSLSASVGDRVTITCRASQGISSWLAWYQQ 
               
               
                   
                   
                 KPEKAPKSLIYAASSLQSGVPSRFSGSGSGTDFTLTIS 
               
               
                   
                   
                 SLQPEDFATYYCQQYNSYPYTFGQGTKLEIK 
               
               
                   
               
               
                 54 
                 3C3 (VL2) 
                 EIVLTQSPATLSLSPGERATLSCRASQGVSSYLAWYQQ 
               
               
                   
                   
                 KPGQAPRLLIYDASNRATGIPARFSGSGPGTDFTLTIS 
               
               
                   
                   
                 SLEPEDFAVYYCQQRSNWHTFGQGTKLEIK 
               
               
                   
               
               
                 55 
                 3C3 (full length wild-type 
                 QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWTWIR 
               
               
                   
                 heavy chain) 
                 QPPGKGLEWIGKINHSGNTNYNPSLKSRVTISVDTSKN 
               
               
                   
                 The constant region is 
                 QFSLKLSSVTAADTAVYYCARLGAFDAFDIWGQGTMVT 
               
               
                   
                 underlined 
                 VSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPE   
               
               
                   
                   
                 
                   PVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPS 
                 
               
               
                   
                   
                 
                   SSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPP 
                 
               
               
                   
                   
                 
                   CPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDV 
                 
               
               
                   
                   
                 
                   SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVS 
                 
               
               
                   
                   
                 
                   VLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQ 
                 
               
               
                   
                   
                 
                   PREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVE 
                 
               
               
                   
                   
                 
                   WESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ 
                 
               
               
                   
                   
                 
                   QGNVFSCSVMHEALHNHYTQKSLSLSPGK 
                 
               
               
                   
               
               
                 56 
                 3C3 L1 (full length wild-type 
                 DIQMTQSPSSLSASVGDRVTITCRASQGISSWLAWYQQ 
               
               
                   
                 light chain 1) 
                 KPEKAPKSLIYAASSLQSGVPSRFSGSGSGTDFTLTIS 
               
               
                   
                 The constant region is 
                 SLQPEDFATYYCQQYNSYPYTFGQGTKLEIK RTVAAPS   
               
               
                   
                 underlined 
                 
                   VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDN 
                 
               
               
                   
                   
                 
                   ALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHK 
                 
               
               
                   
                   
                 
                   VYACEVTHQGLSSPVTKSFNRGEC 
                 
               
               
                   
               
               
                 57 
                 3C3 L2 (full length wild-type 
                 EIVLTQSPATLSLSPGERATLSCRASQGVSSYLAWYQQ 
               
               
                   
                 light chain 2) 
                 KPGQAPRLLIYDASNRATGIPARFSGSGPGTDFTLTIS 
               
               
                   
                 The constant region is 
                 SLEPEDFAVYYCQQRSNWHTFGQGTKLEIKRTVAAPSV 
               
               
                   
                 underlined 
                 FIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNA 
               
               
                   
                   
                 LQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKV 
               
               
                   
                   
                 YACEVTHQGLSSPVTKSFNRGEC 
               
               
                   
               
               
                 58 
                 3C3.1gG1 (VH + IgG1) 
                 QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWTWIR 
               
               
                   
                   
                 QPPGKGLEWIGKINHSGNTNYNPSLKSRVTISVDTSKN 
               
               
                   
                   
                 QFSLKLSSVTAADTAVYYCARLGAFDAFDIWGQGTMVT 
               
               
                   
                   
                 VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPE 
               
               
                   
                   
                 PVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPS 
               
               
                   
                   
                 SSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPP 
               
               
                   
                   
                 CPAPELLGGPSVFLF 
               
               
                   
                   
                 PPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDG 
               
               
                   
                   
                 VE 
               
               
                   
                   
                 VHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC 
               
               
                   
                   
                 KV 
               
               
                   
                   
                 SNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKN 
               
               
                   
                   
                 QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD 
               
               
                   
                   
                 SDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT 
               
               
                   
                   
                 QKSLSLSPG 
               
               
                   
               
               
                 59 
                 3C3.IgG1.1 (VH + IgG1.1) 
                 QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWTWIR 
               
               
                   
                   
                 QPPGKGLEWIGKINHSGNTNYNPSLKSRVTISVDTSKN 
               
               
                   
                   
                 QFSLKLSSVTAADTAVYYCARLGAFDAFDIWGQGTMVT 
               
               
                   
                   
                 VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPE 
               
               
                   
                   
                 PVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPS 
               
               
                   
                   
                 SSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPP 
               
               
                   
                   
                 CPAPE AE G A PSVFLFPPKPKDTLMISRTPEVTCVVVDV 
               
               
                   
                   
                 SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVS 
               
               
                   
                   
                 VLTVLHQDWLNGKEYKCKVSNKALP SS IEKTISKAKGQ 
               
               
                   
                   
                 PREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE 
               
               
                   
                   
                 WESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ 
               
               
                   
                   
                 QGNVFSCSVMHEALHNHYTQKSLSLSPG 
               
               
                   
               
               
                 60 
                 3C3.IgG1 (VL1 + CL) 
                 DIQMTQSPSSLSASVGDRVTITCRASQGISSWLAWYQQ 
               
               
                   
                   
                 KPEKAPKSLIYAASSLQSGVPSRFSGSGSGTDFTLTIS 
               
               
                   
                   
                 SLQPEDFATYYCQQYNSYPYTFGQGTKLEIKRTVAAPS 
               
               
                   
                   
                 VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDN 
               
               
                   
                   
                 ALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHK 
               
               
                   
                   
                 VYACEVTHQGLSSPVTKSFNRGEC 
               
               
                   
               
               
                 61 
                 3C3IgG1.2 (VL2 + CL) 
                 EIVLTQSPATLSLSPGERATLSCRASQGVSSYLAWYQQ 
               
               
                   
                   
                 KPGQAPRLLIYDASNRATGIPARFSGSGPGTDFTLTIS 
               
               
                   
                   
                 SLEPEDFAVYYCQQRSNWHTFGQGTKLEIKRTVAAPSV 
               
               
                   
                   
                 FIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNA 
               
               
                   
                   
                 LQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKV 
               
               
                   
                   
                 YACEVTHQGLSSPVTKSFNRGEC 
               
               
                   
               
               
                 62 
                 3C3 VH CDR1 
                 GYYWT 
               
               
                   
               
               
                 63 
                 3C3 VH CDR2 
                 KINHSGNTNYNPSLKS 
               
               
                   
               
               
                 64 
                 3C3 VH CDR3 
                 LGAFDAFDI 
               
               
                   
               
               
                 65 
                 3C3 VL1 CDR1 
                 RASQGISSWLA 
               
               
                   
               
               
                 66 
                 3C3 VL1 CDR2 
                 AASSLQS 
               
               
                   
               
               
                 67 
                 3C3 VL1 CDR3 
                 QQYNSYPYT 
               
               
                   
               
               
                 68 
                 3C3 VL2 CDR1 
                 RASQGVSSYLA 
               
               
                   
               
               
                 69 
                 3C3 VL2 CDR2 
                 DASNRAT 
               
               
                   
               
               
                 70 
                 3C3 VL2 CDR3 
                 QQRSNWHT 
               
               
                   
               
               
                 71 
                 2G6 (VH) 
                 QVQLVESGGGVVQPGGSLRLSCAASGFILSDYGMHWVR 
               
               
                   
                   
                 QAPGKGLEWVTVIWYDGSNKFYVDSVKGRFTISRDNSK 
               
               
                   
                   
                 NTLYLQMNSLRVEDTAVYYCARGGRLATGHFYYVMDVW 
               
               
                   
                   
                 GQGTTVTVSS 
               
               
                   
               
               
                 72 
                 2G6 (VL) 
                 DIQMTQSPSSLSASVGDRVTITCRASQGISSWLAWYQQ 
               
               
                   
                   
                 KPEKAPKSLIYAASSLQSGVPSRFSGSGSGTDFTLTIS 
               
               
                   
                   
                 SLQPEDFATYYCQQYNSYPYTFGQGTKLEIK 
               
               
                   
               
               
                 73 
                 2G6 (full length wild-type 
                 QVQLVESGGGVVQPGGSLRLSCAASGFILSDYGMHWVR 
               
               
                   
                 heavy chain) 
                 QAPGKGLEWVTVIWYDGSNKFYVDSVKGRFTISRDNSK 
               
               
                   
                 The constant region is 
                 NTLYLQMNSLRVEDTAVYYCARGGRLATGHFYYVMDVW 
               
               
                   
                 underlined 
                 GQGTTVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCL   
               
               
                   
                   
                 
                   VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS 
                 
               
               
                   
                   
                 
                   SVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCV 
                 
               
               
                   
                   
                 
                   ECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVV 
                 
               
               
                   
                   
                 
                   VDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFR 
                 
               
               
                   
                   
                 
                   VVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKI 
                 
               
               
                   
                   
                 
                   KGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDI 
                 
               
               
                   
                   
                 
                   AVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKS 
                 
               
               
                   
                   
                 
                   RWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 
                 
               
               
                   
               
               
                 74 
                 2G6 (full length wild-type 
                 DIQMTQSPSSLSASVGDRVTITCRASQGISSWLAWYQQ 
               
               
                   
                 light chain) 
                 KPEKAPKSLIYAASSLQSGVPSRFSGSGSGTDFTLTIS 
               
               
                   
                 The constant region is 
                 SLQPEDFATYYCQQYNSYPYTFGQGTKLEIK RTVAAPS   
               
               
                   
                 underlined 
                 
                   VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDN 
                 
               
               
                   
                   
                 
                   ALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHK 
                 
               
               
                   
                   
                 
                   VYACEVTHQGLSSPVTKSFNRGEC 
                 
               
               
                   
               
               
                 75 
                 2G6.IgG1 (VH + IgG1) 
                 QVQLVESGGGVVQPGGSLRLSCAASGFILSDYGMHWVR 
               
               
                   
                   
                 QAPGKGLEWVTVIWYDGSNKFYVDSVKGRFTISRDNSK 
               
               
                   
                   
                 NTLYLQMNSLRVEDTAVYYCARGGRLATGHFYYVMDVW 
               
               
                   
                   
                 GQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL 
               
               
                   
                   
                 VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS 
               
               
                   
                   
                 SVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCD 
               
               
                   
                   
                 KTHTCPPCPAPELLGGPSVFLF 
               
               
                   
                   
                 PPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDG 
               
               
                   
                   
                 VE 
               
               
                   
                   
                 VHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC 
               
               
                   
                   
                 KV 
               
               
                   
                   
                 SNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKN 
               
               
                   
                   
                 QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD 
               
               
                   
                   
                 SDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT 
               
               
                   
                   
                 QKSLSLSPG 
               
               
                   
               
               
                 76 
                 2G6.IgG1.1 (VH + IgG1.1) 
                 QVQLVESGGGVVQPGGSLRLSCAASGFILSDYGMHWVR 
               
               
                   
                   
                 QAPGKGLEWVTVIWYDGSNKFYVDSVKGRFTISRDNSK 
               
               
                   
                   
                 NTLYLQMNSLRVEDTAVYYCARGGRLATGHFYYVMDVW 
               
               
                   
                   
                 GQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL 
               
               
                   
                   
                 VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS 
               
               
                   
                   
                 SVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCD 
               
               
                   
                   
                 KTHTCPPCPAPE AE G A PSVFLFPPKPKDTLMISRTPEV 
               
               
                   
                   
                 TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYN 
               
               
                   
                   
                 STYRVVSVLTVLHQDWLNGKEYKCKVSNKALP SS IEKT 
               
               
                   
                   
                 ISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFY 
               
               
                   
                   
                 PSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLT 
               
               
                   
                   
                 VDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 
               
               
                   
               
               
                 77 
                 2G6.IgG1 (VL + CL) 
                 DIQMTQSPSSLSASVGDRVTITCRASQGISSWLAWYQQ 
               
               
                   
                   
                 KPEKAPKSLIYAASSLQSGVPSRFSGSGSGTDFTLTIS 
               
               
                   
                   
                 SLQPEDFATYYCQQYNSYPYTFGQGTKLEIKRTVAAPS 
               
               
                   
                   
                 VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDN 
               
               
                   
                   
                 ALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHK 
               
               
                   
                   
                 VYACEVTHQGLSSPVTKSFNRGEC 
               
               
                   
               
               
                 78 
                 2G6 VH CDR1 
                 DYGMH 
               
               
                   
               
               
                 79 
                 2G6 VH CDR2 
                 VIWYDGSNKFYVDSVKG 
               
               
                   
               
               
                 80 
                 2G6 VH CDR3 
                 GGRLATGHFYYVMDV 
               
               
                   
               
               
                 81 
                 2G6 VL CDR1 
                 RASQGISSWLA 
               
               
                   
               
               
                 82 
                 2G6 VL CDR2 
                 AASSLQS 
               
               
                   
               
               
                 83 
                 2G6 VL CDR3 
                 QQYNSYPYT 
               
               
                   
               
               
                 84 
                 8A6 (VH) 
                 QVQLVESGGGVVQPGRSLRLSCTASGFTFSSYGMQWVR 
               
               
                   
                   
                 QAPGKGLEWVAVIWYEGSNKYYADSVKGRFTISRENSK 
               
               
                   
                   
                 NTLYLQMNSLRAEDTAVYYCARGGLMVRGLFYYGMDVW 
               
               
                   
                   
                 GQGTTVTVSS 
               
               
                   
               
               
                 85 
                 8A6 (VL) 
                 AIQLTQSPSSLSASVGDRVTITCRASQGISSALAWYQQ 
               
               
                   
                   
                 KPGKAPKFLIYDASSLESGVPSRFSGSGSGTDFTLTIS 
               
               
                   
                   
                 SLQPEDFATYYCQQFNSYPYTFGQGTKLEIK 
               
               
                   
               
               
                 86 
                 8A6 (full length wild-type 
                 QVQLVESGGGVVQPGRSLRLSCTASGFTFSSYGMQWVR 
               
               
                   
                 heavy chain) 
                 QAPGKGLEWVAVIWYEGSNKYYADSVKGRFTISRENSK 
               
               
                   
                   
                 NTLYLQMNSLRAEDTAVYYCARGGLMVRGLFYYGMDVW 
               
               
                   
                 The constant region is 
                 GQGTTVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCL   
               
               
                   
                 underlined 
                 
                   VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS 
                 
               
               
                   
                   
                 
                   SVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCV 
                 
               
               
                   
                   
                 
                   ECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVV 
                 
               
               
                   
                   
                 
                   VDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFR 
                 
               
               
                   
                   
                 
                   VVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKI 
                 
               
               
                   
                   
                 
                   KGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDI 
                 
               
               
                   
                   
                 
                   AVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKS 
                 
               
               
                   
                   
                 
                   RWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 
                 
               
               
                   
               
               
                 87 
                 8A6 (full length wild-type 
                 AIQLTQSPSSLSASVGDRVTITCRASQGISSALAWYQQ 
               
               
                   
                 light chain) 
                 KPGKAPKFLIYDASSLESGVPSRFSGSGSGTDFTLTIS 
               
               
                   
                   
                 SLQPEDFATYYCQQFNSYPYTFGQGTKLEIK RTVAAPS   
               
               
                   
                 The constant region is 
                 
                   VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDN 
                 
               
               
                   
                 underlined 
                 
                   ALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHK 
                 
               
               
                   
                   
                 
                   VYACEVTHQGLSSPVTKSFNRGEC 
                 
               
               
                   
               
               
                 88 
                 8A6.IgG1 (VH + IgG1) 
                 QVQLVESGGGVVQPGRSLRLSCTASGFTFSSYGMQWVR 
               
               
                   
                   
                 QAPGKGLEWVAVIWYEGSNKYYADSVKGRFTISRENSK 
               
               
                   
                   
                 NTLYLQMNSLRAEDTAVYYCARGGLMVRGLFYYGMDVW 
               
               
                   
                   
                 GQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL 
               
               
                   
                   
                 VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS 
               
               
                   
                   
                 SVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCD 
               
               
                   
                   
                 KTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEV 
               
               
                   
                   
                 TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYN 
               
               
                   
                   
                 STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT 
               
               
                   
                   
                 ISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFY 
               
               
                   
                   
                 PSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLT 
               
               
                   
                   
                 VDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 
               
               
                   
               
               
                 89 
                 8A6.IgG1.1 (VH + IgG1.1) 
                 QVQLVESGGGVVQPGRSLRLSCTASGFTFSSYGMQWVR 
               
               
                   
                   
                 QAPGKGLEWVAVIWYEGSNKYYADSVKGRFTISRENSK 
               
               
                   
                   
                 NTLYLQMNSLRAEDTAVYYCARGGLMVRGLFYYGMDVW 
               
               
                   
                   
                 GQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL 
               
               
                   
                   
                 VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS 
               
               
                   
                   
                 SVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCD 
               
               
                   
                   
                 KTHTCPPCPAPE AE G A PSVFLFPPKPKDTLMISRTPEV 
               
               
                   
                   
                 TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYN 
               
               
                   
                   
                 STYRVVSVLTVLHQDWLNGKEYKCKVSNKALP SS IEKT 
               
               
                   
                   
                 ISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFY 
               
               
                   
                   
                 PSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLT 
               
               
                   
                   
                 VDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 
               
               
                   
               
               
                 90 
                 8A6.IgG1 (VL + CL) 
                 AIQLTQSPSSLSASVGDRVTITCRASQGISSALAWYQQ 
               
               
                   
                   
                 KPGKAPKFLIYDASSLESGVPSRFSGSGSGTDFTLTIS 
               
               
                   
                   
                 SLQPEDFATYYCQQFNSYPYTFGQGTKLEIKRTVAAPS 
               
               
                   
                   
                 VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDN 
               
               
                   
                   
                 ALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHK 
               
               
                   
                   
                 VYACEVTHQGLSSPVTKSFNRGEC 
               
               
                   
               
               
                 91 
                 8A6 VH CDR1 
                 SYGMQ 
               
               
                   
               
               
                 92 
                 8A6 VH CDR2 
                 VIWYEGSNKYYADSVKG 
               
               
                   
               
               
                 93 
                 8A6 VH CDR3 
                 GGLMVRGLFYYGMDV 
               
               
                   
               
               
                 94 
                 8A6 VL CDR1 
                 RASQGISSALA 
               
               
                   
               
               
                 95 
                 8A6 VL CDR2 
                 DASSLES 
               
               
                   
               
               
                 96 
                 8A6 VL CDR3 
                 QQFNSYPYT 
               
               
                   
               
               
                 97 
                 9G7 (VH) 
                 EVQLVESGGGLVKPGGSLRLSCAASGFTFSTVWMSWVR 
               
               
                   
                   
                 QAPGKGLEWVGRIKSKTDGGTTDYAAPVKGRFTISRDD 
               
               
                   
                   
                 SKNTLYLQMNSLHTEDTAVYYCTTGQLIPYSYYYGMDV 
               
               
                   
                   
                 WGQGTSVTVSS 
               
               
                   
               
               
                 98 
                 9G7 (VL1) 
                 EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQ 
               
               
                   
                   
                 QKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTI 
               
               
                   
                   
                 SRLEPEDFAVYYCQQYGSSPWTFGQGTKVEIK 
               
               
                   
               
               
                 99 
                 9G7 (VL2) 
                 EIVLTQSPGTLSLSPGERATLSCRASQSVTSSYLAWYQ 
               
               
                   
                   
                 QKPGQAPRLLIYGASSRATGIPERFSGSGSGTDFTLTI 
               
               
                   
                   
                 SRLEPEDFAVYYCQQYGSSPITFGQGTRLEIK 
               
               
                   
               
               
                 100 
                 9G7 (full length wild-type 
                 EVQLVESGGGLVKPGGSLRLSCAASGFTFSTVWMSWVR 
               
               
                   
                 heavy chain) 
                 QAPGKGLEWVGRIKSKTDGGTTDYAAPVKGRFTISRDD 
               
               
                   
                 The constant region is 
                 SKNTLYLQMNSLHTEDTAVYYCTTGQLIPYSYYYGMDV 
               
               
                   
                 underlined 
                 WGQGTSVTVSS ASTKGPSVFPLAPCSRSTSESTAALGC   
               
               
                   
                   
                 
                   LVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSL 
                 
               
               
                   
                   
                 
                   SSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYG 
                 
               
               
                   
                   
                 
                   PPCPSCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTC 
                 
               
               
                   
                   
                 
                   VVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNST 
                 
               
               
                   
                   
                 
                   YRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTIS 
                 
               
               
                   
                   
                 
                   KAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPS 
                 
               
               
                   
                   
                 
                   DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVD 
                 
               
               
                   
                   
                 
                   KSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK 
                 
               
               
                   
               
               
                 101 
                 9G7 L2 (full length wild- 
                 EIVLTQSPGTLSLSPGERATLSCRASQSVTSSYLAWYQ 
               
               
                   
                 type light chain 2) 
                 QKPGQAPRLLIYGASSRATGIPERFSGSGSGTDFTLTI 
               
               
                   
                 The constant region is 
                 SRLEPEDFAVYYCQQYGSSPITFGQGTRLEIK RTVAAP   
               
               
                   
                 underlined 
                 
                   SVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVD 
                 
               
               
                   
                   
                 
                   NALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKH 
                 
               
               
                   
                   
                 
                   KVYACEVTHQGLSSPVTKSFNRGEC 
                 
               
               
                   
               
               
                 102 
                 9G7.IgG1 (VH + IgG1) 
                 EVQLVESGGGLVKPGGSLRLSCAASGFTFSTVWMSWVR 
               
               
                   
                   
                 QAPGKGLEWVGRIKSKTDGGTTDYAAPVKGRFTISRDD 
               
               
                   
                   
                 SKNTLYLQMNSLHTEDTAVYYCTTGQLIPYSYYYGMDV 
               
               
                   
                   
                 WGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGC 
               
               
                   
                   
                 LVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSL 
               
               
                   
                   
                 SSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC 
               
               
                   
                   
                 DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPE 
               
               
                   
                   
                 VTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY 
               
               
                   
                   
                 NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK 
               
               
                   
                   
                 IISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGF 
               
               
                   
                   
                 YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKL 
               
               
                   
                   
                 TVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 
               
               
                   
               
               
                 103 
                 9G7.IgG1.1 (VH + IgG1.1) 
                 EVQLVESGGGLVKPGGSLRLSCAASGFTFSTVWMSWVR 
               
               
                   
                   
                 QAPGKGLEWVGRIKSKTDGGTTDYAAPVKGRFTISRDD 
               
               
                   
                   
                 SKNTLYLQMNSLHTEDTAVYYCTTGQLIPYSYYYGMDV 
               
               
                   
                   
                 WGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGC 
               
               
                   
                   
                 LVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSL 
               
               
                   
                   
                 SSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC 
               
               
                   
                   
                 DKTHTCPPCPAPE AE G A PSVFLFPPKPKDTLMISRTPE 
               
               
                   
                   
                 VTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY 
               
               
                   
                   
                 NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALP SS IEK 
               
               
                   
                   
                 IISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGF 
               
               
                   
                   
                 YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKL 
               
               
                   
                   
                 TVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 
               
               
                   
               
               
                 104 
                 9G7.IgG1 (VL1 + CL) 
                 EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQ 
               
               
                   
                   
                 QKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTI 
               
               
                   
                   
                 SRLEPEDFAVYYCQQYGSSPWTFGQGTKVEIKRTVAAP 
               
               
                   
                   
                 SVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVD 
               
               
                   
                   
                 NALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKH 
               
               
                   
                   
                 KVYACEVTHQGLSSPVTKSFNRGEC 
               
               
                   
               
               
                 105 
                 9G7.IgG1.2 (VL2 + CL) 
                 EIVLTQSPGTLSLSPGERATLSCRASQSVTSSYLAWYQ 
               
               
                   
                   
                 QKPGQAPRLLIYGASSRATGIPERFSGSGSGTDFTLTI 
               
               
                   
                   
                 SRLEPEDFAVYYCQQYGSSPITFGQGTRLEIKRTVAAP 
               
               
                   
                   
                 SVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVD 
               
               
                   
                   
                 NALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKH 
               
               
                   
                   
                 KVYACEVTHQGLSSPVTKSFNRGEC 
               
               
                   
               
               
                 106 
                 9G7 VH CDR1 
                 TVWMS 
               
               
                   
               
               
                 107 
                 9G7 VH CDR2 
                 RIKSKTDGGTTDYAAPVKG 
               
               
                   
               
               
                 108 
                 9G7 VH CDR3 
                 GQLIPYSYYYGMDV 
               
               
                   
               
               
                 109 
                 9G7 VL1 CDR1 
                 RASQSVSSSYLA 
               
               
                   
               
               
                 110 
                 9G7 VL1 CDR2 
                 GASSRAT 
               
               
                   
               
               
                 111 
                 9G7 VL1 CDR3 
                 QQYGSSPWT 
               
               
                   
               
               
                 112 
                 9G7 VL2 CDR1 
                 RASQSVTSSYLA 
               
               
                   
               
               
                 113 
                 9G7 VL2 CDR2 
                 GASSRAT 
               
               
                   
               
               
                 114 
                 9G7 VL2 CDR3 
                 QQYGSSPIT 
               
               
                   
               
               
                 115 
                 14E3 (VH) 
                 QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWSWIR 
               
               
                   
                   
                 QPPGKGLEWIGEINHSGNTYYNPSLKSRVTISVDTSKN 
               
               
                   
                   
                 QLSLKLSSVTAADTAVYYCARFGSNDAFDIWGQGTMVT 
               
               
                   
                   
                 VSS 
               
               
                   
               
               
                 116 
                 14E3 (VL) 
                 DIQMTQSPSSLSASVGDRVTITCRASQGISSWLAWYQQ 
               
               
                   
                   
                 KPEKAPKSLIYAASSLQSGVPSRFSGSGSGTDFTLTIS 
               
               
                   
                   
                 SLQPEDFATYYCQQYNSYPPTFGQGTKVEIK 
               
               
                   
               
               
                 117 
                 14E3 (full length wild-type 
                 QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWSWIR 
               
               
                   
                 heavy chain) 
                 QPPGKGLEWIGEINHSGNTYYNPSLKSRVTISVDTSKN 
               
               
                   
                 The constant region is 
                 QLSLKLSSVTAADTAVYYCARFGSNDAFDIWGQGTMVT 
               
               
                   
                 underlined 
                 VSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPE   
               
               
                   
                   
                 
                   PVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPS 
                 
               
               
                   
                   
                 
                   SSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPP 
                 
               
               
                   
                   
                 
                   CPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDV 
                 
               
               
                   
                   
                 
                   SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVS 
                 
               
               
                   
                   
                 
                   VLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQ 
                 
               
               
                   
                   
                 
                   PREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVE 
                 
               
               
                   
                   
                 
                   WESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ 
                 
               
               
                   
                   
                 
                   QGNVFSCSVMHEALHNHYTQKSLSLSPGK 
                 
               
               
                   
               
               
                 118 
                 14E3 (full length wild-type 
                 DIQMTQSPSSLSASVGDRVTITCRASQGISSWLAWYQQ 
               
               
                   
                 light chain) 
                 KPEKAPKSLIYAASSLQSGVPSRFSGSGSGTDFTLTIS 
               
               
                   
                 The constant region is 
                 SLQPEDFATYYCQQYNSYPPTFGQGTKVEIK RTVAAPS   
               
               
                   
                 underlined 
                 
                   VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDN 
                 
               
               
                   
                   
                 
                   ALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHK 
                 
               
               
                   
                   
                 
                   VYACEVTHQGLSSPVTKSFNRGEC 
                 
               
               
                   
               
               
                 119 
                 14E3.IgG1 (VH + IgG1) 
                 QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWSWIR 
               
               
                   
                   
                 QPPGKGLEWIGEINHSGNTYYNPSLKSRVTISVDTSKN 
               
               
                   
                   
                 QLSLKLSSVTAADTAVYYCARFGSNDAFDIWGQGTMVT 
               
               
                   
                   
                 VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPE 
               
               
                   
                   
                 PVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPS 
               
               
                   
                   
                 SSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPP 
               
               
                   
                   
                 CPAPELLGGPSVFLF 
               
               
                   
                   
                 PPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDG 
               
               
                   
                   
                 VE 
               
               
                   
                   
                 VHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC 
               
               
                   
                   
                 KV 
               
               
                   
                   
                 SNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKN 
               
               
                   
                   
                 QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD 
               
               
                   
                   
                 SDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT 
               
               
                   
                   
                 QKSLSLSPG 
               
               
                   
               
               
                 120 
                 14E3.IgG1.1 (VH + IgG1.1) 
                 QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWSWIR 
               
               
                   
                   
                 QPPGKGLEWIGEINHSGNTYYNPSLKSRVTISVDTSKN 
               
               
                   
                   
                 QLSLKLSSVTAADTAVYYCARFGSNDAFDIWGQGTMVT 
               
               
                   
                   
                 VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPE 
               
               
                   
                   
                 PVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPS 
               
               
                   
                   
                 SSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPP 
               
               
                   
                   
                 CPAPE AE G A PSVFLFPPKPKDTLMISRTPEVTCVVVDV 
               
               
                   
                   
                 SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVS 
               
               
                   
                   
                 VLTVLHQDWLNGKEYKCKVSNKALP SS IEKTISKAKGQ 
               
               
                   
                   
                 PREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE 
               
               
                   
                   
                 WESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ 
               
               
                   
                   
                 QGNVFSCSVMHEALHNHYTQKSLSLSPG 
               
               
                   
               
               
                 121 
                 14E3.1gG1 (VL + CL) 
                 DIQMTQSPSSLSASVGDRVTITCRASQGISSWLAWYQQ 
               
               
                   
                   
                 KPEKAPKSLIYAASSLQSGVPSRFSGSGSGTDFTLTIS 
               
               
                   
                   
                 SLQPEDFATYYCQQYNSYPPTFGQGTKVEIKRTVAAPS 
               
               
                   
                   
                 VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDN 
               
               
                   
                   
                 ALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHK 
               
               
                   
                   
                 VYACEVTHQGLSSPVTKSFNRGEC 
               
               
                   
               
               
                 122 
                 14E3 VH CDR1 
                 GYYWS 
               
               
                   
               
               
                 123 
                 14E3 VH CDR2 
                 EINHSGNTYYNPSLKS 
               
               
                   
               
               
                 124 
                 14E3 VH CDR3 
                 FGSNDAFDI 
               
               
                   
               
               
                 125 
                 14E3 VL CDR1 
                 RASQGISSWLA 
               
               
                   
               
               
                 126 
                 14E3 VL CDR2 
                 AASSLQS 
               
               
                   
               
               
                 127 
                 14E3 VL CDR3 
                 QQYNSYPPT 
               
               
                   
               
               
                 128 
                 19H8 (VH) 
                 QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMHWVR 
               
               
                   
                   
                 QAPGKGLEWMAVIWYGGSNKFYADSVKGRFTISRDNSK 
               
               
                   
                   
                 NSLSLQMNSLRAEDTAVYYCARGGAMVRGVYYYGMDVW 
               
               
                   
                   
                 GQGTTVTVSS 
               
               
                   
               
               
                 129 
                 19H8 (VL1) 
                 AIQLTQSPSSLSASVGDRVTITCRASQGISSALAWYQQ 
               
               
                   
                   
                 KPGKAPKFLIYDASSLESGVPSRFSGSGSGTDFTLTIS 
               
               
                   
                   
                 SLQPEDFATYYCQQFNSYPQTFGQGTKVEIK 
               
               
                   
               
               
                 130 
                 19H8 (VL2) 
                 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQ 
               
               
                   
                   
                 KPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTIS 
               
               
                   
                   
                 SLEPEDFAVYYCQQRSNWPLTFGGGTKVEIK 
               
               
                   
               
               
                 131 
                 19H8 (full length wild-type 
                 QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMHWVR 
               
               
                   
                 heavy chain) 
                 QAPGKGLEWMAVIWYGGSNKFYADSVKGRFTISRDNSK 
               
               
                   
                 The constant region is 
                 NSLSLQMNSLRAEDTAVYYCARGGAMVRGVYYYGMDVW 
               
               
                   
                 underlined 
                 GQGTTVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCL   
               
               
                   
                   
                 
                   VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS 
                 
               
               
                   
                   
                 
                   SVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCV 
                 
               
               
                   
                   
                 
                   ECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVV 
                 
               
               
                   
                   
                 
                   VDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFR 
                 
               
               
                   
                   
                 
                   VVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKI 
                 
               
               
                   
                   
                 
                   KGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDI 
                 
               
               
                   
                   
                 
                   AVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKS 
                 
               
               
                   
                   
                 
                   RWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 
                 
               
               
                   
               
               
                 132 
                 19H8 L1 (full length wild- 
                 AIQLTQSPSSLSASVGDRVTITCRASQGISSALAWYQQ 
               
               
                   
                 type light chain 1) 
                 KPGKAPKFLIYDASSLESGVPSRFSGSGSGTDFTLTIS 
               
               
                   
                 The constant region is 
                 SLQPEDFATYYCQQFNSYPQTFGQGTKVEIK RTVAAPS   
               
               
                   
                 underlined 
                 
                   VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDN 
                 
               
               
                   
                   
                 
                   ALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHK 
                 
               
               
                   
                   
                 
                   VYACEVTHQGLSSPVTKSFNRGEC 
                 
               
               
                   
               
               
                 133 
                 19H8 L2 (full length wild- 
                 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQ 
               
               
                   
                 type light chain 2) 
                 KPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTIS 
               
               
                   
                   
                 SLEPEDFAVYYCQQRSNWPLTFGGGTKVEIK RTVAAPS   
               
               
                   
                   
                 
                   VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDN 
                 
               
               
                   
                   
                 
                   ALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHK 
                 
               
               
                   
                   
                 
                   VYACEVTHQGLSSPVTKSFNRGEC 
                 
               
               
                   
               
               
                 134 
                 19H8.IgG1 (VH + IgG1) 
                 QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMHWVR 
               
               
                   
                   
                 QAPGKGLEWMAVIWYGGSNKFYADSVKGRFTISRDNSK 
               
               
                   
                   
                 NSLSLQMNSLRAEDTAVYYCARGGAMVRGVYYYGMDVW 
               
               
                   
                   
                 GQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL 
               
               
                   
                   
                 VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS 
               
               
                   
                   
                 SVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCD 
               
               
                   
                   
                 KTHTCPPCPAPELLGGPSVFLF 
               
               
                   
                   
                 PPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDG 
               
               
                   
                   
                 VE 
               
               
                   
                   
                 VHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC 
               
               
                   
                   
                 KV 
               
               
                   
                   
                 SNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKN 
               
               
                   
                   
                 QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD 
               
               
                   
                   
                 SDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT 
               
               
                   
                   
                 QKSLSLSPG 
               
               
                   
               
               
                 135 
                 19H8.IgG1.1 (VH + IgG1.1) 
                 QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMHWVR 
               
               
                   
                   
                 QAPGKGLEWMAVIWYGGSNKFYADSVKGRFTISRDNSK 
               
               
                   
                   
                 NSLSLQMNSLRAEDTAVYYCARGGAMVRGVYYYGMDVW 
               
               
                   
                   
                 GQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL 
               
               
                   
                   
                 VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS 
               
               
                   
                   
                 SVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCD 
               
               
                   
                   
                 KTHTCPPCPAPE AE G A PSVFLFPPKPKDTLMISRTPEV 
               
               
                   
                   
                 TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYN 
               
               
                   
                   
                 STYRVVSVLTVLHQDWLNGKEYKCKVSNKALP SS IEKT 
               
               
                   
                   
                 ISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFY 
               
               
                   
                   
                 PSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLT 
               
               
                   
                   
                 VDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 
               
               
                   
               
               
                 136 
                 19H8.IgG1 (VL1 + CL) 
                 AIQLTQSPSSLSASVGDRVTITCRASQGISSALAWYQQ 
               
               
                   
                   
                 KPGKAPKFLIYDASSLESGVPSRFSGSGSGTDFTLTIS 
               
               
                   
                   
                 SLQPEDFATYYCQQFNSYPQTFGQGTKVEIKRTVAAPS 
               
               
                   
                   
                 VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDN 
               
               
                   
                   
                 ALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHK 
               
               
                   
                   
                 VYACEVTHQGLSSPVTKSFNRGEC 
               
               
                   
               
               
                 137 
                 19H8.IgG1.2 (VL2 + CL) 
                 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQ 
               
               
                   
                   
                 KPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTIS 
               
               
                   
                   
                 SLEPEDFAVYYCQQRSNWPLTFGGGTKVEIKRTVAAPS 
               
               
                   
                   
                 VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDN 
               
               
                   
                   
                 ALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHK 
               
               
                   
                   
                 VYACEVTHQGLSSPVTKSFNRGEC 
               
               
                   
               
               
                 138 
                 19H8 VH CDR1 
                 NYGMH 
               
               
                   
               
               
                 139 
                 19H8 VH CDR2 
                 VIWYGGSNKFYADSVKG 
               
               
                   
               
               
                 140 
                 19H8 VH CDR3 
                 GGAMVRGVYYYGMDV 
               
               
                   
               
               
                 141 
                 19H8 VL1 CDR1 
                 RASQGISSALA 
               
               
                   
               
               
                 142 
                 19H8 VL1 CDR2 
                 DASSLES 
               
               
                   
               
               
                 143 
                 19H8 VL1 CDR3 
                 QQFNSYPQT 
               
               
                   
               
               
                 144 
                 19H8 VL2 CDR1 
                 RASQSVSSYLA 
               
               
                   
               
               
                 145 
                 19H8 VL2 CDR2 
                 DASNRAT 
               
               
                   
               
               
                 146 
                 19H8 VL2 CDR3 
                 QQRSNWPLT 
               
               
                   
               
               
                 147 
                 28F3 (VH) nucleotide 
                 CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCA 
               
               
                   
                 sequence 
                 GCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGCGTCTG 
               
               
                   
                   
                 GATTCACCTTCAGTAGCTATGGCATGCACTGGGTCCGC 
               
               
                   
                   
                 CAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTAT 
               
               
                   
                   
                 ATGGTATGAAGGAAGTAATAAATATTATGCAGACTCCG 
               
               
                   
                   
                 TGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAG 
               
               
                   
                   
                 AACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGA 
               
               
                   
                   
                 GGACACGGCTGTGTATTACTGTGCGAGAGGGGGGAGTA 
               
               
                   
                   
                 TGGTTCGGGGGGACTACTACTACGGTATGGACGTCTGG 
               
               
                   
                   
                 GGCCAAGGGACCACGGTCACCGTCTCCTCA 
               
               
                   
               
               
                 148 
                 28F3 (VL) nucleotide 
                 GCCATCCAGTTGACCCAGTCTCCATCCTCCCTGTCTGC 
               
               
                   
                 sequence 
                 ATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAA 
               
               
                   
                   
                 GTCAGGGCATTAGCAGTGCTTTAGCCTGGTATCAGCAG 
               
               
                   
                   
                 AAACCAGGGAAAGCTCCTAAGCTCCTGATCTATGATGC 
               
               
                   
                   
                 CTCCAGTTTGGAAAGTGGGGTCCCATCAAGGTTCAGCG 
               
               
                   
                   
                 GCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGC 
               
               
                   
                   
                 AGCCTGCAGCCTGAAGATTTTGCAACTTATTACTGTCA 
               
               
                   
                   
                 ACAGTTTAATAGTTACCCGTACACTTTTGGCCAGGGGA 
               
               
                   
                   
                 CCAAGCTGGAGATCAAA 
               
               
                   
               
               
                 149 
                 28F3 (full length wild-type 
                 CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCA 
               
               
                   
                 heavy chain) nucleotide 
                 GCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGCGTCTG 
               
               
                   
                 sequence 
                 GATTCACCTTCAGTAGCTATGGCATGCACTGGGTCCGC 
               
               
                   
                 The sequence encoding the 
                 CAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTAT 
               
               
                   
                 constant region is underlined 
                 ATGGTATGAAGGAAGTAATAAATATTATGCAGACTCCG 
               
               
                   
                   
                 TGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAG 
               
               
                   
                   
                 AACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGA 
               
               
                   
                   
                 GGACACGGCTGTGTATTACTGTGCGAGAGGGGGGAGTA 
               
               
                   
                   
                 TGGTTCGGGGGGACTACTACTACGGTATGGACGTCTGG 
               
               
                   
                   
                 GGCCAAGGGACCACGGTCACCGTCTCCTCA GCCTCCAC   
               
               
                   
                   
                 
                   CAAGGGCCCATCGGTCTTCCCCCTGGCGCCCTGCTCCA 
                 
               
               
                   
                   
                 
                   GGAGCACCTCCGAGAGCACAGCGGCCCTGGGCTGCCTG 
                 
               
               
                   
                   
                 
                   GTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTG 
                 
               
               
                   
                   
                 
                   GAACTCAGGCGCTCTGACCAGCGGCGTGCACACCTTCC 
                 
               
               
                   
                   
                 
                   CAGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGC 
                 
               
               
                   
                   
                 
                   AGCGTGGTGACCGTGCCCTCCAGCAACTTCGGCACCCA 
                 
               
               
                   
                   
                 
                   GACCTACACCTGCAACGTAGATCACAAGCCCAGCAACA 
                 
               
               
                   
                   
                 
                   CCAAGGTGGACAAGACAGTTGAGCGCAAATGTTGTGTC 
                 
               
               
                   
                   
                 
                   GAGTGCCCACCGTGCCCAGCACCACCTGTGGCAGGACC 
                 
               
               
                   
                   
                 
                   GTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCC 
                 
               
               
                   
                   
                 
                   TCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTG 
                 
               
               
                   
                   
                 
                   GTGGACGTGAGCCACGAAGACCCCGAGGTCCAGTTCAA 
                 
               
               
                   
                   
                 
                   CTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGA 
                 
               
               
                   
                   
                 
                   CAAAGCCACGGGAGGAGCAGTTCAACAGCACGTTCCGT 
                 
               
               
                   
                   
                 
                   GTGGTCAGCGTCCTCACCGTTGTGCACCAGGACTGGCT 
                 
               
               
                   
                   
                 
                   GAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAG 
                 
               
               
                   
                   
                 
                   GCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAACC 
                 
               
               
                   
                   
                 
                   AAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCC 
                 
               
               
                   
                   
                 
                   CCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCC 
                 
               
               
                   
                   
                 
                   TGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATC 
                 
               
               
                   
                   
                 
                   GCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAA 
                 
               
               
                   
                   
                 
                   CTACAAGACCACACCTCCCATGCTGGACTCCGACGGCT 
                 
               
               
                   
                   
                 
                   CCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGC 
                 
               
               
                   
                   
                 
                   AGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGAT 
                 
               
               
                   
                   
                 
                   GCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCC 
                 
               
               
                   
                   
                 
                   TCTCCCTGTCTCCGGGTAAA 
                 
               
               
                   
               
               
                 150 
                 28F3 (full length wild-type 
                 GCCATCCAGTTGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAG 
               
               
                   
                 light chain) nucleotide 
                 GAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGGGCATTAGCAG 
               
               
                   
                 sequence 
                 TGCTTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCTCCTAAGCTC 
               
               
                   
                 The sequence encoding the 
                 CTGATCTATGATGCCTCCAGTTTGGAAAGTGGGGTCCCATCAAGGT 
               
               
                   
                 constant region is underlined 
                 TCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAG 
               
               
                   
                   
                 CCTGCAGCCTGAAGATTTTGCAACTTATTACTGTCAACAGTTTAAT 
               
               
                   
                   
                 AGTTACCCGTACACTTTTGGCCAGGGGACCAAGCTGGAGATCAAA C   
               
               
                   
                   
                 
                   GAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGA 
                 
               
               
                   
                   
                 
                   GCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAAC 
                 
               
               
                   
                   
                 
                   TTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCC 
                 
               
               
                   
                   
                 
                   TCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAA 
                 
               
               
                   
                   
                 
                   GGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCA 
                 
               
               
                   
                   
                 
                   GACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGG 
                 
               
               
                   
                   
                 
                   GCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT 
                 
               
               
                   
               
               
                 151 
                 28F3.IgG1 (VH + IgG1) 
                 caggtgcagc tggtggagtc tgggggaggc gtggtccagc 
               
               
                   
                 nucleotide sequence 
                 ctgggaggtc cctgagactc tcctgtgcag cgtctggatt 
               
               
                   
                   
                 caccttcagt agctatggca tgcactgggt ccgccaggct 
               
               
                   
                   
                 ccaggcaagg ggctggagtg ggtggcagtt atatggtatg 
               
               
                   
                   
                 aaggaagtaa taaatattat gcagactccg tgaagggccg 
               
               
                   
                   
                 attcaccatc tccagagaca attccaagaa cacgctgtat 
               
               
                   
                   
                 ctgcaaatga acagcctgag agccgaggac acggctgtgt 
               
               
                   
                   
                 attactgtgc gagagggggg agtatggttc ggggggacta 
               
               
                   
                   
                 ctactacggt atggacgtct ggggccaagg gaccacggtc 
               
               
                   
                   
                 accgtctcct cagctagcac caagggccca tcggtcttcc 
               
               
                   
                   
                 ccctggcacc ctcctccaag agcacctctg ggggcacagc 
               
               
                   
                   
                 ggccctgggc tgcctggtca aggactactt ccccgaaccg 
               
               
                   
                   
                 gtgacggtgt cgtggaactc aggcgccctg accagcggcg 
               
               
                   
                   
                 tgcacacctt cccggctgtc ctacagtcct caggactcta 
               
               
                   
                   
                 ctccctcagc agcgtggtga ccgtgccctc cagcagcttg 
               
               
                   
                   
                 ggcacccaga cctacatctg caacgtgaat cacaagccca 
               
               
                   
                   
                 gcaacaccaa ggtggacaag agagttgagc ccaaatcttg 
               
               
                   
                   
                 tgacaaaact cacacatgcc caccgtgccc agcacctgaa 
               
               
                   
                   
                 ctcctggggg gaccgtcagt cttcctcttc cccccaaaac 
               
               
                   
                   
                 ccaaggacac cctcatgatc tcccggaccc ctgaggtcac 
               
               
                   
                   
                 atgcgtggtg gtggacgtga gccacgaaga ccctgaggtc 
               
               
                   
                   
                 aagttcaact ggtacgtgga cggcgtggag gtgcataatg 
               
               
                   
                   
                 ccaagacaaa gccgcgggag gagcagtaca acagcacgta 
               
               
                   
                   
                 ccgtgtggtc agcgtcctca ccgtcctgca ccaggactgg 
               
               
                   
                   
                 ctgaatggca aggagtacaa gtgcaaggtc tccaacaaag 
               
               
                   
                   
                 ccctcccagc ccccatcgag aaaaccatct ccaaagccaa 
               
               
                   
                   
                 agggcagccc cgagaaccac aggtgtacac cctgccccca 
               
               
                   
                   
                 tcccgggagg agatgaccaa gaaccaggtc agcctgacct 
               
               
                   
                   
                 gcctggtcaa aggcttctat cccagcgaca tcgccgtgga 
               
               
                   
                   
                 gtgggagagc aatgggcagc cggagaacaa ctacaagacc 
               
               
                   
                   
                 acgcctcccg tgctggactc cgacggctcc ttcttcctct 
               
               
                   
                   
                 atagcaagct caccgtggac aagagcaggt ggcagcaggg 
               
               
                   
                   
                 gaacgtcttc tcatgctccg tgatgcatga ggctctgcac 
               
               
                   
                   
                 aaccactaca cgcagaagag cctctccctg 
               
               
                   
                   
                 tccccgggtt ga 
               
               
                   
               
               
                 152 
                 28F3.IgG1.1 (VH + IgG1.1) 
                 caggtgcagc tggtggagtc tgggggaggc gtggtccagc 
               
               
                   
                 nucleotide sequence 
                 ctgggaggtc cctgagactc tcctgtgcag cgtctggatt 
               
               
                   
                   
                 caccttcagt agctatggca tgcactgggt ccgccaggct 
               
               
                   
                   
                 ccaggcaagg ggctggagtg ggtggcagtt atatggtatg 
               
               
                   
                   
                 aaggaagtaa taaatattat gcagactccg tgaagggccg 
               
               
                   
                   
                 attcaccatc tccagagaca attccaagaa cacgctgtat 
               
               
                   
                   
                 ctgcaaatga acagcctgag agccgaggac acggctgtgt 
               
               
                   
                   
                 attactgtgc gagagggggg agtatggttc ggggggacta 
               
               
                   
                   
                 ctactacggt atggacgtct ggggccaagg gaccacggtc 
               
               
                   
                   
                 accgtctcct cagctagcac caagggccca tcggtcttcc 
               
               
                   
                   
                 ccctggcacc ctcctccaag agcacctctg ggggcacagc 
               
               
                   
                   
                 ggccctgggc tgcctggtca aggactactt ccccgaaccg 
               
               
                   
                   
                 gtgacggtgt cgtggaactc aggcgccctg accagcggcg 
               
               
                   
                   
                 tgcacacctt cccggctgtc ctacagtcct caggactcta 
               
               
                   
                   
                 ctccctcagc agcgtggtga ccgtgccctc cagcagcttg 
               
               
                   
                   
                 ggcacccaga cctacatctg caacgtgaat cacaagccca 
               
               
                   
                   
                 gcaacaccaa ggtggacaag agagttgagc ccaaatcttg 
               
               
                   
                   
                 tgacaaaact cacacatgcc caccgtgccc agcacctgaa 
               
               
                   
                   
                 gccgaagggg ccccgtcagt cttcctcttc cccccaaaac 
               
               
                   
                   
                 ccaaggacac cctcatgatc tcccggaccc ctgaggtcac 
               
               
                   
                   
                 atgcgtggtg gtggacgtga gccacgaaga ccctgaggtc 
               
               
                   
                   
                 aagttcaact ggtacgtgga cggcgtggag gtgcataatg 
               
               
                   
                   
                 ccaagacaaa gccgcgggag gagcagtaca acagcacgta 
               
               
                   
                   
                 ccgtgtggtc agcgtcctca ccgtcctgca ccaggactgg 
               
               
                   
                   
                 ctgaatggca aggagtacaa gtgcaaggtc tccaacaaag 
               
               
                   
                   
                 ccctcccaag cagcatcgag aaaaccatct ccaaagccaa 
               
               
                   
                   
                 agggcagccc cgagaaccac aggtgtacac cctgccccca 
               
               
                   
                   
                 tcccgggagg agatgaccaa gaaccaggtc agcctgacct 
               
               
                   
                   
                 gcctggtcaa aggcttctat cccagcgaca tcgccgtgga 
               
               
                   
                   
                 gtgggagagc aatgggcagc cggagaacaa ctacaagacc 
               
               
                   
                   
                 acgcctcccg tgctggactc cgacggctcc ttcttcctct 
               
               
                   
                   
                 atagcaagct caccgtggac aagagcaggt ggcagcaggg 
               
               
                   
                   
                 gaacgtcttc tcatgctccg tgatgcatga ggctctgcac 
               
               
                   
                   
                 aaccactaca cgcagaagag cctctccctg 
               
               
                   
                   
                 tccccgggtt ga 
               
               
                   
               
               
                 153 
                 28F3.IgG1 (VL + CL) 
                 gccatccagt tgacccagtc tccatcctcc ctgtctgcat 
               
               
                   
                 nucleotide sequence 
                 ctgtaggaga cagagtcacc atcacttgcc gggcaagtca 
               
               
                   
                   
                 gggcattagc agtgctttag cctggtatca gcagaaacca 
               
               
                   
                   
                 gggaaagctc ctaagctcct gatctatgat gcctccagtt 
               
               
                   
                   
                 tggaaagtgg ggtcccatca aggttcagcg gcagtggatc 
               
               
                   
                   
                 tgggacagat ttcactctca ccatcagcag cctgcagcct 
               
               
                   
                   
                 gaagattttg caacttatta ctgtcaacag tttaatagtt 
               
               
                   
                   
                 acccgtacac ttttggccag gggaccaagc tggagatcaa 
               
               
                   
                   
                 acgtacggtg gctgcaccat ctgtcttcat cttcccgcca 
               
               
                   
                   
                 tctgatgagc agttgaaatc tggaactgcc tctgttgtgt 
               
               
                   
                   
                 gcctgctgaa taacttctat cccagagagg ccaaagtaca 
               
               
                   
                   
                 gtggaaggtg gataacgccc tccaatcggg taactcccag 
               
               
                   
                   
                 gagagtgtca cagagcagga cagcaaggac agcacctaca 
               
               
                   
                   
                 gcctcagcag caccctgacg ctgagcaaag cagactacga 
               
               
                   
                   
                 gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 
               
               
                   
                   
                 ctgagctcgc ccgtcacaaa gagcttcaac 
               
               
                   
                   
                 aggggagagt gttag 
               
               
                   
               
               
                 154 
                 19D3 (VH) nucleotide 
                 CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCA 
               
               
                   
                 sequence 
                 ACCTGGGAGGTCCCTGAGACTCTCCTGTGCAGCGTCTG 
               
               
                   
                   
                 GATTCACCTTCAGTAGCTATGGCTTCCACTGGGTCCGC 
               
               
                   
                   
                 CAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTAT 
               
               
                   
                   
                 ATGGTATGCTGGAAGTAATAAATTCTATGCAGACTCCG 
               
               
                   
                   
                 TGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAG 
               
               
                   
                   
                 AACACGCTGTATCTGCAAATGAACAGCCTAAGAGCCGA 
               
               
                   
                   
                 GGACACGGCTGTGTATTACTGTGCGAGAGGGGGACAGT 
               
               
                   
                   
                 TGGACTACTACTACTATTACGTTATGGACGTCTGGGGC 
               
               
                   
                   
                 CAAGGGACCACGGTCACCGTCTCCTCA 
               
               
                   
               
               
                 155 
                 19D3 (VL) nucleotide 
                 GACATCCAGATGACCCAGTCTCCATCCTCACTGTCTGC 
               
               
                   
                 sequence 
                 ATCTGTAGGAGACAGAGTCACCATCACTTGTCGGGCGA 
               
               
                   
                   
                 GTCAGGGTATTAGCAGCTGGTTAGCCTGGTATCAGCAG 
               
               
                   
                   
                 AAACCAGAGAAAGCCCCTAAGTCCCTGATCTATGCTGC 
               
               
                   
                   
                 ATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGCG 
               
               
                   
                   
                 GCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGC 
               
               
                   
                   
                 AGCCTGCAGCCTGAAGATTTTGCAACTTATTACTGCCA 
               
               
                   
                   
                 ACAGTATAATAGTTACCCGTACACTTTTGGCCAGGGGA 
               
               
                   
                   
                 CCAAGCTGGAGATCAAA 
               
               
                   
               
               
                 156 
                 19D3 (full length wild-type 
                 CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCA 
               
               
                   
                 heavy chain) nucleotide 
                 ACCTGGGAGGTCCCTGAGACTCTCCTGTGCAGCGTCTG 
               
               
                   
                 sequence 
                 GATTCACCTTCAGTAGCTATGGCTTCCACTGGGTCCGC 
               
               
                   
                 The sequence encoding the 
                 CAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTAT 
               
               
                   
                 constant region is underlined 
                 ATGGTATGCTGGAAGTAATAAATTCTATGCAGACTCCG 
               
               
                   
                   
                 TGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAG 
               
               
                   
                   
                 AACACGCTGTATCTGCAAATGAACAGCCTAAGAGCCGA 
               
               
                   
                   
                 GGACACGGCTGTGTATTACTGTGCGAGAGGGGGACAGT 
               
               
                   
                   
                 TGGACTACTACTACTATTACGTTATGGACGTCTGGGGC 
               
               
                   
                   
                 CAAGGGACCACGGTCACCGTCTCCTCA GCCTCCACCAA   
               
               
                   
                   
                 
                   GGGCCCATCGGTCTTCCCCCTGGCGCCCTGCTCCAGGA 
                 
               
               
                   
                   
                 
                   GCACCTCCGAGAGCACAGCGGCCCTGGGCTGCCTGGTC 
                 
               
               
                   
                   
                 
                   AAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAA 
                 
               
               
                   
                   
                 
                   CTCAGGCGCTCTGACCAGCGGCGTGCACACCTTCCCAG 
                 
               
               
                   
                   
                 
                   CTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGC 
                 
               
               
                   
                   
                 
                   GTGGTGACCGTGCCCTCCAGCAACTTCGGCACCCAGAC 
                 
               
               
                   
                   
                 
                   CTACACCTGCAACGTAGATCACAAGCCCAGCAACACCA 
                 
               
               
                   
                   
                 
                   AGGTGGACAAGACAGTTGAGCGCAAATGTTGTGTCGAG 
                 
               
               
                   
                   
                 
                   TGCCCACCGTGCCCAGCACCACCTGTGGCAGGACCGTC 
                 
               
               
                   
                   
                 
                   AGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCA 
                 
               
               
                   
                   
                 
                   TGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTG 
                 
               
               
                   
                   
                 
                   GACGTGAGCCACGAAGACCCCGAGGTCCAGTTCAACTG 
                 
               
               
                   
                   
                 
                   GTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAA 
                 
               
               
                   
                   
                 
                   AGCCACGGGAGGAGCAGTTCAACAGCACGTTCCGTGTG 
                 
               
               
                   
                   
                 
                   GTCAGCGTCCTCACCGTTGTGCACCAGGACTGGCTGAA 
                 
               
               
                   
                   
                 
                   CGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCC 
                 
               
               
                   
                   
                 
                   TCCCAGCCCCCATCGAGAAAACCATCTCCAAAACCAAA 
                 
               
               
                   
                   
                 
                   GGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCC 
                 
               
               
                   
                   
                 
                   ATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGA 
                 
               
               
                   
                   
                 
                   CCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCC 
                 
               
               
                   
                   
                 
                   GTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTA 
                 
               
               
                   
                   
                 
                   CAAGACCACACCTCCCATGCTGGACTCCGACGGCTCCT 
                 
               
               
                   
                   
                 
                   TCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGG 
                 
               
               
                   
                   
                 
                   TGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCA 
                 
               
               
                   
                   
                 
                   TGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCT 
                 
               
               
                   
                   
                 
                   CCCTGTCTCCGGGTAAA 
                 
               
               
                   
               
               
                 157 
                 19D3 (full length wild-type 
                 GACATCCAGATGACCCAGTCTCCATCCTCACTGTCTGC 
               
               
                   
                 light chain) nucleotide 
                 ATCTGTAGGAGACAGAGTCACCATCACTTGTCGGGCGA 
               
               
                   
                 sequence 
                 GTCAGGGTATTAGCAGCTGGTTAGCCTGGTATCAGCAG 
               
               
                   
                 The sequence encoding the 
                 AAACCAGAGAAAGCCCCTAAGTCCCTGATCTATGCTGC 
               
               
                   
                 constant region is underlined 
                 ATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGCG 
               
               
                   
                   
                 GCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGC 
               
               
                   
                   
                 AGCCTGCAGCCTGAAGATTTTGCAACTTATTACTGCCA 
               
               
                   
                   
                 ACAGTATAATAGTTACCCGTACACTTTTGGCCAGGGGA 
               
               
                   
                   
                 CCAAGCTGGAGATCAAA CGAACTGTGGCTGCACCATCT   
               
               
                   
                   
                 
                   GTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATC 
                 
               
               
                   
                   
                 
                   TGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCT 
                 
               
               
                   
                   
                 
                   ATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAAC 
                 
               
               
                   
                   
                 
                   GCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGA 
                 
               
               
                   
                   
                 
                   GCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCA 
                 
               
               
                   
                   
                 
                   CCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAA 
                 
               
               
                   
                   
                 
                   GTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTC 
                 
               
               
                   
                   
                 
                   GCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT 
                 
               
               
                   
               
               
                 158 
                 18E10 (VH) nucleotide 
                 CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCA 
               
               
                   
                 sequence 
                 GCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGCGTCTG 
               
               
                   
                   
                 GATTCACCTTCAGTAGCTATGGCATGCACTGGGTCCGC 
               
               
                   
                   
                 CAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTAT 
               
               
                   
                   
                 ATGGTATGCTGGAAGTAATAAATACTATGCAGACTCCG 
               
               
                   
                   
                 TGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAG 
               
               
                   
                   
                 AACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGA 
               
               
                   
                   
                 GGACACGGCTGTGTATTACTGTGCGAGAGGGGGGCGTA 
               
               
                   
                   
                 TAGCAGTGGCCTTCTACTACAGTATGGACGTCTGGGGC 
               
               
                   
                   
                 CAAGGGACCACGGTCACCGTCTCCTCA 
               
               
                   
               
               
                 159 
                 18E10 (VL) nucleotide 
                 GACATCCAGATGACCCAGTCTCCATCCTCACTGTCTGC 
               
               
                   
                 sequence 
                 ATCTGTAGGAGACAGAGTCACCATCACTTGTCGGGCGA 
               
               
                   
                   
                 GTCAGGGTATTAGCAGCTGGTTAGCCTGGTATCAGCAG 
               
               
                   
                   
                 AAACCAGAGAAAGCCCCTAAGTCCCTGATCTATGCTGC 
               
               
                   
                   
                 ATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGCG 
               
               
                   
                   
                 GCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGC 
               
               
                   
                   
                 AGCCTGCAGCCTGAAGATTTTGCAACTTATTACTGCCA 
               
               
                   
                   
                 ACAGTATAATAGTTACCCGTACACTTTTGGCCAGGGGA 
               
               
                   
                   
                 CCAAGCTGGAGATCAAA 
               
               
                   
               
               
                 160 
                 18E10 (full length wild-type 
                 CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCA 
               
               
                   
                 heavy chain) nucleotide 
                 GCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGCGTCTG 
               
               
                   
                 sequence 
                 GATTCACCTTCAGTAGCTATGGCATGCACTGGGTCCGC 
               
               
                   
                   
                 CAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTAT 
               
               
                   
                   
                 ATGGTATGCTGGAAGTAATAAATACTATGCAGACTCCG 
               
               
                   
                   
                 TGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAG 
               
               
                   
                   
                 AACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGA 
               
               
                   
                   
                 GGACACGGCTGTGTATTACTGTGCGAGAGGGGGGCGTA 
               
               
                   
                   
                 TAGCAGTGGCCTTCTACTACAGTATGGACGTCTGGGGC 
               
               
                   
                   
                 CAAGGGACCACGGTCACCGTCTCCTCA GCCTCCACCAA   
               
               
                   
                   
                 
                   GGGCCCATCGGTCTTCCCCCTGGCGCCCTGCTCCAGGA 
                 
               
               
                   
                   
                 
                   GCACCTCCGAGAGCACAGCGGCCCTGGGCTGCCTGGTC 
                 
               
               
                   
                   
                 
                   AAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAA 
                 
               
               
                   
                   
                 
                   CTCAGGCGCTCTGACCAGCGGCGTGCACACCTTCCCAG 
                 
               
               
                   
                   
                 
                   CTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGC 
                 
               
               
                   
                   
                 
                   GTGGTGACCGTGCCCTCCAGCAACTTCGGCACCCAGAC 
                 
               
               
                   
                   
                 
                   CTACACCTGCAACGTAGATCACAAGCCCAGCAACACCA 
                 
               
               
                   
                   
                 
                   AGGTGGACAAGACAGTTGAGCGCAAATGTTGTGTCGAG 
                 
               
               
                   
                   
                 
                   TGCCCACCGTGCCCAGCACCACCTGTGGCAGGACCGTC 
                 
               
               
                   
                   
                 
                   AGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCA 
                 
               
               
                   
                   
                 
                   TGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTG 
                 
               
               
                   
                   
                 
                   GACGTGAGCCACGAAGACCCCGAGGTCCAGTTCAACTG 
                 
               
               
                   
                   
                 
                   GTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAA 
                 
               
               
                   
                   
                 
                   AGCCACGGGAGGAGCAGTTCAACAGCACGTTCCGTGTG 
                 
               
               
                   
                   
                 
                   GTCAGCGTCCTCACCGTTGTGCACCAGGACTGGCTGAA 
                 
               
               
                   
                   
                 
                   CGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCC 
                 
               
               
                   
                   
                 
                   TCCCAGCCCCCATCGAGAAAACCATCTCCAAAACCAAA 
                 
               
               
                   
                   
                 
                   GGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCC 
                 
               
               
                   
                   
                 
                   ATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGA 
                 
               
               
                   
                   
                 
                   CCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCC 
                 
               
               
                   
                   
                 
                   GTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTA 
                 
               
               
                   
                   
                 
                   CAAGACCACACCTCCCATGCTGGACTCCGACGGCTCCT 
                 
               
               
                   
                   
                 
                   TCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGG 
                 
               
               
                   
                   
                 
                   TGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCA 
                 
               
               
                   
                   
                 
                   TGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCT 
                 
               
               
                   
                   
                 
                   CCCTGTCTCCGGGTAAA 
                 
               
               
                   
               
               
                 161 
                 18E10 (full length wild-type 
                 GACATCCAGATGACCCAGTCTCCATCCTCACTGTCTGC 
               
               
                   
                 light chain) nucleotide 
                 ATCTGTAGGAGACAGAGTCACCATCACTTGTCGGGCGA 
               
               
                   
                 sequence 
                 GTCAGGGTATTAGCAGCTGGTTAGCCTGGTATCAGCAG 
               
               
                   
                   
                 AAACCAGAGAAAGCCCCTAAGTCCCTGATCTATGCTGC 
               
               
                   
                   
                 ATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGCG 
               
               
                   
                   
                 GCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGC 
               
               
                   
                   
                 AGCCTGCAGCCTGAAGATTTTGCAACTTATTACTGCCA 
               
               
                   
                   
                 ACAGTATAATAGTTACCCGTACACTTTTGGCCAGGGGA 
               
               
                   
                   
                 CCAAGCTGGAGATCAAA CGAACTGTGGCTGCACCATCT   
               
               
                   
                   
                 
                   GTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATC 
                 
               
               
                   
                   
                 
                   TGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCT 
                 
               
               
                   
                   
                 
                   ATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAAC 
                 
               
               
                   
                   
                 
                   GCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGA 
                 
               
               
                   
                   
                 
                   GCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCA 
                 
               
               
                   
                   
                 
                   CCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAA 
                 
               
               
                   
                   
                 
                   GTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTC 
                 
               
               
                   
                   
                 
                   GCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT 
                 
               
               
                   
               
               
                 162 
                 3C3 (VH) nucleotide 
                 CAGGTGCAACTACAGCAGTGGGGCGCAGGACTGTTGAA 
               
               
                   
                 sequence 
                 GCCTTCGGAGACCCTGTCCCTCACCTGCGCTGTCTATG 
               
               
                   
                   
                 GTGGGTCCTTCAGTGGTTACTACTGGACCTGGATCCGC 
               
               
                   
                   
                 CAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGGAAAAT 
               
               
                   
                   
                 CAATCATAGTGGAAACACCAACTACAACCCGTCCCTCA 
               
               
                   
                   
                 AGAGTCGAGTCACCATATCAGTAGACACGTCCAAGAAC 
               
               
                   
                   
                 CAGTTCTCCCTGAAGCTGAGCTCTGTGACCGCCGCGGA 
               
               
                   
                   
                 CACGGCTGTGTATTACTGTGCGAGACTGGGGGCCTTTG 
               
               
                   
                   
                 ATGCTTTTGATATCTGGGGCCAAGGGACAATGGTCACC 
               
               
                   
                   
                 GTCTCTTCA 
               
               
                   
               
               
                 163 
                 3C3 (VL1) nucleotide 
                 GACATCCAGATGACCCAGTCTCCATCCTCACTGTCTGC 
               
               
                   
                 sequence 
                 ATCTGTAGGAGACAGAGTCACCATCACTTGTCGGGCGA 
               
               
                   
                   
                 GTCAGGGTATTAGCAGCTGGTTAGCCTGGTATCAGCAG 
               
               
                   
                   
                 AAACCAGAGAAAGCCCCTAAGTCCCTGATCTATGCTGC 
               
               
                   
                   
                 ATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGCG 
               
               
                   
                   
                 GCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGC 
               
               
                   
                   
                 AGCCTGCAGCCTGAAGATTTTGCAACTTATTACTGCCA 
               
               
                   
                   
                 ACAGTATAATAGTTACCCGTACACTTTTGGCCAGGGGA 
               
               
                   
                   
                 CCAAGCTGGAGATCAAA 
               
               
                   
               
               
                 164 
                 3C3 (VL2) nucleotide 
                 GAAATTGTGTTGACACAGTCTCCAGCCACCCTGTCTTT 
               
               
                   
                 sequence 
                 GTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCA 
               
               
                   
                   
                 GTCAGGGTGTTAGCAGCTACTTAGCCTGGTACCAGCAG 
               
               
                   
                   
                 AAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGATGC 
               
               
                   
                   
                 ATCCAACAGGGCCACTGGCATCCCAGCCAGGTTCAGTG 
               
               
                   
                   
                 GCAGTGGGCCTGGGACAGACTTCACTCTCACCATCAGC 
               
               
                   
                   
                 AGCCTAGAGCCTGAAGATTTTGCAGTTTATTACTGTCA 
               
               
                   
                   
                 GCAGCGTAGCAACTGGCACACTTTTGGCCAGGGGACCA 
               
               
                   
                   
                 AGCTGGAGATCAAA 
               
               
                   
               
               
                 165 
                 3C3 (full length wild-type 
                 CAGGTGCAACTACAGCAGTGGGGCGCAGGACTGTTGAA 
               
               
                   
                 heavy chain) nucleotide 
                 GCCTTCGGAGACCCTGTCCCTCACCTGCGCTGTCTATG 
               
               
                   
                 sequence 
                 GTGGGTCCTTCAGTGGTTACTACTGGACCTGGATCCGC 
               
               
                   
                 The sequence encoding the 
                 CAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGGAAAAT 
               
               
                   
                 constant region is underlined 
                 CAATcATAGTGGAAAcAccAAcTACAACCCGTCCCTCA 
               
               
                   
                   
                 AGAGTCGAGTCACCATATCAGTAGACACGTCCAAGAAC 
               
               
                   
                   
                 CAGTTCTCCCTGAAGCTGAGCTCTGTGACCGCCGCGGA 
               
               
                   
                   
                 CACGGCTGTGTATTACTGTGCGAGACTGGGGGCCTTTG 
               
               
                   
                   
                 ATGCTTTTGATATCTGGGGCCAAGGGACAATGGTCACC 
               
               
                   
                   
                 GTCTCTTCA GCCTCCACCAAGGGCCCATCGGTCTTCCC   
               
               
                   
                   
                 
                   CCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAG 
                 
               
               
                   
                   
                 
                   CGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAA 
                 
               
               
                   
                   
                 
                   CCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAG 
                 
               
               
                   
                   
                 
                   CGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAG 
                 
               
               
                   
                   
                 
                   GACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCC 
                 
               
               
                   
                   
                 
                   AGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAA 
                 
               
               
                   
                   
                 
                   TCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTG 
                 
               
               
                   
                   
                 
                   AGCCCAAATCTTGTGACAAAACTCACACATGCCCACCG 
                 
               
               
                   
                   
                 
                   TGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTT 
                 
               
               
                   
                   
                 
                   CCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCT 
                 
               
               
                   
                   
                 
                   CCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTG 
                 
               
               
                   
                   
                 
                   AGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGT 
                 
               
               
                   
                   
                 
                   GGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGC 
                 
               
               
                   
                   
                 
                   GGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGC 
                 
               
               
                   
                   
                 
                   GTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAA 
                 
               
               
                   
                   
                 
                   GGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAG 
                 
               
               
                   
                   
                 
                   CCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAG 
                 
               
               
                   
                   
                 
                   CCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCG 
                 
               
               
                   
                   
                 
                   GGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCC 
                 
               
               
                   
                   
                 
                   TGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAG 
                 
               
               
                   
                   
                 
                   TGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGAC 
                 
               
               
                   
                   
                 
                   CACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCC 
                 
               
               
                   
                   
                 
                   TCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAG 
                 
               
               
                   
                   
                 
                   CAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGC 
                 
               
               
                   
                   
                 
                   TCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGT 
                 
               
               
                   
                   
                 
                   CTCCGGGTAAA 
                 
               
               
                   
               
               
                 166 
                 3C3 L1 (full length wild-type 
                 GACATCCAGATGACCCAGTCTCCATCCTCACTGTCTGC 
               
               
                   
                 light chain) nucleotide 
                 ATCTGTAGGAGACAGAGTCACCATCACTTGTCGGGCGA 
               
               
                   
                 sequence 
                 GTCAGGGTATTAGCAGCTGGTTAGCCTGGTATCAGCAG 
               
               
                   
                 The sequence encoding the 
                 AAACCAGAGAAAGCCCCTAAGTCCCTGATCTATGCTGC 
               
               
                   
                 constant region is underlined 
                 ATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGCG 
               
               
                   
                   
                 GCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGC 
               
               
                   
                   
                 AGCCTGCAGCCTGAAGATTTTGCAACTTATTACTGCCA 
               
               
                   
                   
                 ACAGTATAATAGTTACCCGTACACTTTTGGCCAGGGGA 
               
               
                   
                   
                 CCAAGCTGGAGATCAAA CGAACTGTGGCTGCACCATCT   
               
               
                   
                   
                 
                   GTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATC 
                 
               
               
                   
                   
                 
                   TGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCT 
                 
               
               
                   
                   
                 
                   ATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAAC 
                 
               
               
                   
                   
                 
                   GCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGA 
                 
               
               
                   
                   
                 
                   GCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCA 
                 
               
               
                   
                   
                 
                   CCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAA 
                 
               
               
                   
                   
                 
                   GTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTC 
                 
               
               
                   
                   
                 
                   GCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT 
                 
               
               
                   
               
               
                 167 
                 3C3 L2 (full length wild-type 
                 GAAATTGTGTTGACACAGTCTCCAGCCACCCTGTCTTT 
               
               
                   
                 light chain) nucleotide 
                 GTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCA 
               
               
                   
                 sequence 
                 GTCAGGGTGTTAGCAGCTACTTAGCCTGGTACCAGCAG 
               
               
                   
                 The sequence encoding the 
                 AAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGATGC 
               
               
                   
                 constant region is underlined 
                 ATCCAACAGGGCCACTGGCATCCCAGCCAGGTTCAGTG 
               
               
                   
                   
                 GCAGTGGGCCTGGGACAGACTTCACTCTCACCATCAGC 
               
               
                   
                   
                 AGCCTAGAGCCTGAAGATTTTGCAGTTTATTACTGTCA 
               
               
                   
                   
                 GCAGCGTAGCAACTGGCACACTTTTGGCCAGGGGACCA 
               
               
                   
                   
                 AGCTGGAGATCAAA CGAACTGTGGCTGCACCATCTGTC   
               
               
                   
                   
                 
                   TTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGG 
                 
               
               
                   
                   
                 
                   AACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATC 
                 
               
               
                   
                   
                 
                   CCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCC 
                 
               
               
                   
                   
                 
                   CTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCA 
                 
               
               
                   
                   
                 
                   GGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCC 
                 
               
               
                   
                   
                 
                   TGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTC 
                 
               
               
                   
                   
                 
                   TACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCC 
                 
               
               
                   
                   
                 
                   CGTCACAAAGAGCTTCAACAGGGGAGAGTGT 
                 
               
               
                   
               
               
                 168 
                 2G6 (VH) nucleotide 
                 CAGGTTCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCA 
               
               
                   
                 sequence 
                 GCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCGTCTG 
               
               
                   
                   
                 GATTCATCTTGAGTGACTATGGCATGCACTGGGTCCGC 
               
               
                   
                   
                 CAGGCTCCAGGCAAGGGACTGGAGTGGGTGACAGTTAT 
               
               
                   
                   
                 CTGGTATGATGGAAGTAATAAATTCTATGTAGACTCCG 
               
               
                   
                   
                 TGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAG 
               
               
                   
                   
                 AACACGTTGTATCTGCAAATGAACAGCCTGAGAGTCGA 
               
               
                   
                   
                 GGACACGGCTGTGTATTACTGTGCGAGAGGGGGACGTC 
               
               
                   
                   
                 TAGCAACAGGTCACTTCTACTACGTTATGGACGTCTGG 
               
               
                   
                   
                 GGCCAAGGGACCACGGTCACCGTCTCCTCA 
               
               
                   
               
               
                 169 
                 2G6 (VL) nucleotide 
                 GACATCCAGATGACCCAGTCTCCATCCTCACTGTCTGC 
               
               
                   
                 sequence 
                 ATCTGTAGGAGACAGAGTCACCATCACTTGTCGGGCGA 
               
               
                   
                   
                 GTCAGGGTATTAGCAGCTGGTTAGCCTGGTATCAGCAG 
               
               
                   
                   
                 AAACCAGAGAAAGCCCCTAAGTCCCTGATCTATGCTGC 
               
               
                   
                   
                 ATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGCG 
               
               
                   
                   
                 GCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGC 
               
               
                   
                   
                 AGCCTGCAGCCTGAAGATTTTGCAACTTATTACTGCCA 
               
               
                   
                   
                 ACAGTATAATAGTTACCCGTACACTTTTGGCCAGGGGA 
               
               
                   
                   
                 CCAAGCTGGAGATCAAA 
               
               
                   
               
               
                 170 
                 2G6 (full length wild-type 
                 CAGGTTCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCA 
               
               
                   
                 heavy chain) nucleotide 
                 GCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCGTCTG 
               
               
                   
                 sequence 
                 GATTCATCTTGAGTGACTATGGCATGCACTGGGTCCGC 
               
               
                   
                 The sequence encoding the 
                 CAGGCTCCAGGCAAGGGACTGGAGTGGGTGACAGTTAT 
               
               
                   
                 constant region is underlined 
                 CTGGTATGATGGAAGTAATAAATTCTATGTAGACTCCG 
               
               
                   
                   
                 TGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAG 
               
               
                   
                   
                 AACACGTTGTATCTGCAAATGAACAGCCTGAGAGTCGA 
               
               
                   
                   
                 GGACACGGCTGTGTATTACTGTGCGAGAGGGGGACGTC 
               
               
                   
                   
                 TAGCAACAGGTCACTTCTACTACGTTATGGACGTCTGG 
               
               
                   
                   
                 GGCCAAGGGACCACGGTCACCGTCTCCTCA GCCTCCAC   
               
               
                   
                   
                 
                   CAAGGGCCCATCGGTCTTCCCCCTGGCGCCCTGCTCCA 
                 
               
               
                   
                   
                 
                   GGAGCACCTCCGAGAGCACAGCGGCCCTGGGCTGCCTG 
                 
               
               
                   
                   
                 
                   GTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTG 
                 
               
               
                   
                   
                 
                   GAACTCAGGCGCTCTGACCAGCGGCGTGCACACCTTCC 
                 
               
               
                   
                   
                 
                   CAGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGC 
                 
               
               
                   
                   
                 
                   AGCGTGGTGACCGTGCCCTCCAGCAACTTCGGCACCCA 
                 
               
               
                   
                   
                 
                   GACCTACACCTGCAACGTAGATCACAAGCCCAGCAACA 
                 
               
               
                   
                   
                 
                   CCAAGGTGGACAAGACAGTTGAGCGCAAATGTTGTGTC 
                 
               
               
                   
                   
                 
                   GAGTGCCCACCGTGCCCAGCACCACCTGTGGCAGGACC 
                 
               
               
                   
                   
                 
                   GTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCC 
                 
               
               
                   
                   
                 
                   TCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTG 
                 
               
               
                   
                   
                 
                   GTGGACGTGAGCCACGAAGACCCCGAGGTCCAGTTCAA 
                 
               
               
                   
                   
                 
                   CTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGA 
                 
               
               
                   
                   
                 
                   CAAAGCCACGGGAGGAGCAGTTCAACAGCACGTTCCGT 
                 
               
               
                   
                   
                 
                   GTGGTCAGCGTCCTCACCGTTGTGCACCAGGACTGGCT 
                 
               
               
                   
                   
                 
                   GAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAG 
                 
               
               
                   
                   
                 
                   GCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAACC 
                 
               
               
                   
                   
                 
                   AAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCC 
                 
               
               
                   
                   
                 
                   CCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCC 
                 
               
               
                   
                   
                 
                   TGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATC 
                 
               
               
                   
                   
                 
                   GCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAA 
                 
               
               
                   
                   
                 
                   CTACAAGACCACACCTCCCATGCTGGACTCCGACGGCT 
                 
               
               
                   
                   
                 
                   CCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGC 
                 
               
               
                   
                   
                 
                   AGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGAT 
                 
               
               
                   
                   
                 
                   GCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCC 
                 
               
               
                   
                   
                 
                   TCTCCCTGTCTCCGGGTAAA 
                 
               
               
                   
               
               
                 171 
                 2G6 (full length wild-type 
                 GACATCCAGATGACCCAGTCTCCATCCTCACTGTCTGC 
               
               
                   
                 light chain) nucleotide 
                 ATCTGTAGGAGACAGAGTCACCATCACTTGTCGGGCGA 
               
               
                   
                 sequence 
                 GTCAGGGTATTAGCAGCTGGTTAGCCTGGTATCAGCAG 
               
               
                   
                 The sequence encoding the 
                 AAACCAGAGAAAGCCCCTAAGTCCCTGATCTATGCTGC 
               
               
                   
                 constant region is underlined 
                 ATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGCG 
               
               
                   
                   
                 GCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGC 
               
               
                   
                   
                 AGCCTGCAGCCTGAAGATTTTGCAACTTATTACTGCCA 
               
               
                   
                   
                 ACAGTATAATAGTTACCCGTACACTTTTGGCCAGGGGA 
               
               
                   
                   
                 CCAAGCTGGAGATCAAA CGAACTGTGGCTGCACCATCT   
               
               
                   
                   
                 
                   GTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATC 
                 
               
               
                   
                   
                 
                   TGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCT 
                 
               
               
                   
                   
                 
                   ATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAAC 
                 
               
               
                   
                   
                 
                   GCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGA 
                 
               
               
                   
                   
                 
                   GCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCA 
                 
               
               
                   
                   
                 
                   CCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAA 
                 
               
               
                   
                   
                 
                   GTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTC 
                 
               
               
                   
                   
                 
                   GCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT 
                 
               
               
                   
               
               
                 172 
                 8A6 (VH) nucleotide 
                 CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCA 
               
               
                   
                 sequence 
                 GCCTGGGAGGTCCCTGAGACTCTCCTGTACAGCGTCTG 
               
               
                   
                   
                 GATTCACCTTCAGTAGCTATGGCATGCAGTGGGTCCGC 
               
               
                   
                   
                 CAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTAT 
               
               
                   
                   
                 ATGGTATGAAGGAAGTAATAAATACTATGCAGACTCCG 
               
               
                   
                   
                 TGAAGGGCCGATTCACCATCTCCAGAGAAAATTCCAAG 
               
               
                   
                   
                 AACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGA 
               
               
                   
                   
                 GGACACGGCTGTGTATTACTGTGCGAGAGGCGGTCTTA 
               
               
                   
                   
                 TGGTTCGGGGTCTCTTCTACTACGGTATGGACGTCTGG 
               
               
                   
                   
                 GGCCAAGGGACCACGGTCACCGTCTCCTCA 
               
               
                   
               
               
                 173 
                 8A6 (VL) nucleotide 
                 GCCATCCAGTTGACCCAGTCTCCATCCTCCCTGTCTGC 
               
               
                   
                 sequence 
                 ATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAA 
               
               
                   
                   
                 GTCAGGGCATTAGCAGTGCTTTAGCCTGGTATCAGCAG 
               
               
                   
                   
                 AAACCAGGGAAAGCTCCTAAGTTCCTGATCTATGATGC 
               
               
                   
                   
                 CTCCAGTTTGGAAAGTGGGGTCCCATCAAGGTTCAGCG 
               
               
                   
                   
                 GCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGC 
               
               
                   
                   
                 AGCCTGCAGCCTGAAGATTTTGCAACTTATTACTGTCA 
               
               
                   
                   
                 ACAGTTTAATAGTTACCCGTACACTTTTGGCCAGGGGA 
               
               
                   
                   
                 CCAAGCTGGAGATCAAA 
               
               
                   
               
               
                 174 
                 8A6 (full length wild-type 
                 CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCA 
               
               
                   
                 heavy chain) nucleotide 
                 GCCTGGGAGGTCCCTGAGACTCTCCTGTACAGCGTCTG 
               
               
                   
                 sequence 
                 GATTCACCTTCAGTAGCTATGGCATGCAGTGGGTCCGC 
               
               
                   
                 The sequence encoding the 
                 CAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTAT 
               
               
                   
                 constant region is underlined 
                 ATGGTATGAAGGAAGTAATAAATACTATGCAGACTCCG 
               
               
                   
                   
                 TGAAGGGCCGATTCACCATCTCCAGAGAAAATTCCAAG 
               
               
                   
                   
                 AACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGA 
               
               
                   
                   
                 GGACACGGCTGTGTATTACTGTGCGAGAGGCGGTCTTA 
               
               
                   
                   
                 TGGTTCGGGGTCTCTTCTACTACGGTATGGACGTCTGG 
               
               
                   
                   
                 GGCCAAGGGACCACGGTCACCGTCTCCTCA GCCTCCAC   
               
               
                   
                   
                 
                   CAAGGGCCCATCGGTCTTCCCCCTGGCGCCCTGCTCCA 
                 
               
               
                   
                   
                 
                   GGAGCACCTCCGAGAGCACAGCGGCCCTGGGCTGCCTG 
                 
               
               
                   
                   
                 
                   GTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTG 
                 
               
               
                   
                   
                 
                   GAACTCAGGCGCTCTGACCAGCGGCGTGCACACCTTCC 
                 
               
               
                   
                   
                 
                   CAGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGC 
                 
               
               
                   
                   
                 
                   AGCGTGGTGACCGTGCCCTCCAGCAACTTCGGCACCCA 
                 
               
               
                   
                   
                 
                   GACCTACACCTGCAACGTAGATCACAAGCCCAGCAACA 
                 
               
               
                   
                   
                 
                   CCAAGGTGGACAAGACAGTTGAGCGCAAATGTTGTGTC 
                 
               
               
                   
                   
                 
                   GAGTGCCCACCGTGCCCAGCACCACCTGTGGCAGGACC 
                 
               
               
                   
                   
                 
                   GTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCC 
                 
               
               
                   
                   
                 
                   TCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTG 
                 
               
               
                   
                   
                 
                   GTGGACGTGAGCCACGAAGACCCCGAGGTCCAGTTCAA 
                 
               
               
                   
                   
                 
                   CTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGA 
                 
               
               
                   
                   
                 
                   CAAAGCCACGGGAGGAGCAGTTCAACAGCACGTTCCGT 
                 
               
               
                   
                   
                 
                   GTGGTCAGCGTCCTCACCGTTGTGCACCAGGACTGGCT 
                 
               
               
                   
                   
                 
                   GAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAG 
                 
               
               
                   
                   
                 
                   GCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAACC 
                 
               
               
                   
                   
                 
                   AAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCC 
                 
               
               
                   
                   
                 
                   CCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCC 
                 
               
               
                   
                   
                 
                   TGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATC 
                 
               
               
                   
                   
                 
                   GCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAA 
                 
               
               
                   
                   
                 
                   CTACAAGACCACACCTCCCATGCTGGACTCCGACGGCT 
                 
               
               
                   
                   
                 
                   CCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGC 
                 
               
               
                   
                   
                 
                   AGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGAT 
                 
               
               
                   
                   
                 
                   GCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCC 
                 
               
               
                   
                   
                 
                   TCTCCCTGTCTCCGGGTAAA 
                 
               
               
                   
               
               
                 175 
                 8A6 (full length wild-type 
                 GCCATCCAGTTGACCCAGTCTCCATCCTCCCTGTCTGC 
               
               
                   
                 light chain) nucleotide 
                 ATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAA 
               
               
                   
                 sequence 
                 GTCAGGGCATTAGCAGTGCTTTAGCCTGGTATCAGCAG 
               
               
                   
                 The sequence encoding the 
                 AAACCAGGGAAAGCTCCTAAGTTCCTGATCTATGATGC 
               
               
                   
                 constant region is underlined 
                 CTCCAGTTTGGAAAGTGGGGTCCCATCAAGGTTCAGCG 
               
               
                   
                   
                 GCAGIGGATCTGGGACAGATTTCACTCTCACCATCAGC 
               
               
                   
                   
                 AGCCTGCAGCCTGAAGATTTTGCAACTTATTACTGTCA 
               
               
                   
                   
                 ACAGTTTAATAGTTACCCGTACACTTTTGGCCAGGGGA 
               
               
                   
                   
                 CCAAGCTGGAGATCAAA CGAACTGTGGCTGCACCATCT   
               
               
                   
                   
                 
                   GTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATC 
                 
               
               
                   
                   
                 
                   TGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCT 
                 
               
               
                   
                   
                 
                   ATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAAC 
                 
               
               
                   
                   
                 
                   GCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGA 
                 
               
               
                   
                   
                 
                   GCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCA 
                 
               
               
                   
                   
                 
                   CCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAA 
                 
               
               
                   
                   
                 
                   GTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTC 
                 
               
               
                   
                   
                 
                   GCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT 
                 
               
               
                   
               
               
                 176 
                 9G7 (VH) nucleotide 
                 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTAGTAAA 
               
               
                   
                 sequence 
                 GCCTGGGGGGTCCCTTAGACTCTCCTGTGCAGCCTCTG 
               
               
                   
                   
                 GATTCACTTTCAGTACCGTCTGGATGAGCTGGGTCCGC 
               
               
                   
                   
                 CAGGCTCCAGGGAAGGGGCTGGAGTGGGTTGGCCGTAT 
               
               
                   
                   
                 TAAAAGCAAAACTGATGGTGGGACAACAGACTACGCTG 
               
               
                   
                   
                 CACCCGTGAAAGGCAGATTCACCATCTCAAGAGATGAT 
               
               
                   
                   
                 TCAAAAAACACGCTGTATCTGCAAATGAACAGCCTGCA 
               
               
                   
                   
                 CACCGAGGACACAGCCGTGTATTACTGTACCACAGGGC 
               
               
                   
                   
                 AGCTGATCCCTTACTCCTACTACTACGGTATGGACGTC 
               
               
                   
                   
                 TGGGGCCAAGGGACCTCGGTCACCGTCTCCTCA 
               
               
                   
               
               
                 177 
                 9G7 (VL1) nucleotide 
                 GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTT 
               
               
                   
                 sequence 
                 GTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCA 
               
               
                   
                   
                 GTCAGAGTGTTAGCAGCAGCTACTTAGCCTGGTACCAG 
               
               
                   
                   
                 CAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGG 
               
               
                   
                   
                 TGCATCCAGCAGGGCCACTGGCATCCCAGACAGGTTCA 
               
               
                   
                   
                 GTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATC 
               
               
                   
                   
                 AGCAGACTGGAGCCTGAAGATTTTGCAGTGTATTACTG 
               
               
                   
                   
                 TCAGCAGTATGGTAGCTCACCGTGGACGTTCGGCCAAG 
               
               
                   
                   
                 GGACCAAGGTGGAAATCAAA 
               
               
                   
               
               
                 178 
                 9G7 (VL2) nucleotide 
                 GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTT 
               
               
                   
                 sequence 
                 GTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCA 
               
               
                   
                   
                 GTCAGAGTGTTACCAGCAGCTACTTAGCCTGGTACCAG 
               
               
                   
                   
                 CAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGG 
               
               
                   
                   
                 TGCATCCAGCAGGGCCACTGGCATCCCAGAGAGGTTCA 
               
               
                   
                   
                 GTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATC 
               
               
                   
                   
                 AGCAGACTGGAGCCTGAAGATTTTGCAGTGTATTACTG 
               
               
                   
                   
                 TCAGCAGTATGGTAGCTCACCGATCACCTTCGGCCAAG 
               
               
                   
                   
                 GGACACGACTGGAGATTAAA 
               
               
                   
               
               
                 179 
                 9G7 (full length wild-type 
                 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTAGTAAA 
               
               
                   
                 heavy chain) nucleotide 
                 GCCTGGGGGGTCCCTTAGACTCTCCTGTGCAGCCTCTG 
               
               
                   
                 sequence 
                 GATTCACTTTCAGTACCGTCTGGATGAGCTGGGTCCGC 
               
               
                   
                 The sequence encoding the 
                 CAGGCTCCAGGGAAGGGGCTGGAGTGGGTTGGCCGTAT 
               
               
                   
                 constant region is underlined 
                 TAAAAGCAAAACTGATGGTGGGACAACAGACTACGCTG 
               
               
                   
                   
                 CACCCGTGAAAGGCAGATTCACCATCTCAAGAGATGAT 
               
               
                   
                   
                 TCAAAAAACACGCTGTATCTGCAAATGAACAGCCTGCA 
               
               
                   
                   
                 CACCGAGGACACAGCCGTGTATTACTGTACCACAGGGC 
               
               
                   
                   
                 AGCTGATCCCTTACTCCTACTACTACGGTATGGACGTC 
               
               
                   
                   
                 TGGGGCCAAGGGACCTCGGTCACCGTCTCCTCA GCTTC   
               
               
                   
                   
                 
                   CACCAAGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCT 
                 
               
               
                   
                   
                 
                   CCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGC 
                 
               
               
                   
                   
                 
                   CTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTC 
                 
               
               
                   
                   
                 
                   GTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCT 
                 
               
               
                   
                   
                 
                   TCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTC 
                 
               
               
                   
                   
                 
                   AGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCAC 
                 
               
               
                   
                   
                 
                   GAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCA 
                 
               
               
                   
                   
                 
                   ACACCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGT 
                 
               
               
                   
                   
                 
                   CCCCCATGCCCATCATGCCCAGCACCTGAGTTCCTGGG 
                 
               
               
                   
                   
                 
                   GGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGG 
                 
               
               
                   
                   
                 
                   ACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGC 
                 
               
               
                   
                   
                 
                   GTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGTCCA 
                 
               
               
                   
                   
                 
                   GTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATG 
                 
               
               
                   
                   
                 
                   CCAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACG 
                 
               
               
                   
                   
                 
                   TACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGA 
                 
               
               
                   
                   
                 
                   CTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCA 
                 
               
               
                   
                   
                 
                   ACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCC 
                 
               
               
                   
                   
                 
                   AAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACAC 
                 
               
               
                   
                   
                 
                   CCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGG 
                 
               
               
                   
                   
                 
                   TCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGC 
                 
               
               
                   
                   
                 
                   GACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGA 
                 
               
               
                   
                   
                 
                   GAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCG 
                 
               
               
                   
                   
                 
                   ACGGCTCCTTCTTCCTCTACAGCAGGCTAACCGTGGAC 
                 
               
               
                   
                   
                 
                   AAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTC 
                 
               
               
                   
                   
                 
                   CGTGATGCATGAGGCTCTGCACAACCACTACACACAGA 
                 
               
               
                   
                   
                 
                   AGAGCCTCTCCCTGTCTCTGGGTAAA 
                 
               
               
                   
               
               
                 180 
                 9G7 L2 (full length wild- 
                 GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTT 
               
               
                   
                 type light chain) nucleotide 
                 GTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCA 
               
               
                   
                 sequence 
                 GTCAGAGTGTTACCAGCAGCTACTTAGCCTGGTACCAG 
               
               
                   
                 The sequence encoding the 
                 CAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGG 
               
               
                   
                 constant region is underlined 
                 TGCATCCAGCAGGGCCACTGGCATCCCAGAGAGGTTCA 
               
               
                   
                   
                 GTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATC 
               
               
                   
                   
                 AGCAGACTGGAGCCTGAAGATTTTGCAGTGTATTACTG 
               
               
                   
                   
                 TCAGCAGTATGGTAGCTCACCGATCACCTTCGGCCAAG 
               
               
                   
                   
                 GGACACGACTGGAGATTAAA CGAACTGTGGCTGCACCA   
               
               
                   
                   
                 
                   TCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAA 
                 
               
               
                   
                   
                 
                   ATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACT 
                 
               
               
                   
                   
                 
                   TCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGAT 
                 
               
               
                   
                   
                 
                   AACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCAC 
                 
               
               
                   
                   
                 
                   AGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCA 
                 
               
               
                   
                   
                 
                   GCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACAC 
                 
               
               
                   
                   
                 
                   AAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAG 
                 
               
               
                   
                   
                 
                   CTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT 
                 
               
               
                   
               
               
                 181 
                 9G7 L1 (full length wild- 
                 GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTT 
               
               
                   
                 type light chain) nucleotide 
                 GTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCA 
               
               
                   
                 sequence 
                 GTCAGAGTGTTAGCAGCAGCTACTTAGCCTGGTACCAG 
               
               
                   
                 The sequence encoding the 
                 CAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGG 
               
               
                   
                 constant region is underlined 
                 TGCATCCAGCAGGGCCACTGGCATCCCAGACAGGTTCA 
               
               
                   
                   
                 GTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATC 
               
               
                   
                   
                 AGCAGACTGGAGCCTGAAGATTTTGCAGTGTATTACTG 
               
               
                   
                   
                 TCAGCAGTATGGTAGCTCACCGTGGACGTTCGGCCAAG 
               
               
                   
                   
                 GGACCAAGGTGGAAATCAAA CGAACTGTGGCTGCACCA   
               
               
                   
                   
                 
                   TCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAA 
                 
               
               
                   
                   
                 
                   ATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACT 
                 
               
               
                   
                   
                 
                   TCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGAT 
                 
               
               
                   
                   
                 
                   AACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCAC 
                 
               
               
                   
                   
                 
                   AGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCA 
                 
               
               
                   
                   
                 
                   GCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACAC 
                 
               
               
                   
                   
                 
                   AAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAG 
                 
               
               
                   
                   
                 
                   CTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT 
                 
               
               
                   
               
               
                 182 
                 14E3 (VH) nucleotide 
                 CAGGTGCAGCTACAGCAGTGGGGCGCAGGACTGTTGAA 
               
               
                   
                 sequence 
                 GCCTTCGGAGACCCTGTCCCTCACCTGCGCTGTCTATG 
               
               
                   
                   
                 GTGGGTCCTTCAGTGGTTACTACTGGAGCTGGATCCGC 
               
               
                   
                   
                 CAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGAGAAAT 
               
               
                   
                   
                 CAATCATAGTGGAAACACCTACTACAACCCGTCCCTCA 
               
               
                   
                   
                 AGAGTCGCGTCACCATATCAGTAGACACGTCCAAGAAC 
               
               
                   
                   
                 CAGTTATCCCTGAAGCTGAGCTCTGTGACCGCCGCGGA 
               
               
                   
                   
                 CACGGCTGTGTATTACTGTGCGAGATTTGGGAGTAATG 
               
               
                   
                   
                 ATGCTTTTGATATCTGGGGCCAAGGGACAATGGTCACC 
               
               
                   
                   
                 GTCTCTTCA 
               
               
                   
               
               
                 183 
                 14E3 (VL) nucleotide 
                 GACATCCAGATGACCCAGTCTCCATCCTCACTGTCTGC 
               
               
                   
                 sequence 
                 ATCTGTAGGAGACAGAGTCACCATCACTTGTCGGGCGA 
               
               
                   
                   
                 GTCAGGGTATTAGCAGCTGGTTAGCCTGGTATCAGCAG 
               
               
                   
                   
                 AAACCAGAGAAAGCCCCTAAGTCCCTGATCTATGCTGC 
               
               
                   
                   
                 ATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGCG 
               
               
                   
                   
                 GCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGC 
               
               
                   
                   
                 AGCCTGCAGCCTGAAGATTTTGCAACTTATTACTGCCA 
               
               
                   
                   
                 ACAGTATAATAGTTACCCTCCGACGTTCGGCCAAGGGA 
               
               
                   
                   
                 CCAAGGTGGAAATCAAA 
               
               
                   
               
               
                 184 
                 14E3 (full length wild-type 
                 CAGGTGCAGCTACAGCAGTGGGGCGCAGGACTGTTGAA 
               
               
                   
                 heavy chain) nucleotide 
                 GCCTTCGGAGACCCTGTCCCTCACCTGCGCTGTCTATG 
               
               
                   
                 sequence 
                 GTGGGTCCTTCAGTGGTTACTACTGGAGCTGGATCCGC 
               
               
                   
                 The sequence encoding the 
                 CAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGAGAAAT 
               
               
                   
                 constant region is underlined 
                 CAATcATAGTGGAAAcAccTACTACAACCCGTCCCTCA 
               
               
                   
                   
                 AGAGTCGCGTCACCATATCAGTAGACACGTCCAAGAAC 
               
               
                   
                   
                 CAGTTATCCCTGAAGCTGAGCTCTGTGACCGCCGCGGA 
               
               
                   
                   
                 CACGGCTGTGTATTACTGTGCGAGATTTGGGAGTAATG 
               
               
                   
                   
                 ATGCTTTTGATATCTGGGGCCAAGGGACAATGGTCACC 
               
               
                   
                   
                 GTCTCTTCA GCCTCCACCAAGGGCCCATCGGTCTTCCC   
               
               
                   
                   
                 
                   CCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAG 
                 
               
               
                   
                   
                 
                   CGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAA 
                 
               
               
                   
                   
                 
                   CCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAG 
                 
               
               
                   
                   
                 
                   CGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAG 
                 
               
               
                   
                   
                 
                   GACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCC 
                 
               
               
                   
                   
                 
                   AGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAA 
                 
               
               
                   
                   
                 
                   TCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTG 
                 
               
               
                   
                   
                 
                   AGCCCAAATCTTGTGACAAAACTCACACATGCCCACCG 
                 
               
               
                   
                   
                 
                   TGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTT 
                 
               
               
                   
                   
                 
                   CCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCT 
                 
               
               
                   
                   
                 
                   CCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTG 
                 
               
               
                   
                   
                 
                   AGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGT 
                 
               
               
                   
                   
                 
                   GGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGC 
                 
               
               
                   
                   
                 
                   GGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGC 
                 
               
               
                   
                   
                 
                   GTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAA 
                 
               
               
                   
                   
                 
                   GGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAG 
                 
               
               
                   
                   
                 
                   CCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAG 
                 
               
               
                   
                   
                 
                   CCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCG 
                 
               
               
                   
                   
                 
                   GGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCC 
                 
               
               
                   
                   
                 
                   TGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAG 
                 
               
               
                   
                   
                 
                   TGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGAC 
                 
               
               
                   
                   
                 
                   CACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCC 
                 
               
               
                   
                   
                 
                   TCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAG 
                 
               
               
                   
                   
                 
                   CAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGC 
                 
               
               
                   
                   
                 
                   TCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGT 
                 
               
               
                   
                   
                 
                   CTCCGGGTAAA 
                 
               
               
                   
               
               
                 185 
                 14E3 (full length wild-type 
                 GACATCCAGATGACCCAGTCTCCATCCTCACTGTCTGC 
               
               
                   
                 light chain) nucleotide 
                 ATCTGTAGGAGACAGAGTCACCATCACTTGTCGGGCGA 
               
               
                   
                 sequence 
                 GTCAGGGTATTAGCAGCTGGTTAGCCTGGTATCAGCAG 
               
               
                   
                 The sequence encoding the 
                 AAACCAGAGAAAGCCCCTAAGTCCCTGATCTATGCTGC 
               
               
                   
                 constant region is underlined 
                 ATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGCG 
               
               
                   
                   
                 GCAGIGGATCTGGGACAGATTTCACTCTCACCATCAGC 
               
               
                   
                   
                 AGCCTGCAGCCTGAAGATTTTGCAACTTATTACTGCCA 
               
               
                   
                   
                 ACAGTATAATAGTTACCCTCCGACGTTCGGCCAAGGGA 
               
               
                   
                   
                 CCAAGGTGGAAATCAAA CGAACTGTGGCTGCACCATCT   
               
               
                   
                   
                 
                   GTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATC 
                 
               
               
                   
                   
                 
                   TGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCT 
                 
               
               
                   
                   
                 
                   ATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAAC 
                 
               
               
                   
                   
                 
                   GCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGA 
                 
               
               
                   
                   
                 
                   GCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCA 
                 
               
               
                   
                   
                 
                   CCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAA 
                 
               
               
                   
                   
                 
                   GTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTC 
                 
               
               
                   
                   
                 
                   GCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT 
                 
               
               
                   
               
               
                 186 
                 19H8 (VH) nucleotide 
                 CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCA 
               
               
                   
                 sequence 
                 GCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGCGTCTG 
               
               
                   
                   
                 GATTCACCTTCAGTAACTATGGCATGCACTGGGTCCGC 
               
               
                   
                   
                 CAGGCTCCAGGCAAGGGGCTGGAGTGGATGGCAGTTAT 
               
               
                   
                   
                 ATGGTATGGTGGAAGTAATAAATTCTATGCAGACTCCG 
               
               
                   
                   
                 TGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAG 
               
               
                   
                   
                 AACTCGCTGTCTCTGCAAATGAACAGCCTGAGAGCCGA 
               
               
                   
                   
                 GGACACGGCTGTGTATTACTGTGCGAGAGGGGGGGCTA 
               
               
                   
                   
                 TGGTTCGGGGAGTCTACTACTACGGTATGGACGTCTGG 
               
               
                   
                   
                 GGCCAAGGGACCACGGTCAC CGTCTCCTCA 
               
               
                   
               
               
                 187 
                 19H8 (VL1) nucleotide 
                 GCCATCCAGTTGACCCAGTCTCCATCCTCCCTGTCTGC 
               
               
                   
                 sequence 
                 ATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAA 
               
               
                   
                   
                 GTCAGGGCATTAGCAGTGCTTTAGCCTGGTATCAGCAG 
               
               
                   
                   
                 AAACCAGGGAAAGCTCCTAAGTTCCTGATCTATGATGC 
               
               
                   
                   
                 CTCCAGTTTGGAAAGTGGGGTCCCATCAAGGTTCAGCG 
               
               
                   
                   
                 GCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGC 
               
               
                   
                   
                 AGCCTGCAGCCTGAAGATTTTGCAACTTATTACTGTCA 
               
               
                   
                   
                 ACAGTTTAATAGTTACCCTCAGACGTTCGGCCAAGGGA 
               
               
                   
                   
                 CCAAGGTGGAAATCAAA 
               
               
                   
               
               
                 188 
                 19H8 (VL2) nucleotide 
                 GAAATTGTGTTGACACAGTCTCCAGCCACCCTGTCTTT 
               
               
                   
                 sequence 
                 GTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCA 
               
               
                   
                   
                 GTCAGAGTGTTAGCAGCTACTTAGCCTGGTACCAACAG 
               
               
                   
                   
                 AAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGATGC 
               
               
                   
                   
                 ATCCAACAGGGCCACTGGCATCCCAGCCAGGTTCAGTG 
               
               
                   
                   
                 GCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGC 
               
               
                   
                   
                 AGCCTAGAGCCTGAAGATTTTGCAGTTTATTACTGTCA 
               
               
                   
                   
                 GCAGCGTAGCAACTGGCCGCTCACTTTCGGCGGAGGGA 
               
               
                   
                   
                 CCAAGGTGGAGATCAAA 
               
               
                   
               
               
                 189 
                 19H8 (full length wild-type 
                 CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCA 
               
               
                   
                 heavy chain) nucleotide 
                 GCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGCGTCTG 
               
               
                   
                 sequence 
                 GATTCACCTTCAGTAACTATGGCATGCACTGGGTCCGC 
               
               
                   
                 The sequence encoding the 
                 CAGGCTCCAGGCAAGGGGCTGGAGTGGATGGCAGTTAT 
               
               
                   
                 constant region is underlined 
                 ATGGTATGGTGGAAGTAATAAATTCTATGCAGACTCCG 
               
               
                   
                   
                 TGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAG 
               
               
                   
                   
                 AACTCGCTGTCTCTGCAAATGAACAGCCTGAGAGCCGA 
               
               
                   
                   
                 GGACACGGCTGTGTATTACTGTGCGAGAGGGGGGGCTA 
               
               
                   
                   
                 TGGTTCGGGGAGTCTACTACTACGGTATGGACGTCTGG 
               
               
                   
                   
                 GGCCAAGGGACCACGGTCACCGTCTCCTCA GCCTCCAC   
               
               
                   
                   
                 
                   CAAGGGCCCATCGGTCTTCCCCCTGGCGCCCTGCTCCA 
                 
               
               
                   
                   
                 
                   GGAGCACCTCCGAGAGCACAGCGGCCCTGGGCTGCCTG 
                 
               
               
                   
                   
                 
                   GTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTG 
                 
               
               
                   
                   
                 
                   GAACTCAGGCGCTCTGACCAGCGGCGTGCACACCTTCC 
                 
               
               
                   
                   
                 
                   CAGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGC 
                 
               
               
                   
                   
                 
                   AGCGTGGTGACCGTGCCCTCCAGCAACTTCGGCACCCA 
                 
               
               
                   
                   
                 
                   GACCTACACCTGCAACGTAGATCACAAGCCCAGCAACA 
                 
               
               
                   
                   
                 
                   CCAAGGTGGACAAGACAGTTGAGCGCAAATGTTGTGTC 
                 
               
               
                   
                   
                 
                   GAGTGCCCACCGTGCCCAGCACCACCTGTGGCAGGACC 
                 
               
               
                   
                   
                 
                   GTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCC 
                 
               
               
                   
                   
                 
                   TCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTG 
                 
               
               
                   
                   
                 
                   GTGGACGTGAGCCACGAAGACCCCGAGGTCCAGTTCAA 
                 
               
               
                   
                   
                 
                   CTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGA 
                 
               
               
                   
                   
                 
                   CAAAGCCACGGGAGGAGCAGTTCAACAGCACGTTCCGT 
                 
               
               
                   
                   
                 
                   GTGGTCAGCGTCCTCACCGTTGTGCACCAGGACTGGCT 
                 
               
               
                   
                   
                 
                   GAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAG 
                 
               
               
                   
                   
                 
                   GCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAACC 
                 
               
               
                   
                   
                 
                   AAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCC 
                 
               
               
                   
                   
                 
                   CCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCC 
                 
               
               
                   
                   
                 
                   TGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATC 
                 
               
               
                   
                   
                 
                   GCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAA 
                 
               
               
                   
                   
                 
                   CTACAAGACCACACCTCCCATGCTGGACTCCGACGGCT 
                 
               
               
                   
                   
                 
                   CCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGC 
                 
               
               
                   
                   
                 
                   AGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGAT 
                 
               
               
                   
                   
                 
                   GCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCC 
                 
               
               
                   
                   
                 
                   TCTCCCTGTCTCCGGGTAAA 
                 
               
               
                   
               
               
                 190 
                 19H8 L1 (full length wild- 
                 GCCATCCAGTTGACCCAGTCTCCATCCTCCCTGTCTGC 
               
               
                   
                 type light chain) nucleotide 
                 ATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAA 
               
               
                   
                 sequence 
                 GTCAGGGCATTAGCAGTGCTTTAGCCTGGTATCAGCAG 
               
               
                   
                 The sequence encoding the 
                 AAACCAGGGAAAGCTCCTAAGTTCCTGATCTATGATGC 
               
               
                   
                 constant region is underlined 
                 CTCCAGTTTGGAAAGTGGGGTCCCATCAAGGTTCAGCG 
               
               
                   
                   
                 GCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGC 
               
               
                   
                   
                 AGCCTGCAGCCTGAAGATTTTGCAACTTATTACTGTCA 
               
               
                   
                   
                 ACAGTTTAATAGTTACCCTCAGACGTTCGGCCAAGGGA 
               
               
                   
                   
                 CCAAGGTGGAAATCAAA CGAACTGTGGCTGCACCATCT   
               
               
                   
                   
                 
                   GTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATC 
                 
               
               
                   
                   
                 
                   TGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCT 
                 
               
               
                   
                   
                 
                   ATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAAC 
                 
               
               
                   
                   
                 
                   GCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGA 
                 
               
               
                   
                   
                 
                   GCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCA 
                 
               
               
                   
                   
                 
                   CCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAA 
                 
               
               
                   
                   
                 
                   GTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTC 
                 
               
               
                   
                   
                 
                   GCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT 
                 
               
               
                   
               
               
                 191 
                 19H8 L2 (full length wild- 
                 GAAATTGTGTTGACACAGTCTCCAGCCACCCTGTCTTT 
               
               
                   
                 type light chain) nucleotide 
                 GTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCA 
               
               
                   
                 sequence 
                 GTCAGAGTGTTAGCAGCTACTTAGCCTGGTACCAACAG 
               
               
                   
                 The sequence encoding the 
                 AAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGATGC 
               
               
                   
                 constant region is underlined 
                 ATCCAACAGGGCCACTGGCATCCCAGCCAGGTTCAGTG 
               
               
                   
                   
                 GCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGC 
               
               
                   
                   
                 AGCCTAGAGCCTGAAGATTTTGCAGTTTATTACTGTCA 
               
               
                   
                   
                 GCAGCGTAGCAACTGGCCGCTCACTTTCGGCGGAGGGA 
               
               
                   
                   
                 CCAAGGTGGAGATCAAA CGAACTGTGGCTGCACCATCT   
               
               
                   
                   
                 
                   GTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATC 
                 
               
               
                   
                   
                 
                   TGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCT 
                 
               
               
                   
                   
                 
                   ATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAAC 
                 
               
               
                   
                   
                 
                   GCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGA 
                 
               
               
                   
                   
                 
                   GCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCA 
                 
               
               
                   
                   
                 
                   CCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAA 
                 
               
               
                   
                   
                 
                   GTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTC 
                 
               
               
                   
                   
                 
                   GCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT 
                 
               
               
                   
               
               
                 192 
                 VH 3-33 (28F3, 18E10, 
                 QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVR 
               
               
                   
                 19D3, 2G6, 8A6, 19H8) 
                 QAPGKGLEWVAVIWYDGSNKYYADSVKGRFTISRDNSK 
               
               
                   
                   
                 NTLYLQMNSLRAEDTAVYYCAR 
               
               
                   
               
               
                 193 
                 VH 3-10 (28F3, 8A6) 
                 MVRG 
               
               
                   
               
               
                 194 
                 VH 3-10 (9G7) 
                 YYYG 
               
               
                   
               
               
                 195 
                 VH 3-10 (19H8) 
                 YYY 
               
               
                   
               
               
                 196 
                 VH JH6 (28F3, 19H8) 
                 YYYGMDVWGQGTTVTVSS 
               
               
                   
               
               
                 197 
                 VH JH6 (18E10, 2G6, 8A6) 
                 YYGMDVWGQGTTVTVSS 
               
               
                   
               
               
                 198 
                 VH JH6 (19D3, 9G7) 
                 YYYYYGMDVWGQGTTVTVSS 
               
               
                   
               
               
                 199 
                 VH 6-19 (18E10) 
                 IAVA 
               
               
                   
               
               
                 200 
                 VH 3-16 (19D3) 
                 DY 
               
               
                   
               
               
                 201 
                 VH 4-34 (3C3, 14E3) 
                 QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWSWIR 
               
               
                   
                   
                 QPPGKGLEWIGEINHSGSTNYNPSLKSRVTISVDTSKN 
               
               
                   
                   
                 QFSLKLSSVTAADTAVYYCAR 
               
               
                   
               
               
                 202 
                 VH JH3 (3C3, 14E3) 
                 DAFDIWGQGTMVTVSS 
               
               
                   
               
               
                 203 
                 VH 3-15 (9G7) 
                 EVQLVESGGGLVKPGGSLRLSCAASGFTFSNAWMSWVR 
               
               
                   
                   
                 QAPGKGLEWVGRIKSKTDGGTTDYAAPVKGRFTISRDD 
               
               
                   
                   
                 SKNTLYLQMNSLKTEDTAVYYCTT 
               
               
                   
               
               
                 204 
                 VL L18 (28F3, 8A6, 
                 AIQLTQSPSSLSASVGDRVTITCRASQGISSALAWYQQ 
               
               
                   
                 19H8VK1) 
                 KPGKAPKLLIYDASSLESGVPSRFSGSGSGTDFTLTIS 
               
               
                   
                   
                 SLQPEDFATYYCQQFNNY 
               
               
                   
               
               
                 205 
                 VL JK2 (28F3, 18E10, 
                 YTFGQGTKLEIK 
               
               
                   
                 19D3, 3C3VK1, 8A6, 2G6) 
                   
               
               
                   
               
               
                 206 
                 VL JK2 (3C3VK2) 
                 TFGQGTKLEIK 
               
               
                   
               
               
                 207 
                 VL L15 (18E10, 19D3, 
                 DIQMTQSPSSLSASVGDRVTITCRASQGISSWLAWYQQ 
               
               
                   
                 3C3VK1, 2G6, 14E3) 
                 KPEKAPKSLIYAASSLQSGVPSRFSGSGSGTDFTLTIS 
               
               
                   
                   
                 SLQPEDFATYYCQQYNSY 
               
               
                   
               
               
                 208 
                 VL L20 (3C3VK2) 
                 EIVLTQSPATLSLSPGERATLSCRASQGVSSYLAWYQQ 
               
               
                   
                   
                 KPGQAPRLLIYDASNRATGIPARFSGSGPGTDFTLTIS 
               
               
                   
                   
                 SLEPEDFAVYYCQQRSNW 
               
               
                   
               
               
                 209 
                 VL A27 (9G7VK1, 
                 EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQ 
               
               
                   
                 9G7VK2) 
                 QKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTI 
               
               
                   
                   
                 SRLEPEDFAVYYCQQYGSS 
               
               
                   
               
               
                 210 
                 VL JK1 (9G7VK1) 
                 WTFGQGTKVEIK 
               
               
                   
               
               
                 211 
                 VL JK1 (14E3, 19H8VK1) 
                 TFGQGTKVEIK 
               
               
                   
               
               
                 212 
                 VL JK5 (9G7VK2) 
                 ITFGQGTRLEIK 
               
               
                   
               
               
                 213 
                 VL L6 (19H8VK2) 
                 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQ 
               
               
                   
                   
                 KPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTIS 
               
               
                   
                   
                 SLEPEDFAVYYCQQRSNW 
               
               
                   
               
               
                 214 
                 VL JK4 (19H8VK2) 
                 LTFGGGTKVEIK 
               
               
                   
               
               
                 215 
                 GITR epitope 
                 QRPTGGPGCGPGRLLLGTGTDARCCRVHTTRCCRDYPG 
               
               
                   
                   
                 E 
               
               
                   
               
               
                 216 
                 GITR epitope 
                 QRPTGGPGCGPGRLLLGTGT 
               
               
                   
               
               
                 217 
                 GITR epitope (region 1) 
                 PTGGPGCGPGRLLLGTGT 
               
               
                   
               
               
                 218 
                 GITR epitope (region 2) 
                 CRDYPGEE 
               
               
                   
               
               
                 219 
                 Peptide linker 
                 PVGVV 
               
               
                   
               
               
                 220 
                 Heavy chain C-terminus 
                 LSPGK 
               
               
                   
               
               
                 221 
                 G2 constant region 
                 ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVT 
               
               
                   
                   
                 VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNF 
               
               
                   
                   
                 GTQTYTCNVDHKPSNTKVDKTV ERKCCVECPPCPAPPV   
               
               
                   
                   
                   AG PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEV 
               
               
                   
                   
                 QFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQ 
               
               
                   
                   
                 DWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVY 
               
               
                   
                   
                 TLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP 
               
               
                   
                   
                 ENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSC 
               
               
                   
                   
                 SVMHEALHNHYTQKSLSLSPG 
               
               
                   
               
               
                 222 
                 G2(C219S) constant region 
                 ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVT 
               
               
                   
                   
                 VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNF 
               
               
                   
                   
                 GTQTYTCNVDHKPSNTKVDKTV ERKSCVECPPCPAPPV   
               
               
                   
                   
                   AG PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEV 
               
               
                   
                   
                 QFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQ 
               
               
                   
                   
                 DWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVY 
               
               
                   
                   
                 TLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP 
               
               
                   
                   
                 ENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSC 
               
               
                   
                   
                 SVMHEALHNHYTQKSLSLSPG 
               
               
                   
               
               
                 223 
                 G2.g1 modified constant 
                 ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVT 
               
               
                   
                 region 
                 VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNF 
               
               
                   
                   
                 GTQTYTCNVDHKPSNTKVDKTV ERKCCVECPPCPAPEL   
               
               
                   
                   
                   LGG PSVFLEPPKPKDTLMISRTPEVTCVVVDVSHEDPE 
               
               
                   
                   
                 VKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH 
               
               
                   
                   
                 QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQV 
               
               
                   
                   
                 YTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQ 
               
               
                   
                   
                 PENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS 
               
               
                   
                   
                 CSVMHEALHNHYTQKSLSLSPG 
               
               
                   
               
               
                 224 
                 G2.g1.1 modified constant 
                 ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVT 
               
               
                   
                 region 
                 VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNF 
               
               
                   
                   
                 GTQTYTCNVDHKPSNTKVDKTVE RKCCVECPPCPAPPV   
               
               
                   
                   
                   AG PSVFLEPPKPKDTLMISRTPEVTCVVVDVSHEDPEV 
               
               
                   
                   
                 KFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQ 
               
               
                   
                   
                 DWLNGKEYKCKVSNKALPSSIEKTISKAKGQPREPQVY 
               
               
                   
                   
                 TLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP 
               
               
                   
                   
                 ENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSC 
               
               
                   
                   
                 SVMHEALHNHYTQKSLSLSPG 
               
               
                   
               
               
                 225 
                 G2(C219S).g1 modified 
                 ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVT 
               
               
                   
                 constant region 
                 VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNF 
               
               
                   
                   
                 GTQTYTCNVDHKPSNTKVDKTV ERKSCVECPPCPAPEL   
               
               
                   
                   
                   LGG PSVFLEPPKPKDTLMISRTPEVTCVVVDVSHEDPE 
               
               
                   
                   
                 VKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH 
               
               
                   
                   
                 QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQV 
               
               
                   
                   
                 YTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQ 
               
               
                   
                   
                 PENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS 
               
               
                   
                   
                 CSVMHEALHNHYTQKSLSLSPG 
               
               
                   
               
               
                 226 
                 G2(C219S).g1.1 modified 
                 ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVT 
               
               
                   
                 constant region 
                 VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNF 
               
               
                   
                   
                 GTQTYTCNVDHKPSNTKVDKTV ERKSCVECPPCPAPPV   
               
               
                   
                   
                   AG PSVFLEPPKPKDTLMISRTPEVTCVVVDVSHEDPEV 
               
               
                   
                   
                 KFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQ 
               
               
                   
                   
                 DWLNGKEYKCKVSNKALP SS IEKTISKAKGQPREPQVY 
               
               
                   
                   
                 TLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP 
               
               
                   
                   
                 ENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSC 
               
               
                   
                   
                 SVMHEALHNHYTQKSLSLSPG 
               
               
                   
               
               
                 15 
                 28F3 (VH + G2) or 
                 SEQ ID NO: 15 
               
               
                   
                 28F3-IgG2 
                   
               
               
                   
               
               
                 227 
                 28F3 (VH + G2(C219S)) or 
                 QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVR 
               
               
                   
                 28F3-IgG2-C219S 
                 QAPGKGLEWVAVIWYEGSNKYYADSVKGRFTISRDNSK 
               
               
                   
                   
                 NTLYLQMNSLRAEDTAVYYCARGGSMVRGDYYYGMDVW 
               
               
                   
                   
                 GQGTTVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCL   
               
               
                   
                   
                 
                   VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS 
                 
               
               
                   
                   
                 
                   SVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKSCV 
                 
               
               
                   
                   
                 
                   ECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVV 
                 
               
               
                   
                   
                 
                   VDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFR 
                 
               
               
                   
                   
                 
                   VVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKI 
                 
               
               
                   
                   
                 
                   KGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDI 
                 
               
               
                   
                   
                 
                   AVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKS 
                 
               
               
                   
                   
                 
                   RWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 
                 
               
               
                   
               
               
                 228 
                 28F3 (VH + G2.g1) or 
                 QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVR 
               
               
                   
                 28F3-IgG2-IgG1 
                 QAPGKGLEWVAVIWYEGSNKYYADSVKGRFTISRDNSK 
               
               
                   
                   
                 NTLYLQMNSLRAEDTAVYYCARGGSMVRGDYYYGMDVW 
               
               
                   
                   
                 GQGTTVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCL   
               
               
                   
                   
                 
                   VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS 
                 
               
               
                   
                   
                 
                   SVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCV 
                 
               
               
                   
                   
                 
                   ECPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
                 
               
               
                   
                   
                 
                   VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY 
                 
               
               
                   
                   
                 
                   RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISK 
                 
               
               
                   
                   
                 
                   AKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD 
                 
               
               
                   
                   
                 
                   IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDK 
                 
               
               
                   
                   
                 
                   SRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 
                 
               
               
                   
               
               
                 229 
                 28F3 (VH + G2.g1.1) or 
                 QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVR 
               
               
                   
                 28F3-IgG2-IgG1.1 
                 QAPGKGLEWVAVIWYEGSNKYYADSVKGRFTISRDNSK 
               
               
                   
                   
                 NTLYLQMNSLRAEDTAVYYCARGGSMVRGDYYYGMDVW 
               
               
                   
                   
                 GQGTTVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCL   
               
               
                   
                   
                 
                   VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS 
                 
               
               
                   
                   
                 
                   SVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCV 
                 
               
               
                   
                   
                 
                   ECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVV 
                 
               
               
                   
                   
                 
                   VDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR 
                 
               
               
                   
                   
                 
                   VVSVLTVLHQDWLNGKEYKCKVSNKALPSSIEKTISKA 
                 
               
               
                   
                   
                 
                   KGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDI 
                 
               
               
                   
                   
                 
                   AVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKS 
                 
               
               
                   
                   
                 
                   RWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 
                 
               
               
                   
               
               
                 230 
                 28F3 (VH + G2(C219S).g1) 
                 QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVR 
               
               
                   
                 or 
                 QAPGKGLEWVAVIWYEGSNKYYADSVKGRFTISRDNSK 
               
               
                   
                 28F3-IgG2-C219S-IgG1 
                 NTLYLQMNSLRAEDTAVYYCARGGSMVRGDYYYGMDVW 
               
               
                   
                   
                 GQGTTVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCL   
               
               
                   
                   
                 
                   VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS 
                 
               
               
                   
                   
                 
                   SVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKSCV 
                 
               
               
                   
                   
                 
                   ECPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
                 
               
               
                   
                   
                 
                   VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY 
                 
               
               
                   
                   
                 
                   RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISK 
                 
               
               
                   
                   
                 
                   AKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD 
                 
               
               
                   
                   
                 
                   IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDK 
                 
               
               
                   
                   
                 
                   SRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 
                 
               
               
                   
               
               
                 231 
                 28F3 (VH  
                 QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVR 
               
               
                   
                 G2(C219S).g1.1) or 
                 QAPGKGLEWVAVIWYEGSNKYYADSVKGRFTISRDNSK 
               
               
                   
                 28F3-IgG2-C219S-IgG1.1 
                 NTLYLQMNSLRAEDTAVYYCARGGSMVRGDYYYGMDVW 
               
               
                   
                   
                 GQGTTVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCL   
               
               
                   
                   
                 
                   VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS 
                 
               
               
                   
                   
                 
                   SVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKSCV 
                 
               
               
                   
                   
                 
                   ECPPCPAPPVAGPSVFLEPPKPKDTLMISRTPEVTCVV 
                 
               
               
                   
                   
                 
                   VDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR 
                 
               
               
                   
                   
                 
                   VVSVLTVLHQDWLNGKEYKCKVSNKALPSSIEKTISKA 
                 
               
               
                   
                   
                 
                   KGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDI 
                 
               
               
                   
                   
                 
                   AVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKS 
                 
               
               
                   
                   
                 
                   RWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 
                 
               
               
                   
               
               
                 28 
                 19D3 (VH + G2) or 
                 SEQ ID NO: 28 
               
               
                   
                 19D3-IgG2 
                   
               
               
                   
               
               
                 232 
                 19D3 (VH + G2(C219S)) or 
                 QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGFHWVR 
               
               
                   
                 19D3-IgG2-C219S 
                 QAPGKGLEWVAVIWYAGSNKFYADSVKGRFTISRDNSK 
               
               
                   
                   
                 NTLYLQMNSLRAEDTAVYYCARGGQLDYYYYYVMDVWG 
               
               
                   
                   
                 QGTTVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLV   
               
               
                   
                   
                 
                   KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSS 
                 
               
               
                   
                   
                 
                   VVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKSCVE 
                 
               
               
                   
                   
                 
                   CPPCPAPPVAGPSVFLEPPKPKDTLMISRTPEVTCVVV 
                 
               
               
                   
                   
                 
                   DVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRV 
                 
               
               
                   
                   
                 
                   VSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTK 
                 
               
               
                   
                   
                 
                   GQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIA 
                 
               
               
                   
                   
                 
                   VEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSR 
                 
               
               
                   
                   
                 
                   WQQGNVFSCSVMHEALHNHYTQKSLSLSPG 
                 
               
               
                   
               
               
                 233 
                 19D3 (VH + G2.g1) or 
                 QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGFHWVR 
               
               
                   
                 19D3-IgG2-IgG1 
                 QAPGKGLEWVAVIWYAGSNKFYADSVKGRFTISRDNSK 
               
               
                   
                   
                 NTLYLQMNSLRAEDTAVYYCARGGQLDYYYYYVMDVWG 
               
               
                   
                   
                 QGTTVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLV   
               
               
                   
                   
                 
                   KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSS 
                 
               
               
                   
                   
                 
                   VVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVE 
                 
               
               
                   
                   
                 
                   CPPCPAPELLGGPSVFLEPPKPKDTLMISRTPEVTCVV 
                 
               
               
                   
                   
                 
                   VDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR 
                 
               
               
                   
                   
                 
                   VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKA 
                 
               
               
                   
                   
                 
                   KGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDI 
                 
               
               
                   
                   
                 
                   AVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKS 
                 
               
               
                   
                   
                 
                   RWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 
                 
               
               
                   
               
               
                 234 
                 19D3 (VH + G2.g1.1) or 
                 QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGFHWVR 
               
               
                   
                 19D3-IgG2-IgG1.1 
                 QAPGKGLEWVAVIWYAGSNKFYADSVKGRFTISRDNSK 
               
               
                   
                   
                 NTLYLQMNSLRAEDTAVYYCARGGQLDYYYYYVMDVWG 
               
               
                   
                   
                 QGTTVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLV   
               
               
                   
                   
                 
                   KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSS 
                 
               
               
                   
                   
                 
                   VVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVE 
                 
               
               
                   
                   
                 
                   CPPCPAPPVAGPSVFLEPPKPKDTLMISRTPEVTCVVV 
                 
               
               
                   
                   
                 
                   DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV 
                 
               
               
                   
                   
                 
                   VSVLTVLHQDWLNGKEYKCKVSNKALPSSIEKTISKAK 
                 
               
               
                   
                   
                 
                   GQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIA 
                 
               
               
                   
                   
                 
                   VEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSR 
                 
               
               
                   
                   
                 
                   WQQGNVFSCSVMHEALHNHYTQKSLSLSPG 
                 
               
               
                   
               
               
                 235 
                 19D3 (VH + G2(C219S).g1) 
                 QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGFHWVR 
               
               
                   
                 or 
                 QAPGKGLEWVAVIWYAGSNKFYADSVKGRFTISRDNSK 
               
               
                   
                 19D3-IgG2-C219S-IgG1 
                 NTLYLQMNSLRAEDTAVYYCARGGQLDYYYYYVMDVWG 
               
               
                   
                   
                 QGTTVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLV   
               
               
                   
                   
                 
                   KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSS 
                 
               
               
                   
                   
                 
                   VVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKSCVE 
                 
               
               
                   
                   
                 
                   CPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVV 
                 
               
               
                   
                   
                 
                   VDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR 
                 
               
               
                   
                   
                 
                   VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKA 
                 
               
               
                   
                   
                 
                   KGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDI 
                 
               
               
                   
                   
                 
                   AVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKS 
                 
               
               
                   
                   
                 
                   RWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 
                 
               
               
                   
               
               
                 236 
                 19D3 (VH  
                 QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGFHWVR 
               
               
                   
                 G2(C219S).g1.1) or 
                 QAPGKGLEWVAVIWYAGSNKFYADSVKGRFTISRDNSK 
               
               
                   
                 19D3-IgG2-C219S-IgG1.1 
                 NTLYLQMNSLRAEDTAVYYCARGGQLDYYYYYVMDVWG 
               
               
                   
                   
                 QGTTVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLV   
               
               
                   
                   
                 
                   KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSS 
                 
               
               
                   
                   
                 
                   VVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKSCVE 
                 
               
               
                   
                   
                 
                   CPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVV 
                 
               
               
                   
                   
                 
                   DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV 
                 
               
               
                   
                   
                 
                   VSVLTVLHQDWLNGKEYKCKVSNKALPSSIEKTISKAK 
                 
               
               
                   
                   
                 
                   GQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIA 
                 
               
               
                   
                   
                 
                   VEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSR 
                 
               
               
                   
                   
                 
                   WQQGNVFSCSVMHEALHNHYTQKSLSLSPG 
                 
               
               
                   
               
               
                 41 
                 18E10 (VH + G2) or 
                 SEQ ID NO: 41 
               
               
                   
                 18E10-IgG2 
                   
               
               
                   
               
               
                 237 
                 18E10 (VH + G2(C219S)) or 
                 QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVR 
               
               
                   
                 18E10-IgG2-C219S 
                 QAPGKGLEWVAVIWYAGSNKYYADSVKGRFTISRDNSK 
               
               
                   
                   
                 NTLYLQMNSLRAEDTAVYYCARGGRIAVAFYYSMDVWG 
               
               
                   
                   
                 QGTTVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLV   
               
               
                   
                   
                 
                   KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSS 
                 
               
               
                   
                   
                 
                   VVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKSCVE 
                 
               
               
                   
                   
                 
                   CPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVV 
                 
               
               
                   
                   
                 
                   DVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRV 
                 
               
               
                   
                   
                 
                   VSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTK 
                 
               
               
                   
                   
                 
                   GQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIA 
                 
               
               
                   
                   
                 
                   VEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSR 
                 
               
               
                   
                   
                 
                   WQQGNVFSCSVMHEALHNHYTQKSLSLSPG 
                 
               
               
                   
               
               
                 238 
                 18E10 (VH + G2.g1) or 
                 QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVR 
               
               
                   
                 18E10-IgG2-IgG1 
                 QAPGKGLEWVAVIWYAGSNKYYADSVKGRFTISRDNSK 
               
               
                   
                   
                 NTLYLQMNSLRAEDTAVYYCARGGRIAVAFYYSMDVWG 
               
               
                   
                   
                 QGTTVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLV   
               
               
                   
                   
                 
                   KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSS 
                 
               
               
                   
                   
                 
                   VVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVE 
                 
               
               
                   
                   
                 
                   CPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVV 
                 
               
               
                   
                   
                 
                   VDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR 
                 
               
               
                   
                   
                 
                   VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKA 
                 
               
               
                   
                   
                 
                   KGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDI 
                 
               
               
                   
                   
                 
                   AVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKS 
                 
               
               
                   
                   
                 
                   RWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 
                 
               
               
                   
               
               
                 239 
                 18E10 (VH + G2.g1.1) or 
                 QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVR 
               
               
                   
                 18E10-IgG2-IgG1.1 
                 QAPGKGLEWVAVIWYAGSNKYYADSVKGRFTISRDNSK 
               
               
                   
                   
                 NTLYLQMNSLRAEDTAVYYCARGGRIAVAFYYSMDVWG 
               
               
                   
                   
                 QGTTVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLV   
               
               
                   
                   
                 
                   KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSS 
                 
               
               
                   
                   
                 
                   VVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVE 
                 
               
               
                   
                   
                 
                   CPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVV 
                 
               
               
                   
                   
                 
                   DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV 
                 
               
               
                   
                   
                 
                   VSVLTVLHQDWLNGKEYKCKVSNKALPSSIEKTISKAK 
                 
               
               
                   
                   
                 
                   GQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIA 
                 
               
               
                   
                   
                 
                   VEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSR 
                 
               
               
                   
                   
                 
                   WQQGNVFSCSVMHEALHNHYTQKSLSLSPG 
                 
               
               
                   
               
               
                 240 
                 18E10 (VH  
                 QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVR 
               
               
                   
                 G2(C219S).g1) or 
                 QAPGKGLEWVAVIWYAGSNKYYADSVKGRFTISRDNSK 
               
               
                   
                 18E10-IgG2-C219S-IgG1 
                 NTLYLQMNSLRAEDTAVYYCARGGRIAVAFYYSMDVWG 
               
               
                   
                   
                 QGTTVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLV   
               
               
                   
                   
                 
                   KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSS 
                 
               
               
                   
                   
                 
                   VVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKSCVE 
                 
               
               
                   
                   
                 
                   CPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVV 
                 
               
               
                   
                   
                 
                   VDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR 
                 
               
               
                   
                   
                 
                   VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKA 
                 
               
               
                   
                   
                 
                   KGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDI 
                 
               
               
                   
                   
                 
                   AVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKS 
                 
               
               
                   
                   
                 
                   RWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 
                 
               
               
                   
               
               
                 241 
                 18E10 (VH  
                 QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVR 
               
               
                   
                 G2(C219S).g1.1) or 
                 QAPGKGLEWVAVIWYAGSNKYYADSVKGRFTISRDNSK 
               
               
                   
                 18E10-IgG2-C219S-IgG1.1 
                 NTLYLQMNSLRAEDTAVYYCARGGRIAVAFYYSMDVWG 
               
               
                   
                   
                 QGTTVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLV   
               
               
                   
                   
                 
                   KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSS 
                 
               
               
                   
                   
                 
                   VVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKSCVE 
                 
               
               
                   
                   
                 
                   CPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVV 
                 
               
               
                   
                   
                 
                   DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV 
                 
               
               
                   
                   
                 
                   VSVLTVLHQDWLNGKEYKCKVSNKALPSSIEKTISKAK 
                 
               
               
                   
                   
                 
                   GQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIA 
                 
               
               
                   
                   
                 
                   VEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSR 
                 
               
               
                   
                   
                 
                   WQQGNVFSCSVMHEALHNHYTQKSLSLSPG 
                 
               
               
                   
               
               
                 242 
                 3C3 (VH + G2) or 
                 QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWTWIR 
               
               
                   
                 3C3-IgG2 
                 QPPGKGLEWIGKINHSGNTNYNPSLKSRVTISVDTSKN 
               
               
                   
                   
                 QFSLKLSSVTAADTAVYYCARLGAFDAFDIWGQGTMVT 
               
               
                   
                   
                 VSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPE   
               
               
                   
                   
                 
                   PVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPS 
                 
               
               
                   
                   
                 
                   SNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPA 
                 
               
               
                   
                   
                 
                   PPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHED 
                 
               
               
                   
                   
                 
                   PEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTV 
                 
               
               
                   
                   
                 
                   VHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREP 
                 
               
               
                   
                   
                 
                   QVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESN 
                 
               
               
                   
                   
                 
                   GQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNV 
                 
               
               
                   
                   
                 
                   FSCSVMHEALHNHYTQKSLSLSPG 
                 
               
               
                   
               
               
                 243 
                 3C3 (VH + G2(C219S)) or 
                 QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWTWIR 
               
               
                   
                 3C3-IgG2-C219S 
                 QPPGKGLEWIGKINHSGNTNYNPSLKSRVTISVDTSKN 
               
               
                   
                   
                 QFSLKLSSVTAADTAVYYCARLGAFDAFDIWGQGTMVT 
               
               
                   
                   
                 VSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPE   
               
               
                   
                   
                 
                   PVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPS 
                 
               
               
                   
                   
                 
                   SNFGTQTYTCNVDHKPSNTKVDKTVERKSCVECPPCPA 
                 
               
               
                   
                   
                 
                   PPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHED 
                 
               
               
                   
                   
                 
                   PEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTV 
                 
               
               
                   
                   
                 
                   VHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREP 
                 
               
               
                   
                   
                 
                   QVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESN 
                 
               
               
                   
                   
                 
                   GQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNV 
                 
               
               
                   
                   
                 
                   FSCSVMHEALHNHYTQKSLSLSPG 
                 
               
               
                   
               
               
                 244 
                 3C3 (VH + G2.g1) or 
                 QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWTWIR 
               
               
                   
                 3C3-IgG2-IgG1 
                 QPPGKGLEWIGKINHSGNTNYNPSLKSRVTISVDTSKN 
               
               
                   
                   
                 QFSLKLSSVTAADTAVYYCARLGAFDAFDIWGQGTMVT 
               
               
                   
                   
                 VSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPE   
               
               
                   
                   
                 
                   PVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPS 
                 
               
               
                   
                   
                 
                   SNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPA 
                 
               
               
                   
                   
                 
                   PELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE 
                 
               
               
                   
                   
                 
                   DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLT 
                 
               
               
                   
                   
                 
                   VLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPRE 
                 
               
               
                   
                   
                 
                   PQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWES 
                 
               
               
                   
                   
                 
                   NGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN 
                 
               
               
                   
                   
                 
                   VFSCSVMHEALHNHYTQKSLSLSPG 
                 
               
               
                   
               
               
                 245 
                 3C3 (VH + G2.g1.1) or 
                 QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWTWIR 
               
               
                   
                 3C3-IgG2-IgG1.1 
                 QPPGKGLEWIGKINHSGNTNYNPSLKSRVTISVDTSKN 
               
               
                   
                   
                 QFSLKLSSVTAADTAVYYCARLGAFDAFDIWGQGTMVT 
               
               
                   
                   
                 VSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPE   
               
               
                   
                   
                 
                   PVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPS 
                 
               
               
                   
                   
                 
                   SNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPA 
                 
               
               
                   
                   
                 
                   PPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHED 
                 
               
               
                   
                   
                 
                   PEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTV 
                 
               
               
                   
                   
                 
                   LHQDWLNGKEYKCKVSNKALPSSIEKTISKAKGQPREP 
                 
               
               
                   
                   
                 
                   QVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESN 
                 
               
               
                   
                   
                 
                   GQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV 
                 
               
               
                   
                   
                 
                   FSCSVMHEALHNHYTQKSLSLSPG 
                 
               
               
                   
               
               
                 246 
                 3C3 (VH + G2(C219S).g1) 
                 QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWTWIR 
               
               
                   
                 or 
                 QPPGKGLEWIGKINHSGNTNYNPSLKSRVTISVDTSKN 
               
               
                   
                 3C3-IgG2-C219S-IgG1 
                 QFSLKLSSVTAADTAVYYCARLGAFDAFDIWGQGTMVT 
               
               
                   
                   
                 VSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPE   
               
               
                   
                   
                 
                   PVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPS 
                 
               
               
                   
                   
                 
                   SNFGTQTYTCNVDHKPSNTKVDKTVERKSCVECPPCPA 
                 
               
               
                   
                   
                 
                   PELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE 
                 
               
               
                   
                   
                 
                   DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLT 
                 
               
               
                   
                   
                 
                   VLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPRE 
                 
               
               
                   
                   
                 
                   PQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWES 
                 
               
               
                   
                   
                 
                   NGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN 
                 
               
               
                   
                   
                 VFSCSVMHEALHNHYTQKSLSLSPG 
               
               
                   
               
               
                 247 
                 3C3 (VH + G2(C219S).g1.1) 
                 QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWTWIR 
               
               
                   
                 or 
                 QPPGKGLEWIGKINHSGNTNYNPSLKSRVTISVDTSKN 
               
               
                   
                 3C3-IgG2-C219S-IgG1.1 
                 QFSLKLSSVTAADTAVYYCARLGAFDAFDIWGQGTMVT 
               
               
                   
                   
                 VSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPE   
               
               
                   
                   
                 
                   PVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPS 
                 
               
               
                   
                   
                 
                   SNFGTQTYTCNVDHKPSNTKVDKTVERKSCVECPPCPA 
                 
               
               
                   
                   
                 
                   PPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHED 
                 
               
               
                   
                   
                 
                   PEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTV 
                 
               
               
                   
                   
                 
                   LHQDWLNGKEYKCKVSNKALPSSIEKTISKAKGQPREP 
                 
               
               
                   
                   
                 
                   QVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESN 
                 
               
               
                   
                   
                 
                   GQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV 
                 
               
               
                   
                   
                 
                   FSCSVMHEALHNHYTQKSLSLSPG 
                 
               
               
                   
               
               
                 248 
                 2G6 (VH + G2) or 
                 QVQLVESGGGVVQPGGSLRLSCAASGFILSDYGMHWVR 
               
               
                   
                 2G6-IgG2 
                 QAPGKGLEWVTVIWYDGSNKFYVDSVKGRFTISRDNSK 
               
               
                   
                   
                 NTLYLQMNSLRVEDTAVYYCARGGRLATGHFYYVMDVW 
               
               
                   
                   
                 GQGTTVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCL   
               
               
                   
                   
                 
                   VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS 
                 
               
               
                   
                   
                 
                   SVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCV 
                 
               
               
                   
                   
                 
                   ECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVV 
                 
               
               
                   
                   
                 
                   VDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFR 
                 
               
               
                   
                   
                 
                   VVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKI 
                 
               
               
                   
                   
                 
                   KGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDI 
                 
               
               
                   
                   
                 
                   AVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKS 
                 
               
               
                   
                   
                 
                   RWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 
                 
               
               
                   
               
               
                 249 
                 2G6 (VH + G2(C219S)) or 
                 QVQLVESGGGVVQPGGSLRLSCAASGFILSDYGMHWVR 
               
               
                   
                 2G6-IgG2-C219S 
                 QAPGKGLEWVTVIWYDGSNKFYVDSVKGRFTISRDNSK 
               
               
                   
                   
                 NTLYLQMNSLRVEDTAVYYCARGGRLATGHFYYVMDVW 
               
               
                   
                   
                 GQGTTVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCL   
               
               
                   
                   
                 
                   VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS 
                 
               
               
                   
                   
                 
                   SVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKSCV 
                 
               
               
                   
                   
                 
                   ECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVV 
                 
               
               
                   
                   
                 
                   VDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFR 
                 
               
               
                   
                   
                 
                   VVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKI 
                 
               
               
                   
                   
                 
                   KGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDI 
                 
               
               
                   
                   
                 
                   AVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKS 
                 
               
               
                   
                   
                 
                   RWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 
                 
               
               
                   
               
               
                 250 
                 2G6 (VH + G2.g1) or 
                 QVQLVESGGGVVQPGGSLRLSCAASGFILSDYGMHWVR 
               
               
                   
                 2G6-IgG2-IgG1 
                 QAPGKGLEWVTVIWYDGSNKFYVDSVKGRFTISRDNSK 
               
               
                   
                   
                 NTLYLQMNSLRVEDTAVYYCARGGRLATGHFYYVMDVW 
               
               
                   
                   
                 GQGTTVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCL   
               
               
                   
                   
                 
                   VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS 
                 
               
               
                   
                   
                 
                   SVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCV 
                 
               
               
                   
                   
                 
                   ECPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
                 
               
               
                   
                   
                 
                   VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY 
                 
               
               
                   
                   
                 
                   RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISK 
                 
               
               
                   
                   
                 
                   AKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD 
                 
               
               
                   
                   
                 
                   IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDK 
                 
               
               
                   
                   
                 
                   SRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 
                 
               
               
                   
               
               
                 251 
                 2G6 (VH + G2.g1.1) or 
                 QVQLVESGGGVVQPGGSLRLSCAASGFILSDYGMHWVR 
               
               
                   
                 2G6-IgG2-IgG1.1 
                 QAPGKGLEWVTVIWYDGSNKFYVDSVKGRFTISRDNSK 
               
               
                   
                   
                 NTLYLQMNSLRVEDTAVYYCARGGRLATGHFYYVMDVW 
               
               
                   
                   
                 GQGTTVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCL   
               
               
                   
                   
                 
                   VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS 
                 
               
               
                   
                   
                 
                   SVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCV 
                 
               
               
                   
                   
                 
                   ECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVV 
                 
               
               
                   
                   
                 
                   VDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR 
                 
               
               
                   
                   
                 
                   VVSVLTVLHQDWLNGKEYKCKVSNKALPSSIEKTISKA 
                 
               
               
                   
                   
                 
                   KGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDI 
                 
               
               
                   
                   
                 
                   AVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKS 
                 
               
               
                   
                   
                 
                   RWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 
                 
               
               
                   
               
               
                 252 
                 2G6 (VH + G2(C219S).g1) 
                 QVQLVESGGGVVQPGGSLRLSCAASGFILSDYGMHWVR 
               
               
                   
                 or 
                 QAPGKGLEWVTVIWYDGSNKFYVDSVKGRFTISRDNSK 
               
               
                   
                 2G6-IgG2-C219S-IgG1 
                 NTLYLQMNSLRVEDTAVYYCARGGRLATGHFYYVMDVW 
               
               
                   
                   
                 GQGTTVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCL   
               
               
                   
                   
                 
                   VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS 
                 
               
               
                   
                   
                 
                   SVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKSCV 
                 
               
               
                   
                   
                 
                   ECPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
                 
               
               
                   
                   
                 
                   VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY 
                 
               
               
                   
                   
                 
                   RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISK 
                 
               
               
                   
                   
                 
                   AKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD 
                 
               
               
                   
                   
                 
                   IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDK 
                 
               
               
                   
                   
                 
                   SRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 
                 
               
               
                   
               
               
                 253 
                 2G6 (VH + G2(C219S).g1.1) 
                 QVQLVESGGGVVQPGGSLRLSCAASGFILSDYGMHWVR 
               
               
                   
                 or 
                 QAPGKGLEWVTVIWYDGSNKFYVDSVKGRFTISRDNSK 
               
               
                   
                 2G6-IgG2-C219S-IgG1.1 
                 NTLYLQMNSLRVEDTAVYYCARGGRLATGHFYYVMDVW 
               
               
                   
                   
                 GQGTTVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCL   
               
               
                   
                   
                 
                   VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS 
                 
               
               
                   
                   
                 
                   SVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKSCV 
                 
               
               
                   
                   
                 
                   ECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVV 
                 
               
               
                   
                   
                 
                   VDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR 
                 
               
               
                   
                   
                 
                   VVSVLTVLHQDWLNGKEYKCKVSNKALPSSIEKTISKA 
                 
               
               
                   
                   
                 
                   KGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDI 
                 
               
               
                   
                   
                 
                   AVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKS 
                 
               
               
                   
                   
                 
                   RWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 
                 
               
               
                   
               
               
                 86 
                 8A6 (VH + G2) or 
                 SEQ ID NO: 86 
               
               
                   
                 8A6-IgG2 
                   
               
               
                   
               
               
                 254 
                 8A6 (VH + G2(C219S)) or 
                 QVQLVESGGGVVQPGRSLRLSCTASGFTFSSYGMQWVR 
               
               
                   
                 8A6-IgG2-C219S 
                 QAPGKGLEWVAVIWYEGSNKYYADSVKGRFTISRENSK 
               
               
                   
                   
                 NTLYLQMNSLRAEDTAVYYCARGGLMVRGLFYYGMDVW 
               
               
                   
                   
                 GQGTTVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCL   
               
               
                   
                   
                 
                   VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS 
                 
               
               
                   
                   
                 
                   SVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKSCV 
                 
               
               
                   
                   
                 
                   ECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVV 
                 
               
               
                   
                   
                 
                   VDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFR 
                 
               
               
                   
                   
                 
                   VVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKI 
                 
               
               
                   
                   
                 
                   KGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDI 
                 
               
               
                   
                   
                 
                   AVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKS 
                 
               
               
                   
                   
                 
                   RWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 
                 
               
               
                   
               
               
                 255 
                 8A6 (VH + G2.g1) or 
                 QVQLVESGGGVVQPGRSLRLSCTASGFTFSSYGMQWVR 
               
               
                   
                 8A6-IgG2-IgG1 
                 QAPGKGLEWVAVIWYEGSNKYYADSVKGRFTISRENSK 
               
               
                   
                   
                 NTLYLQMNSLRAEDTAVYYCARGGLMVRGLFYYGMDVW 
               
               
                   
                   
                 GQGTTVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCL   
               
               
                   
                   
                 
                   VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS 
                 
               
               
                   
                   
                 
                   SVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCV 
                 
               
               
                   
                   
                 
                   ECPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
                 
               
               
                   
                   
                 
                   VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY 
                 
               
               
                   
                   
                 
                   RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISK 
                 
               
               
                   
                   
                 
                   AKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD 
                 
               
               
                   
                   
                 
                   IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDK 
                 
               
               
                   
                   
                 
                   SRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 
                 
               
               
                   
               
               
                 256 
                 8A6 (VH + G2.g1.1) or 
                 QVQLVESGGGVVQPGRSLRLSCTASGFTFSSYGMQWVR 
               
               
                   
                 8A6-IgG2-IgG1.1 
                 QAPGKGLEWVAVIWYEGSNKYYADSVKGRFTISRENSK 
               
               
                   
                   
                 NTLYLQMNSLRAEDTAVYYCARGGLMVRGLFYYGMDVW 
               
               
                   
                   
                 GQGTTVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCL   
               
               
                   
                   
                 
                   VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS 
                 
               
               
                   
                   
                 
                   SVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCV 
                 
               
               
                   
                   
                 
                   ECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVV 
                 
               
               
                   
                   
                 
                   VDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR 
                 
               
               
                   
                   
                 
                   VVSVLTVLHQDWLNGKEYKCKVSNKALPSSIEKTISKA 
                 
               
               
                   
                   
                 
                   KGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDI 
                 
               
               
                   
                   
                 
                   AVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKS 
                 
               
               
                   
                   
                 
                   RWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 
                 
               
               
                   
               
               
                 257 
                 8A6 (VH + G2(C219S).g1) 
                 QVQLVESGGGVVQPGRSLRLSCTASGFTFSSYGMQWVR 
               
               
                   
                 or 
                 QAPGKGLEWVAVIWYEGSNKYYADSVKGRFTISRENSK 
               
               
                   
                 8A6-IgG2-C219S-IgG1 
                 NTLYLQMNSLRAEDTAVYYCARGGLMVRGLFYYGMDVW 
               
               
                   
                   
                 GQGTTVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCL   
               
               
                   
                   
                 
                   VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS 
                 
               
               
                   
                   
                 
                   SVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKSCV 
                 
               
               
                   
                   
                 
                   ECPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
                 
               
               
                   
                   
                 
                   VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY 
                 
               
               
                   
                   
                 
                   RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISK 
                 
               
               
                   
                   
                 
                   AKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD 
                 
               
               
                   
                   
                 
                   IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDK 
                 
               
               
                   
                   
                 
                   SRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 
                 
               
               
                   
               
               
                 258 
                 8A6 (VH + G2(C219S).g1.1) 
                 QVQLVESGGGVVQPGRSLRLSCTASGFTFSSYGMQWVR 
               
               
                   
                 or 
                 QAPGKGLEWVAVIWYEGSNKYYADSVKGRFTISRENSK 
               
               
                   
                 8A6-IgG2-C219S-IgG1.1 
                 NTLYLQMNSLRAEDTAVYYCARGGLMVRGLFYYGMDVW 
               
               
                   
                   
                 GQGTTVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCL   
               
               
                   
                   
                 
                   VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS 
                 
               
               
                   
                   
                 
                   SVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKSCV 
                 
               
               
                   
                   
                 
                   ECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVV 
                 
               
               
                   
                   
                 
                   VDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR 
                 
               
               
                   
                   
                 
                   VVSVLTVLHQDWLNGKEYKCKVSNKALPSSIEKTISKA 
                 
               
               
                   
                   
                 
                   KGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDI 
                 
               
               
                   
                   
                 
                   AVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKS 
                 
               
               
                   
                   
                 
                   RWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 
                 
               
               
                   
               
               
                 259 
                 9G7 (VH + G2) or 
                 EVQLVESGGGLVKPGGSLRLSCAASGFTFSTVWMSWVR 
               
               
                   
                 9G7-IgG2 
                 QAPGKGLEWVGRIKSKTDGGTTDYAAPVKGRFTISRDD 
               
               
                   
                   
                 SKNTLYLQMNSLHTEDTAVYYCTTGQLIPYSYYYGMDV 
               
               
                   
                   
                 WGQGTSVTVSS ASTKGPSVFPLAPCSRSTSESTAALGC   
               
               
                   
                   
                 
                   LVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSL 
                 
               
               
                   
                   
                 
                   SSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCC 
                 
               
               
                   
                   
                 
                   VECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCV 
                 
               
               
                   
                   
                 
                   VVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTF 
                 
               
               
                   
                   
                 
                   RVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISK 
                 
               
               
                   
                   
                 
                   TKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD 
                 
               
               
                   
                   
                 
                   IAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDK 
                 
               
               
                   
                   
                 
                   SRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 
                 
               
               
                   
               
               
                 260 
                 9G7 (VH + G2(C219S)) or 
                 EVQLVESGGGLVKPGGSLRLSCAASGFTFSTVWMSWVR 
               
               
                   
                 9G7-IgG2-C219S 
                 QAPGKGLEWVGRIKSKTDGGTTDYAAPVKGRFTISRDD 
               
               
                   
                   
                 SKNTLYLQMNSLHTEDTAVYYCTTGQLIPYSYYYGMDV 
               
               
                   
                   
                 WGQGTSVTVSS ASTKGPSVFPLAPCSRSTSESTAALGC   
               
               
                   
                   
                 
                   LVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSL 
                 
               
               
                   
                   
                 
                   SSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKSC 
                 
               
               
                   
                   
                 
                   VECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCV 
                 
               
               
                   
                   
                 
                   VVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTF 
                 
               
               
                   
                   
                 
                   RVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISK 
                 
               
               
                   
                   
                 
                   TKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD 
                 
               
               
                   
                   
                 
                   IAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDK 
                 
               
               
                   
                   
                 
                   SRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 
                 
               
               
                   
               
               
                 261 
                 9G7 (VH + G2.g1) or 
                 EVQLVESGGGLVKPGGSLRLSCAASGFTFSTVWMSWVR 
               
               
                   
                 9G7-IgG2-IgG1 
                 QAPGKGLEWVGRIKSKTDGGTTDYAAPVKGRFTISRDD 
               
               
                   
                   
                 SKNTLYLQMNSLHTEDTAVYYCTTGQLIPYSYYYGMDV 
               
               
                   
                   
                 WGQGTSVTVSS ASTKGPSVFPLAPCSRSTSESTAALGC   
               
               
                   
                   
                 
                   LVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSL 
                 
               
               
                   
                   
                 
                   SSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCC 
                 
               
               
                   
                   
                 
                   VECPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC 
                 
               
               
                   
                   
                 
                   VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST 
                 
               
               
                   
                   
                 
                   YRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS 
                 
               
               
                   
                   
                 
                   KAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPS 
                 
               
               
                   
                   
                 
                   DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVD 
                 
               
               
                   
                   
                 
                   KSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 
                 
               
               
                   
               
               
                 262 
                 9G7 (VH + G2.g1.1) or 
                 EVQLVESGGGLVKPGGSLRLSCAASGFTFSTVWMSWVR 
               
               
                   
                 9G7-IgG2-IgG1.1 
                 QAPGKGLEWVGRIKSKTDGGTTDYAAPVKGRFTISRDD 
               
               
                   
                   
                 SKNTLYLQMNSLHTEDTAVYYCTTGQLIPYSYYYGMDV 
               
               
                   
                   
                 WGQGTSVTVSS ASTKGPSVFPLAPCSRSTSESTAALGC   
               
               
                   
                   
                 
                   LVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSL 
                 
               
               
                   
                   
                 
                   SSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCC 
                 
               
               
                   
                   
                 
                   VECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCV 
                 
               
               
                   
                   
                 
                   VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY 
                 
               
               
                   
                   
                 
                   RVVSVLTVLHQDWLNGKEYKCKVSNKALPSSIEKTISK 
                 
               
               
                   
                   
                 
                   AKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD 
                 
               
               
                   
                   
                 
                   IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDK 
                 
               
               
                   
                   
                 
                   SRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 
                 
               
               
                   
               
               
                 263 
                 9G7 (VH + G2(C219S).g1) 
                 EVQLVESGGGLVKPGGSLRLSCAASGFTFSTVWMSWVR 
               
               
                   
                 or 
                 QAPGKGLEWVGRIKSKTDGGTTDYAAPVKGRFTISRDD 
               
               
                   
                 9G7-IgG2-C219S-IgG1 
                 SKNTLYLQMNSLHTEDTAVYYCTTGQLIPYSYYYGMDV 
               
               
                   
                   
                 WGQGTSVTVSS ASTKGPSVFPLAPCSRSTSESTAALGC   
               
               
                   
                   
                 
                   LVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSL 
                 
               
               
                   
                   
                 
                   SSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKSC 
                 
               
               
                   
                   
                 
                   VECPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC 
                 
               
               
                   
                   
                 
                   VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST 
                 
               
               
                   
                   
                 
                   YRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS 
                 
               
               
                   
                   
                 
                   KAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPS 
                 
               
               
                   
                   
                 
                   DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVD 
                 
               
               
                   
                   
                 
                   KSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 
                 
               
               
                   
               
               
                 264 
                 9G7 (VH + G2(C219S).g1.1) 
                 EVQLVESGGGLVKPGGSLRLSCAASGFTFSTVWMSWVR 
               
               
                   
                 or 
                 QAPGKGLEWVGRIKSKTDGGTTDYAAPVKGRFTISRDD 
               
               
                   
                 9G7-IgG2-C219S-IgG1.1 
                 SKNTLYLQMNSLHTEDTAVYYCTTGQLIPYSYYYGMDV 
               
               
                   
                   
                 WGQGTSVTVSS ASTKGPSVFPLAPCSRSTSESTAALGC   
               
               
                   
                   
                 
                   LVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSL 
                 
               
               
                   
                   
                 
                   SSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKSC 
                 
               
               
                   
                   
                 
                   VECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCV 
                 
               
               
                   
                   
                 
                   VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY 
                 
               
               
                   
                   
                 
                   RVVSVLTVLHQDWLNGKEYKCKVSNKALPSSIEKTISK 
                 
               
               
                   
                   
                 
                   AKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD 
                 
               
               
                   
                   
                 
                   IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDK 
                 
               
               
                   
                   
                 
                   SRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 
                 
               
               
                   
               
               
                 265 
                 14E3 (VH + G2) or 
                 QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWSWIR 
               
               
                   
                 14E3-IgG2 
                 QPPGKGLEWIGEINHSGNTYYNPSLKSRVTISVDTSKN 
               
               
                   
                   
                 QLSLKLSSVTAADTAVYYCARFGSNDAFDIWGQGTMVT 
               
               
                   
                   
                 VSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPE   
               
               
                   
                   
                 
                   PVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPS 
                 
               
               
                   
                   
                 
                   SNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPA 
                 
               
               
                   
                   
                 
                   PPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHED 
                 
               
               
                   
                   
                 
                   PEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTV 
                 
               
               
                   
                   
                 
                   VHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREP 
                 
               
               
                   
                   
                 
                   QVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESN 
                 
               
               
                   
                   
                 
                   GQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNV 
                 
               
               
                   
                   
                 
                   FSCSVMHEALHNHYTQKSLSLSPG 
                 
               
               
                   
               
               
                 266 
                 14E3 (VH + G2(C219S)) or 
                 QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWSWIR 
               
               
                   
                 14E3-IgG2-C219S 
                 QPPGKGLEWIGEINHSGNTYYNPSLKSRVTISVDTSKN 
               
               
                   
                   
                 QLSLKLSSVTAADTAVYYCARFGSNDAFDIWGQGTMVT 
               
               
                   
                   
                 VSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPE   
               
               
                   
                   
                 
                   PVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPS 
                 
               
               
                   
                   
                 
                   SNFGTQTYTCNVDHKPSNTKVDKTVERKSCVECPPCPA 
                 
               
               
                   
                   
                 
                   PPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHED 
                 
               
               
                   
                   
                 
                   PEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTV 
                 
               
               
                   
                   
                 
                   VHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREP 
                 
               
               
                   
                   
                 
                   QVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESN 
                 
               
               
                   
                   
                 
                   GQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNV 
                 
               
               
                   
                   
                 
                   FSCSVMHEALHNHYTQKSLSLSPG 
                 
               
               
                   
               
               
                 267 
                 14E3 (VH + G2.g1) or 
                 QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWSWIR 
               
               
                   
                 14E3-IgG2-IgG1 
                 QPPGKGLEWIGEINHSGNTYYNPSLKSRVTISVDTSKN 
               
               
                   
                   
                 QLSLKLSSVTAADTAVYYCARFGSNDAFDIWGQGTMVT 
               
               
                   
                   
                 VSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPE   
               
               
                   
                   
                 
                   PVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPS 
                 
               
               
                   
                   
                 
                   SNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPA 
                 
               
               
                   
                   
                 
                   PELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE 
                 
               
               
                   
                   
                 
                   DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLT 
                 
               
               
                   
                   
                 
                   VLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPRE 
                 
               
               
                   
                   
                 
                   PQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWES 
                 
               
               
                   
                   
                 
                   NGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN 
                 
               
               
                   
                   
                 
                   VFSCSVMHEALHNHYTQKSLSLSPG 
                 
               
               
                   
               
               
                 268 
                 14E3 (VH + G2.g1.1) or 
                 QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWSWIR 
               
               
                   
                 14E3-IgG2-IgG1.1 
                 QPPGKGLEWIGEINHSGNTYYNPSLKSRVTISVDTSKN 
               
               
                   
                   
                 QLSLKLSSVTAADTAVYYCARFGSNDAFDIWGQGTMVT 
               
               
                   
                   
                 VSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPE   
               
               
                   
                   
                 
                   PVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPS 
                 
               
               
                   
                   
                 
                   SNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPA 
                 
               
               
                   
                   
                 
                   PPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHED 
                 
               
               
                   
                   
                 
                   PEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTV 
                 
               
               
                   
                   
                 
                   LHQDWLNGKEYKCKVSNKALPSSIEKTISKAKGQPREP 
                 
               
               
                   
                   
                 
                   QVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESN 
                 
               
               
                   
                   
                 
                   GQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV 
                 
               
               
                   
                   
                 
                   FSCSVMHEALHNHYTQKSLSLSPG 
                 
               
               
                   
               
               
                 269 
                 14E3 (VH + G2(C219S).g1) 
                 QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWSWIR 
               
               
                   
                 or 
                 QPPGKGLEWIGEINHSGNTYYNPSLKSRVTISVDTSKN 
               
               
                   
                 14E3-IgG2-C219S-IgG1 
                 QLSLKLSSVTAADTAVYYCARFGSNDAFDIWGQGTMVT 
               
               
                   
                   
                 VSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPE   
               
               
                   
                   
                 
                   PVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPS 
                 
               
               
                   
                   
                 
                   SNFGTQTYTCNVDHKPSNTKVDKTVERKSCVECPPCPA 
                 
               
               
                   
                   
                 
                   PELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE 
                 
               
               
                   
                   
                 
                   DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLT 
                 
               
               
                   
                   
                 
                   VLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPRE 
                 
               
               
                   
                   
                 
                   PQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWES 
                 
               
               
                   
                   
                 
                   NGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN 
                 
               
               
                   
                   
                 
                   VFSCSVMHEALHNHYTQKSLSLSPG 
                 
               
               
                   
               
               
                 270 
                 14E3 (VH  
                 QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWSWIR 
               
               
                   
                 G2(C219S).g1.1) or 
                 QPPGKGLEWIGEINHSGNTYYNPSLKSRVTISVDTSKN 
               
               
                   
                 14E3-IgG2-C219S-IgG1.1 
                 QLSLKLSSVTAADTAVYYCARFGSNDAFDIWGQGTMVT 
               
               
                   
                   
                 VSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPE   
               
               
                   
                   
                 
                   PVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPS 
                 
               
               
                   
                   
                 
                   SNFGTQTYTCNVDHKPSNTKVDKTVERKSCVECPPCPA 
                 
               
               
                   
                   
                 
                   PPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHED 
                 
               
               
                   
                   
                 
                   PEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTV 
                 
               
               
                   
                   
                 
                   LHQDWLNGKEYKCKVSNKALPSSIEKTISKAKGQPREP 
                 
               
               
                   
                   
                 
                   QVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESN 
                 
               
               
                   
                   
                 
                   GQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV 
                 
               
               
                   
                   
                 FSCSVMHEALHNHYTQKSLSLSPG 
               
               
                   
               
               
                 131 
                 19H8 (VH + G2) or 
                 SEQ ID NO: 131 
               
               
                   
                 19H8-IgG2 
                   
               
               
                   
               
               
                 271 
                 19H8 (VH + G2(C219S)) or 
                 QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMHWVR 
               
               
                   
                 19H8-IgG2-C219S 
                 QAPGKGLEWMAVIWYGGSNKFYADSVKGRFTISRDNSK 
               
               
                   
                   
                 NSLSLQMNSLRAEDTAVYYCARGGAMVRGVYYYGMDVW 
               
               
                   
                   
                 GQGTTVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCL   
               
               
                   
                   
                 
                   VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS 
                 
               
               
                   
                   
                 
                   SVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKSCV 
                 
               
               
                   
                   
                 
                   ECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVV 
                 
               
               
                   
                   
                 
                   VDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSIFR 
                 
               
               
                   
                   
                 
                   VVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKI 
                 
               
               
                   
                   
                 
                   KGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDI 
                 
               
               
                   
                   
                 
                   AVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKS 
                 
               
               
                   
                   
                 
                   RWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 
                 
               
               
                   
               
               
                 272 
                 19H8 (VH + G2.g1) or 
                 QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMHWVR 
               
               
                   
                 19H8-IgG2-IgG1 
                 QAPGKGLEWMAVIWYGGSNKFYADSVKGRFTISRDNSK 
               
               
                   
                   
                 NSLSLQMNSLRAEDTAVYYCARGGAMVRGVYYYGMDVW 
               
               
                   
                   
                 GQGTTVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCL   
               
               
                   
                   
                 
                   VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS 
                 
               
               
                   
                   
                 
                   SVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCV 
                 
               
               
                   
                   
                 
                   ECPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
                 
               
               
                   
                   
                 
                   VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY 
                 
               
               
                   
                   
                 
                   RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISK 
                 
               
               
                   
                   
                 
                   AKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD 
                 
               
               
                   
                   
                 
                   IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDK 
                 
               
               
                   
                   
                 
                   SRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 
                 
               
               
                   
               
               
                 273 
                 19H8 (VH + G2.g1.1) or 
                 QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMHWVR 
               
               
                   
                 19H8-IgG2-IgG1.1 
                 QAPGKGLEWMAVIWYGGSNKFYADSVKGRFTISRDNSK 
               
               
                   
                   
                 NSLSLQMNSLRAEDTAVYYCARGGAMVRGVYYYGMDVW 
               
               
                   
                   
                 GQGTTVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCL   
               
               
                   
                   
                 
                   VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS 
                 
               
               
                   
                   
                 
                   SVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCV 
                 
               
               
                   
                   
                 
                   ECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVV 
                 
               
               
                   
                   
                 
                   VDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR 
                 
               
               
                   
                   
                 
                   VVSVLTVLHQDWLNGKEYKCKVSNKALPSSIEKTISKA 
                 
               
               
                   
                   
                 
                   KGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDI 
                 
               
               
                   
                   
                 
                   AVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKS 
                 
               
               
                   
                   
                 
                   RWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 
                 
               
               
                   
               
               
                 274 
                 19H8 (VH + G2(C219S).g1) 
                 QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMHWVR 
               
               
                   
                 or 
                 QAPGKGLEWMAVIWYGGSNKFYADSVKGRFTISRDNSK 
               
               
                   
                 19H8-IgG2-C219S-IgG1 
                 NSLSLQMNSLRAEDTAVYYCARGGAMVRGVYYYGMDVW 
               
               
                   
                   
                 GQGTTVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCL   
               
               
                   
                   
                 
                   VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS 
                 
               
               
                   
                   
                 
                   SVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKSCV 
                 
               
               
                   
                   
                 
                   ECPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
                 
               
               
                   
                   
                 
                   VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY 
                 
               
               
                   
                   
                 
                   RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISK 
                 
               
               
                   
                   
                 
                   AKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD 
                 
               
               
                   
                   
                 
                   IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDK 
                 
               
               
                   
                   
                 
                   SRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 
                 
               
               
                   
               
               
                 275 
                 19H8 (VH  
                 QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMHWVR 
               
               
                   
                 G2(C219S).g1.1) or 
                 QAPGKGLEWMAVIWYGGSNKFYADSVKGRFTISRDNSK 
               
               
                   
                 19H8-IgG2-C219S-IgG1.1 
                 NSLSLQMNSLRAEDTAVYYCARGGAMVRGVYYYGMDVW 
               
               
                   
                   
                 GQGTTVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCL   
               
               
                   
                   
                 
                   VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS 
                 
               
               
                   
                   
                 
                   SVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKSCV 
                 
               
               
                   
                   
                 
                   ECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVV 
                 
               
               
                   
                   
                 
                   VDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR 
                 
               
               
                   
                   
                 
                   VVSVLTVLHQDWLNGKEYKCKVSNKALPSSIEKTISKA 
                 
               
               
                   
                   
                 
                   KGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDI 
                 
               
               
                   
                   
                 
                   AVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKS 
                 
               
               
                   
                   
                 
                   RWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 
                 
               
               
                   
               
               
                 276 
                 Heavy chain C-terminus 
                 LSPG 
               
               
                   
               
               
                 277 
                 — 
                   
               
               
                   
               
               
                 278 
                 Wildtype human IgG1 CH1 
                 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT 
               
               
                   
                   
                 VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL 
               
               
                   
                   
                 GTQTYICNVNHKPSNTKVDKKV 
               
               
                   
               
               
                 279 
                 Wildtype human IgG2 CH1 
                 ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVT 
               
               
                   
                   
                 VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNF 
               
               
                   
                   
                 GTQTYTCNVDHKPSNTKVDKTV 
               
               
                   
               
               
                 280 
                 Wildtype human IgG1 CH2 
                 PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF 
               
               
                   
                   
                 NWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW 
               
               
                   
                   
                 LNGKEYKCKVSNKALPAPIEKTISKAK 
               
               
                   
               
               
                 281 
                 Human IgG1 CH2 with 
                 PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF 
               
               
                   
                 A330S/P331S 
                 NWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW 
               
               
                   
                   
                 LNGKEYKCKVSNKALPSSIEKTISKAK 
               
               
                   
               
               
                 282 
                 Wildtype human IgG1 CH3 
                 GQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIA 
               
               
                   
                   
                 VEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSR 
               
               
                   
                   
                 WQQGNVFSCSVMHEALHNHYTQKSLSLSPG 
               
               
                   
               
               
                 283 
                 IgG1-IgG2-IgG1f 
                 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT 
               
               
                   
                   
                 VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL 
               
               
                   
                   
                 GTQTYICNVNHKPSNTKVDKKV ERKCCVECPPCPAPEL   
               
               
                   
                   
                   LGG PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPE 
               
               
                   
                   
                 VKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH 
               
               
                   
                   
                 QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQV 
               
               
                   
                   
                 YTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQ 
               
               
                   
                   
                 PENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS 
               
               
                   
                   
                 CSVMHEALHNHYTQKSLSLSPG 
               
               
                   
               
               
                 284 
                 IgG1-IgG2CS-IgG1f 
                 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT 
               
               
                   
                   
                 VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL 
               
               
                   
                   
                 GTQTYICNVNHKPSNTKVDKKV ERKSCVECPPCPAPPV   
               
               
                   
                   
                   AG PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEV 
               
               
                   
                   
                 KFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQ 
               
               
                   
                   
                 DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVY 
               
               
                   
                   
                 TLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP 
               
               
                   
                   
                 ENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSC 
               
               
                   
                   
                 SVMHEALHNHYTQKSLSLSPG 
               
               
                   
               
               
                 285 
                 IgG1-IgG2-IgG1.1f 
                 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT 
               
               
                   
                   
                 VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL 
               
               
                   
                   
                 GTQTYICNVNHKPSNTKVDKKV ERKCCVECPPCPAPPV   
               
               
                   
                   
                   AG PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEV 
               
               
                   
                   
                 KFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQ 
               
               
                   
                   
                 DWLNGKEYKCKVSNKALPSSIEKTISKAKGQPREPQVY 
               
               
                   
                   
                 TLPPSRREMTKNQVSLTCLVKGFYPSDIAVEWESNGQP 
               
               
                   
                   
                 ENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSC 
               
               
                   
                   
                 SVMHEALHNHYTQKSLSLSPG 
               
               
                   
               
               
                 286 
                 IgG1-IgG2CS-IgG1.1f 
                 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT 
               
               
                   
                   
                 VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL 
               
               
                   
                   
                 GTQTYICNVNHKPSNTKVDKKV ERKSCVECPPCPAPPV   
               
               
                   
                   
                   AG PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEV 
               
               
                   
                   
                 KFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQ 
               
               
                   
                   
                 DWLNGKEYKCKVSNKALP SS IEKTISKAKGQPREPQVY 
               
               
                   
                   
                 TLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP 
               
               
                   
                   
                 ENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSC 
               
               
                   
                   
                 SVMHEALHNHYTQKSLSLSPG 
               
               
                   
               
               
                 287 
                 IgG1-IgG2-1gG1f2 
                 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT 
               
               
                   
                   
                 VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL 
               
               
                   
                   
                 GTQTYICNVNHKPSNTKVDKKV ERKCCVECPPCPAPPV   
               
               
                   
                   
                   AG PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEV 
               
               
                   
                   
                 KFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQ 
               
               
                   
                   
                 DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVY 
               
               
                   
                   
                 TLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP 
               
               
                   
                   
                 ENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSC 
               
               
                   
                   
                 SVMHEALHNHYTQKSLSLSPG 
               
               
                   
               
               
                 288 
                 IgG1-IgG2(C219S)-IgG1f2 
                 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT 
               
               
                   
                   
                 VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL 
               
               
                   
                   
                 GTQTYICNVNHKPSNTKVDKKV ERKSCVECPPCPAPPV   
               
               
                   
                   
                   AG PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEV 
               
               
                   
                   
                 KFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQ 
               
               
                   
                   
                 DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVY 
               
               
                   
                   
                 TLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP 
               
               
                   
                   
                 ENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSC 
               
               
                   
                   
                 SVMHEALHNHYTQKSLSLSPG 
               
               
                   
               
               
                 289 
                 IgG2-IgG1f2 
                 ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVT 
               
               
                   
                   
                 VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNF 
               
               
                   
                   
                 GTQTYTCNVDHKPSNTKVDKTV ERKCCVECPPCPAPPV   
               
               
                   
                   
                   AG PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEV 
               
               
                   
                   
                 KFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQ 
               
               
                   
                   
                 DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVY 
               
               
                   
                   
                 TLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP 
               
               
                   
                   
                 ENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSC 
               
               
                   
                   
                 SVMHEALHNHYTQKSLSLSPG 
               
               
                   
               
               
                 290 
                 IgG2(C219S)-IgG1f2 
                 ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVT 
               
               
                   
                   
                 VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNF 
               
               
                   
                   
                 GTQTYTCNVDHKPSNTKVDKTV ERKSCVECPPCPAPPV   
               
               
                   
                   
                   AG PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEV 
               
               
                   
                   
                 KFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQ 
               
               
                   
                   
                 DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVY 
               
               
                   
                   
                 TLPPSR EEM TKNQVSLTCLVKGFYPSDIAVEWESNGQP 
               
               
                   
                   
                 ENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSC 
               
               
                   
                   
                 SVMHEALHNHYTQKSLSLSPG 
               
               
                   
               
               
                 291 
                 WT human IgG2 hinge 
                 ERKCCVECPPCPAPPVAG 
               
               
                   
               
               
                 292 
                 Human IgG2 hinge with 
                 ERK S CVECPPCPAPPVAG 
               
               
                   
                 C219S 
                   
               
               
                   
               
               
                 293 
                 IgG2/IgG1 hinge 
                 ERKCCVECPPCPAP ELLGG   
               
               
                   
               
               
                 294 
                 IgG2 (C219S)/IgG1 hinge 
                 ERK S CVECPPCPAP ELLGG   
               
               
                   
               
               
                 295 
                 Wild type human IgG1 hinge 
                 EPKSCDKTHTCPPCPAPELLGG 
               
               
                   
               
               
                 296 
                 IgG1.1 Hinge 
                 EPKSCDKTHTCPPCPAPE AE G A   
               
               
                   
                 (L234A/L235E/G237A) 
                   
               
               
                   
               
               
                 297 
                 Wildtype human IgG2 CH2 
                 PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQF 
               
               
                   
                   
                 NWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDW 
               
               
                   
                   
                 LNGKEYKCKVSNKGLPAPIEKTISKTK 
               
               
                   
               
               
                 298 
                 Wildtype human IgG2 CH3 
                 GQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIA 
               
               
                   
                   
                 VEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSR 
               
               
                   
                   
                 WQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 
               
               
                   
               
               
                 299 
                 IgG1 C-termianl C H 1 (same 
                 VDKRV 
               
               
                   
                 for IgG3 (17-15-15-15), 
                   
               
               
                   
                 igG3 (17-15-15), IgG3 (17- 
                   
               
               
                   
                 15), IgG3 (15-15-15), IgG3 
                   
               
               
                   
                 (15), and IgG4 
                   
               
               
                   
               
               
                 300 
                 IgG2 C-termianl C H 1 
                 VDKTV 
               
               
                   
               
               
                 301 
                 IgG1 upper hinge 
                 EPKSCDKTHT 
               
               
                   
               
               
                 302 
                 IgG3 (17-15-15-15) upper 
                 ELKTPLGDTTHT 
               
               
                   
                 hinge (same for IgG3 (17-15- 
                   
               
               
                   
                 15) and IgG3 (17-15)) 
                   
               
               
                   
               
               
                 303 
                 IgG3 (15-15-15) upper hinge 
                 EPKS 
               
               
                   
                 (same for IgG3(15)) 
                   
               
               
                   
               
               
                 304 
                 IgG4 upper hinge 
                 ESKYGPP 
               
               
                   
               
               
                 305 
                 IgG1 middle hinge 
                 CPPCP 
               
               
                   
               
               
                 306 
                 IgG2 middle hinge 
                 CCVECPPCP 
               
               
                   
               
               
                 307 
                 IgG3 (17-15-15-15) middle 
                 CPRCP(EPKSCDTPPPCPRCP) 3   
               
               
                   
                 hinge 
                   
               
               
                   
               
               
                 308 
                 IgG3 (17-15-15) middle 
                 CPRCP(EPKSCDTPPPCPRCP) 2   
               
               
                   
                 hinge 
                   
               
               
                   
               
               
                 309 
                 IgG3 (17-15) middle hinge 
                 CPRCPEPKSCDTPPPCPRCP 
               
               
                   
               
               
                 310 
                 IgG3 (15-15-15) middle 
                 CDTPPPCPRCP(EPKSCDTPPPCPRCP) 2   
               
               
                   
                 hinge 
                   
               
               
                   
               
               
                 311 
                 IgG3 (15) middle hinge 
                 CDTPPPCPRCP 
               
               
                   
               
               
                 312 
                 IgG4 middle hinge 
                 CPSCP 
               
               
                   
               
               
                 313 
                 IgG1 lower hinge (same for 
                 APELLGG 
               
               
                   
                 IgG3 (17-15-15-15), IgG3 
                   
               
               
                   
                 (17-15-15), IgG3 (17-15), 
                   
               
               
                   
                 IgG3 (15-15-15), IgG3 (15), 
                   
               
               
                   
                 and IgG4) 
                   
               
               
                   
               
               
                 314 
                 IgG2 lower hinge 
                 APPVAG 
               
               
                   
               
               
                 315 
                 28F3 VH signal sequence 
                 MEFGLSWVFLVALLRGVQC 
               
               
                   
                 (same for 18E10, 19D3, 
                   
               
               
                   
                 19H8, 6G10) 
                   
               
               
                   
               
               
                 316 
                 28F3 VH signal sequence 
                 ATGGAGTTTGGGCTGAGCTGGGTTTTCCTCGTTGCTCT 
               
               
                   
                 (nucleotide sequence) 
                 TTTAAGAGGTGTCCAGTGT 
               
               
                   
               
               
                 317 
                 28F3 VL signal sequence 
                 MDMRVPAQLLGLLLLWLPGARC 
               
               
                   
                 (same for 18E10, 8A6, 
                   
               
               
                   
                 19H8VL1, 6G10) 
                   
               
               
                   
               
               
                 318 
                 28F3 VL signal sequence 
                 ATGGACATGAGGGTCCCCGCTCAGCTCCTGGGGCTTCT 
               
               
                   
                 (nucleotide sequence) 
                 GCTGCTCTGGCTCCCAGGTGCCAGAT 
               
               
                   
               
               
                 319 
                 19D3 VL signal sequence 
                 MRVLAQLLGLLLLCFPGARC 
               
               
                   
               
               
                 320 
                 19D3 VL signal sequence 
                 ATGAGGGTCCTCGCTCAGCTCCTGGGGCTCCTGCTGCT 
               
               
                   
                 (nucleotide sequence) 
                 CTGTTTCCCAGGTGCCAGATGT 
               
               
                   
               
               
                 321 
                 3C3 VH signal sequence 
                 MKHLWFFLLLVAAPRWVLS 
               
               
                   
                 (same for 14E3) 
                   
               
               
                   
               
               
                 322 
                 3C3 VH signal sequence 
                 ATGAAACACCTGTGGTTCTTCCTCCTCCTGGTGGCAGC 
               
               
                   
                 (nucleotide sequence) 
                 TCCCAGATGGGTCCTGTCC 
               
               
                   
               
               
                 323 
                 3C3 VL signal sequence 
                 MDMRVLAQLLGLLLLCFPGARC 
               
               
                   
                 (same for 14E3) 
                   
               
               
                   
               
               
                 324 
                 3C3 VL signal sequence 
                 ATGGACATGAGGGTCCTCGCTCAGCTCCTGGGGCTCCT 
               
               
                   
                 (nucleotide sequence) 
                 GCTGCTCTGTTTCCCAGGTGCCAGATGT 
               
               
                   
               
               
                 325 
                 3C3 VL2 signal sequence 
                 MEAPAQLLFLLLLWLPDTTG 
               
               
                   
                 (same for 19H8 VL2) 
                   
               
               
                   
               
               
                 326 
                 3C3 VL2 signal sequence 
                 ATGGAAGCCCCAGCGCAGCTTCTCTTCCTCCTGCTACT 
               
               
                   
                 (nucleotide sequence) 
                 CTGGCTCCCAGATACCACCGGA 
               
               
                   
               
               
                 327 
                 8A6 VH signal sequence 
                 MEFGLNWVFLVALLRGVQC 
               
               
                   
               
               
                 328 
                 8A6 VH signal sequence 
                 ATGGAGTTTGGGCTGAACTGGGTTTTCCTCGTTGCTCT 
               
               
                   
                 (nucleotide sequence) 
                 TTTAAGAGGTGTCCAGTGT 
               
               
                   
               
               
                 329 
                 9G7 VH signal sequence 
                 MEFGLSWIFLAAILKGVQC 
               
               
                   
               
               
                 330 
                 9G7 VH signal sequence 
                 ATGGAGTTTGGGCTGAGCTGGATTTTCCTTGCTGCTAT 
               
               
                   
                 (nucleotide sequence) 
                 TTTAAAAGGTGTCCAGTGT 
               
               
                   
               
               
                 331 
                 9G7 VL1 and VL2 signal 
                 METPAQLLFLLLLWLPDTTG 
               
               
                   
                 sequence 
                   
               
               
                   
               
               
                 332 
                 9G7 VL1 and VL2 signal 
                 ATGGAAACCCCAGCGCAGCTTCTCTTCCTCCTGCTACT 
               
               
                   
                 sequence (nucleotide 
                 CTGGCTCCCAGATACCACCGGA 
               
               
                   
                 sequence) 
                   
               
               
                   
               
               
                 333 
                 14E3 VH signal sequence 
                 MKHLWFFLLLVAAPRWVLS 
               
               
                   
               
               
                 334 
                 14E3 VH signal sequence 
                 ATGAAACACCTGTGGTTCTTCCTCCTCCTGGTGGCAGC 
               
               
                   
                 (nucleotide sequence) 
                 TCCCAGATGGGTCCTGTCC 
               
               
                   
               
               
                 335 
                 6G10 (VH) 
                 QVQLVESGGDVVQPGRSLRLSCAASGFTFSTYGMHWVR 
               
               
                   
                   
                 QAPGKGLEWVAVTWYAGSNKFYADSVKGRFTISRDNSK 
               
               
                   
                   
                 NTLYLQMNSLRAEDTAVYYCARGGSMVRGLYYYGMDVW 
               
               
                   
                   
                 GQGTTVTVSS 
               
               
                   
               
               
                 336 
                 6G10 (VL) 
                 AIQLTQSPSSLSASVGDRVTITCRASQGISSALAWYQQ 
               
               
                   
                   
                 KPGKAPKLLIYDASSLESGVPSRFSGSGSGTDFTLTIS 
               
               
                   
                   
                 SLQPEDFATYYCQQFNSYPYTFGQGTKLEIK 
               
               
                   
               
               
                 337 
                 6G10 (full length wild-type 
                 QVQLVESGGDVVQPGRSLRLSCAASGFTFSTYGMHWVR 
               
               
                   
                 heavy chain) 
                 QAPGKGLEWVAVTWYAGSNKFYADSVKGRFTISRDNSK 
               
               
                   
                 The constant region is 
                 NTLYLQMNSLRAEDTAVYYCARGGSMVRGLYYYGMDVW 
               
               
                   
                 underlined 
                 GQGTTVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCL   
               
               
                   
                   
                 
                   VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS 
                 
               
               
                   
                   
                 
                   SVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCV 
                 
               
               
                   
                   
                 
                   ECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVV 
                 
               
               
                   
                   
                 
                   VDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFR 
                 
               
               
                   
                   
                 
                   VVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKI 
                 
               
               
                   
                   
                 
                   KGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDI 
                 
               
               
                   
                   
                 
                   AVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKS 
                 
               
               
                   
                   
                 
                   RWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 
                 
               
               
                   
               
               
                 338 
                 6G10 (full length wild-type 
                 AIQLTQSPSSLSASVGDRVTITCRASQGISSALAWYQQ 
               
               
                   
                 light chain) 
                 KPGKAPKLLIYDASSLESGVPSRFSGSGSGTDFTLTIS 
               
               
                   
                 The constant region is 
                 SLQPEDFATYYCQQFNSYPYTFGQGTKLEIK RTVAAPS   
               
               
                   
                 underlined 
                 
                   VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDN 
                 
               
               
                   
                   
                 
                   ALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHK 
                 
               
               
                   
                   
                 
                   VYACEVTHQGLSSPVTKSFNRGEC 
                 
               
               
                   
               
               
                 339 
                 6G10.IgG1 (VH + IgG1) 
                 QVQLVESGGDVVQPGRSLRLSCAASGFTFSTYGMHWVR 
               
               
                   
                   
                 QAPGKGLEWVAVTWYAGSNKFYADSVKGRFTISRDNSK 
               
               
                   
                   
                 NTLYLQMNSLRAEDTAVYYCARGGSMVRGLYYYGMDVW 
               
               
                   
                   
                 GQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL 
               
               
                   
                   
                 VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS 
               
               
                   
                   
                 SVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCD 
               
               
                   
                   
                 KTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEV 
               
               
                   
                   
                 TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYN 
               
               
                   
                   
                 STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT 
               
               
                   
                   
                 ISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFY 
               
               
                   
                   
                 PSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLT 
               
               
                   
                   
                 VDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 
               
               
                   
               
               
                 340 
                 6G10.IgG1.1 (VH + IgG1.1) 
                 QVQLVESGGDVVQPGRSLRLSCAASGFTFSTYGMHWVR 
               
               
                   
                   
                 QAPGKGLEWVAVTWYAGSNKFYADSVKGRFTISRDNSK 
               
               
                   
                   
                 NTLYLQMNSLRAEDTAVYYCARGGSMVRGLYYYGMDVW 
               
               
                   
                   
                 GQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL 
               
               
                   
                   
                 VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS 
               
               
                   
                   
                 SVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCD 
               
               
                   
                   
                 KTHTCPPCPAPE AE G A PSVFLFPPKPKDTLMISRTPEV 
               
               
                   
                   
                 TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYN 
               
               
                   
                   
                 STYRVVSVLTVLHQDWLNGKEYKCKVSNKALP SS IEKT 
               
               
                   
                   
                 ISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFY 
               
               
                   
                   
                 PSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLT 
               
               
                   
                   
                 VDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 
               
               
                   
               
               
                 341 
                 6G10.IgG1 (VL + CL) 
                 AIQLTQSPSSLSASVGDRVTITCRASQGISSALAWYQQ 
               
               
                   
                   
                 KPGKAPKLLIYDASSLESGVPSRFSGSGSGTDFTLTIS 
               
               
                   
                   
                 SLQPEDFATYYCQQFNSYPYTFGQGTKLEIKRTVAAPS 
               
               
                   
                   
                 VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDN 
               
               
                   
                   
                 ALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHK 
               
               
                   
                   
                 VYACEVTHQGLSSPVTKSFNRGEC 
               
               
                   
               
               
                 342 
                 6G10 VH CDR1 
                 TYGMH 
               
               
                   
               
               
                 343 
                 6G10 VH CDR2 
                 VTWYAGSNKFYADSVKG 
               
               
                   
               
               
                 344 
                 6G10 VH CDR3 
                 GGSMVRGLYYYGMDV 
               
               
                   
               
               
                 345 
                 6G10 VL CDR1 
                 RASQGISSALA 
               
               
                   
               
               
                 346 
                 6G10 VL CDR2 
                 DASSLES 
               
               
                   
               
               
                 347 
                 6G10 VL CDR3 
                 QQFNSYPYT 
               
               
                   
               
               
                 337 
                 6G10 (VH + G2) or 6G10- 
                 SEQ ID NO: 337 
               
               
                   
                 IgG2 
                   
               
               
                   
               
               
                 348 
                 6G10 (VH + G2(C219S)) or 
                 QVQLVESGGDVVQPGRSLRLSCAASGFTFSTYGMHWVR 
               
               
                   
                 6G10-IgG2-C219S 
                 QAPGKGLEWVAVTWYAGSNKFYADSVKGRFTISRDNSK 
               
               
                   
                   
                 NTLYLQMNSLRAEDTAVYYCARGGSMVRGLYYYGMDVW 
               
               
                   
                   
                 GQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCL 
               
               
                   
                   
                 VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS 
               
               
                   
                   
                 SVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTV ERKSCV   
               
               
                   
                   
                   ECPPCPAPPVAG PSVFLFPPKPKDTLMISRTPEVTCVV 
               
               
                   
                   
                 VDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFR 
               
               
                   
                   
                 VVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKI 
               
               
                   
                   
                 KGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDI 
               
               
                   
                   
                 AVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKS 
               
               
                   
                   
                 RWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 
               
               
                   
               
               
                 349 
                 6G10 (VH + G2.g1) or 
                 QVQLVESGGDVVQPGRSLRLSCAASGFTFSTYGMHWVR 
               
               
                   
                 6G10-IgG2-IgG1 
                 QAPGKGLEWVAVTWYAGSNKFYADSVKGRFTISRDNSK 
               
               
                   
                   
                 NTLYLQMNSLRAEDTAVYYCARGGSMVRGLYYYGMDVW 
               
               
                   
                   
                 GQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCL 
               
               
                   
                   
                 VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS 
               
               
                   
                   
                 SVVTVPSSNFGTQTYTCNVDHKPSNTKVDKT VERKCCV   
               
               
                   
                   
                   ECPPCPAPELLGG PSVFLFPPKPKDTLMISRTPEVTCV 
               
               
                   
                   
                 VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY 
               
               
                   
                   
                 RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISK 
               
               
                   
                   
                 AKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD 
               
               
                   
                   
                 IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDK 
               
               
                   
                   
                 SRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 
               
               
                   
               
               
                 350 
                 6G10 (VH + G2.g1.1) or 
                 QVQLVESGGDVVQPGRSLRLSCAASGFTFSTYGMHWVR 
               
               
                   
                 6G10-IgG2-IgG1.1 
                 QAPGKGLEWVAVTWYAGSNKFYADSVKGRFTISRDNSK 
               
               
                   
                   
                 NTLYLQMNSLRAEDTAVYYCARGGSMVRGLYYYGMDVW 
               
               
                   
                   
                 GQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCL 
               
               
                   
                   
                 VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS 
               
               
                   
                   
                 SVVTVPSSNFGTQTYTCNVDHKPSNTKVDKT VERKCCV   
               
               
                   
                   
                   ECPPCPAPPVAG PSVFLFPPKPKDTLMISRTPEVTCVV 
               
               
                   
                   
                 VDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR 
               
               
                   
                   
                 VVSVLTVLHQDWLNGKEYKCKVSNKALPSSIEKTISKA 
               
               
                   
                   
                 KGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDI 
               
               
                   
                   
                 AVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKS 
               
               
                   
                   
                 RWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 
               
               
                   
               
               
                 351 
                 6G10 (VH + G2(C219S).g1) 
                 QVQLVESGGDVVQPGRSLRLSCAASGFTFSTYGMHWVR 
               
               
                   
                 or 6G10-IgG2-C219S-IgG1 
                 QAPGKGLEWVAVTWYAGSNKFYADSVKGRFTISRDNSK 
               
               
                   
                   
                 NTLYLQMNSLRAEDTAVYYCARGGSMVRGLYYYGMDVW 
               
               
                   
                   
                 GQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCL 
               
               
                   
                   
                 VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS 
               
               
                   
                   
                 SVVTVPSSNFGTQTYTCNVDHKPSNTKVDKT VERKSCV   
               
               
                   
                   
                   ECPPCPAPELLGG PSVFLFPPKPKDTLMISRTPEVTCV 
               
               
                   
                   
                 VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY 
               
               
                   
                   
                 RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISK 
               
               
                   
                   
                 AKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD 
               
               
                   
                   
                 IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDK 
               
               
                   
                   
                 SRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 
               
               
                   
               
               
                 352 
                 6G10 (VH  
                 QVQLVESGGDVVQPGRSLRLSCAASGFTFSTYGMHWVR 
               
               
                   
                 G2(C219S).g1.1) or 6G10- 
                 QAPGKGLEWVAVTWYAGSNKFYADSVKGRFTISRDNSK 
               
               
                   
                 IgG2-C219S-IgG1.1 
                 NTLYLQMNSLRAEDTAVYYCARGGSMVRGLYYYGMDVW 
               
               
                   
                   
                 GQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCL 
               
               
                   
                   
                 VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS 
               
               
                   
                   
                 SVVTVPSSNFGTQTYTCNVDHKPSNTKVDKT VERKSCV   
               
               
                   
                   
                   ECPPCPAPPVAG PSVFLFPPKPKDTLMISRTPEVTCVV 
               
               
                   
                   
                 VDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR 
               
               
                   
                   
                 VVSVLTVLHQDWLNGKEYKCKVSNKALP SS IEKTISKA 
               
               
                   
                   
                 KGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDI 
               
               
                   
                   
                 AVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKS 
               
               
                   
                   
                 RWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 
               
               
                   
               
               
                 353 
                 6G10 (VH) nucleotide 
                 CAGGTGCAGCTGGTGGAGTCTGGGGGAGACGTGGTCCA 
               
               
                   
                 sequence 
                 GCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGCGTCTG 
               
               
                   
                   
                 GATTCACCTTCAGTACCTATGGCATGCACTGGGTCCGC 
               
               
                   
                   
                 CAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTAC 
               
               
                   
                   
                 ATGGTATGCTGGAAGTAATAAATTTTATGCAGACTCCG 
               
               
                   
                   
                 TGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAG 
               
               
                   
                   
                 AACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGA 
               
               
                   
                   
                 GGACACGGCTGTGTATTACTGTGCGAGAGGAGGTAGTA 
               
               
                   
                   
                 TGGTTCGGGGACTTTATTATTACGGTATGGACGTCTGG 
               
               
                   
                   
                 GGCCAAGGGACCACGGTCACCGTCTCCTCA 
               
               
                   
               
               
                 354 
                 6G10 (VL) nucleotide 
                 GCCATCCAGTTGACCCAGTCTCCATCCTCCCTGTCTGC 
               
               
                   
                 sequence 
                 ATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAA 
               
               
                   
                   
                 GTCAGGGCATTAGCAGTGCTTTAGCCTGGTATCAGCAG 
               
               
                   
                   
                 AAACCAGGGAAAGCTCCTAAGCTCCTGATCTATGATGC 
               
               
                   
                   
                 CTCCAGTTTGGAAAGTGGGGTCCCATCAAGGTTCAGCG 
               
               
                   
                   
                 GCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGC 
               
               
                   
                   
                 AGCCTGCAGCCTGAAGATTTTGCAACTTATTACTGTCA 
               
               
                   
                   
                 ACAGTTTAATAGTTACCCGTACACTTTTGGCCAGGGGA 
               
               
                   
                   
                 CCAAGCTGGAGATCAAA 
               
               
                   
               
               
                 355 
                 6G10 (full length wild-type 
                 CAGGTGCAGCTGGTGGAGTCTGGGGGAGACGTGGTCCA 
               
               
                   
                 heavy chain) nucleotide 
                 GCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGCGTCTG 
               
               
                   
                 sequence 
                 GATTCACCTTCAGTACCTATGGCATGCACTGGGTCCGC 
               
               
                   
                 The sequence encoding the 
                 CAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTAC 
               
               
                   
                 constant region is underlined 
                 ATGGTATGCTGGAAGTAATAAATTTTATGCAGACTCCG 
               
               
                   
                   
                 TGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAG 
               
               
                   
                   
                 AACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGA 
               
               
                   
                   
                 GGACACGGCTGTGTATTACTGTGCGAGAGGAGGTAGTA 
               
               
                   
                   
                 TGGTTCGGGGACTTTATTATTACGGTATGGACGTCTGG 
               
               
                   
                   
                 GGCCAAGGGACCACGGTCACCGTCTCCTCA GCCTCCAC   
               
               
                   
                   
                 
                   CAAGGGCCCATCGGTCTTCCCCCTGGCGCCCTGCTCCA 
                 
               
               
                   
                   
                 
                   GGAGCACCTCCGAGAGCACAGCGGCCCTGGGCTGCCTG 
                 
               
               
                   
                   
                 
                   GTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTG 
                 
               
               
                   
                   
                 
                   GAACTCAGGCGCTCTGACCAGCGGCGTGCACACCTTCC 
                 
               
               
                   
                   
                 
                   CAGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGC 
                 
               
               
                   
                   
                 
                   AGCGTGGTGACCGTGCCCTCCAGCAACTTCGGCACCCA 
                 
               
               
                   
                   
                 
                   GACCTACACCTGCAACGTAGATCACAAGCCCAGCAACA 
                 
               
               
                   
                   
                 
                   CCAAGGTGGACAAGACAGTTGAGCGCAAATGTTGTGTC 
                 
               
               
                   
                   
                 
                   GAGTGCCCACCGTGCCCAGCACCACCTGTGGCAGGACC 
                 
               
               
                   
                   
                 
                   GTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCC 
                 
               
               
                   
                   
                 
                   TCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTG 
                 
               
               
                   
                   
                 
                   GTGGACGTGAGCCACGAAGACCCCGAGGTCCAGTTCAA 
                 
               
               
                   
                   
                 
                   CTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGA 
                 
               
               
                   
                   
                 
                   CAAAGCCACGGGAGGAGCAGTTCAACAGCACGTTCCGT 
                 
               
               
                   
                   
                 
                   GTGGTCAGCGTCCTCACCGTTGTGCACCAGGACTGGCT 
                 
               
               
                   
                   
                 
                   GAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAG 
                 
               
               
                   
                   
                 
                   GCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAACC 
                 
               
               
                   
                   
                 
                   AAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCC 
                 
               
               
                   
                   
                 
                   CCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCC 
                 
               
               
                   
                   
                 
                   TGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATC 
                 
               
               
                   
                   
                 
                   GCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAA 
                 
               
               
                   
                   
                 
                   CTACAAGACCACACCTCCCATGCTGGACTCCGACGGCT 
                 
               
               
                   
                   
                 
                   CCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGC 
                 
               
               
                   
                   
                 
                   AGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGAT 
                 
               
               
                   
                   
                 
                   GCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCC 
                 
               
               
                   
                   
                 
                   TCTCCCTGTCTCCGGGTAAA 
                 
               
               
                   
               
               
                 356 
                 6G10 (full length wild-type 
                 GCCATCCAGTTGACCCAGTCTCCATCCTCCCTGTCTGC 
               
               
                   
                 light chain) nucleotide 
                 ATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAA 
               
               
                   
                 sequence 
                 GTCAGGGCATTAGCAGTGCTTTAGCCTGGTATCAGCAG 
               
               
                   
                 The sequence enconding the 
                 AAACCAGGGAAAGCTCCTAAGCTCCTGATCTATGATGC 
               
               
                   
                 constant region is underlined 
                 CTCCAGTTTGGAAAGTGGGGTCCCATCAAGGTTCAGCG 
               
               
                   
                   
                 GCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGC 
               
               
                   
                   
                 AGCCTGCAGCCTGAAGATTTTGCAACTTATTACTGTCA 
               
               
                   
                   
                 ACAGTTTAATAGTTACCCGTACACTTTTGGCCAGGGGA 
               
               
                   
                   
                 CCAAGCTGGAGATCAAA CGAACTGTGGCTGCACCATCT   
               
               
                   
                   
                 
                   GTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATC 
                 
               
               
                   
                   
                 
                   TGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCT 
                 
               
               
                   
                   
                 
                   ATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAAC 
                 
               
               
                   
                   
                 
                   GCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGA 
                 
               
               
                   
                   
                 
                   GCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCA 
                 
               
               
                   
                   
                 
                   CCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAA 
                 
               
               
                   
                   
                 
                   GTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTC 
                 
               
               
                   
                   
                 
                   GCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT 
                 
               
               
                   
               
               
                 357 
                 28F3 (VH) (SEQ ID NO: 13) 
                   MRAWIFFLLCLAGRALA QVQLVESGGGVVQPGRSLRLS 
               
               
                   
                 with signal peptide 
                 CAASGFTFSSYGMHWVRQAPGKGLEWVAVIWYEGSNKY 
               
               
                   
                 The signal peptide is 
                 YADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCA 
               
               
                   
                 underlined 
                 RGGSMVRGDYYYGMDVWGQGTTVTVSS 
               
               
                   
               
               
                 358 
                 28F3 (VL) (SEQ ID NO: 14) 
                   MRAWIFFLLCLAGRALA AIQLTQSPSSLSASVGDRVTI 
               
               
                   
                 with signal peptide 
                 TCRASQGISSALAWYQQKPGKAPKLLIYDASSLESGVP 
               
               
                   
                 The signal peptide is 
                 SRFSGSGSGTDFTLTISSLQPEDFATYYCQQFNSYPYT 
               
               
                   
                 underlined 
                 FGQGTKLEIK 
               
               
                   
               
               
                 359 
                 28F3 (VH) with signal 
                 
                   atgagggcttggatcttctttctgctctgcctggccgg 
                 
               
               
                   
                 peptide nucleotide sequence 
                   gagagcgctcgca CAGGTGCAGCTGGTGGAGTCTGGGG 
               
               
                   
                 SEQ ID NO: 147 with 
                 GAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACTCTCC 
               
               
                   
                 sequence encoding signal 
                 TGTGCAGCGTCTGGATTCACCTTCAGTAGCTATGGCAT 
               
               
                   
                 peptide 
                 GCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGT 
               
               
                   
                 The sequence encoding the 
                 GGGTGGCAGTTATATGGTATGAAGGAAGTAATAAATAT 
               
               
                   
                 signal peptide is underlined 
                 TATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAG 
               
               
                   
                   
                 AGACAATTCCAAGAACACGCTGTATCTGCAAATGAACA 
               
               
                   
                   
                 GCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCG 
               
               
                   
                   
                 AGAGGGGGGAGTATGGTTCGGGGGGACTACTACTACGG 
               
               
                   
                   
                 TATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCT 
               
               
                   
                   
                 CCTCA 
               
               
                   
               
               
                 360 
                 28F3 (VL) with signal 
                 
                   atgagggcttggatcttctttctgctctgcctggccgg 
                 
               
               
                   
                 peptide nucleotide sequence 
                   gcgcgccttggcc GCCATCCAGTTGACCCAGTCTCCAT 
               
               
                   
                 SEQ ID NO: 148 with 
                 CCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATC 
               
               
                   
                 sequence encoding signal 
                 ACTTGCCGGGCAAGTCAGGGCATTAGCAGTGCTTTAGC 
               
               
                   
                 peptide 
                 CTGGTATCAGCAGAAACCAGGGAAAGCTCCTAAGCTCC 
               
               
                   
                 The sequence encoding the 
                 TGATCTATGATGCCTCCAGTTTGGAAAGTGGGGTCCCA 
               
               
                   
                 signal peptide is underlined 
                 TCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCAC 
               
               
                   
                   
                 TCTCACCATCAGCAGCCTGCAGCCTGAAGATTTTGCAA 
               
               
                   
                   
                 CTTATTACTGTCAACAGTTTAATAGTTACCCGTACACT 
               
               
                   
                   
                 TTTGGCCAGGGGACCAAGCTGGAGATCAAA 
               
               
                   
               
               
                 361 
                 28F3.IgG1 (VH + IgG1) 
                   MRAWIFFLLCLAGRALA QVQLVESGGGVVQPGRSLRLS 
               
               
                   
                 (SEQ ID NO: 17) with signal 
                 CAASGFTFSSYGMHWVRQAPGKGLEWVAVIWYEGSNKY 
               
               
                   
                 peptide 
                 YADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCA 
               
               
                   
                 The signal peptide and 
                 RGGSMVRGDYYYGMDVWGQGTTVTVSS ASTKGPSVFPL   
               
               
                   
                 constant region are 
                 
                   APSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSG 
                 
               
               
                   
                 underlined 
                 
                   VHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH 
                 
               
               
                   
                   
                 
                   KPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFL 
                 
               
               
                   
                   
                 
                   FPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVD 
                 
               
               
                   
                   
                 
                   GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKE 
                 
               
               
                   
                   
                 
                   YKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRE 
                 
               
               
                   
                   
                 
                   EMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTT 
                 
               
               
                   
                   
                 
                   PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL 
                 
               
               
                   
                   
                 
                   HNHYTQKSLSLSPG 
                 
               
               
                   
               
               
                 362 
                 28F3.IgG1.1 (VH + IgG1.1) 
                   MRAWIFFLLCLAGRALA QVQLVESGGGVVQPGRSLRLS 
               
               
                   
                 (SEQ ID NO: 18) with signal 
                 CAASGFTFSSYGMHWVRQAPGKGLEWVAVIWYEGSNKY 
               
               
                   
                 peptide 
                 YADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCA 
               
               
                   
                 The signal peptide and 
                 RGGSMVRGDYYYGMDVWGQGTTVTVSS ASTKGPSVFPL   
               
               
                   
                 constant region are 
                 
                   APSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSG 
                 
               
               
                   
                 underlined 
                 
                   VHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH 
                 
               
               
                   
                   
                 
                   KPSNTKVDKRVEPKSCDKTHTCPPCPAPEAEGAPSVFL 
                 
               
               
                   
                   
                 
                   FPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVD 
                 
               
               
                   
                   
                 
                   GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKE 
                 
               
               
                   
                   
                 
                   YKCKVSNKALPSSIEKTISKAKGQPREPQVYTLPPSRE 
                 
               
               
                   
                   
                 
                   EMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTT 
                 
               
               
                   
                   
                 
                   PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL 
                 
               
               
                   
                   
                 
                   HNHYTQKSLSLSPG 
                 
               
               
                   
               
               
                 363 
                 28F3.IgG1 (VH + IgG1) 
                 
                   atgagggcttggatcttctttctgctctgcctggccgggagagc 
                 
               
               
                   
                 with signal peptide 
                   gctcgca caggtgcagctggtggagtotgggggaggcgtggtcca 
               
               
                   
                 nucleotide sequence 
                 gcctgggaggtccctgagactctcctgtgcagcgtctggattcacc 
               
               
                   
                 SEQ ID NO: 151 with 
                 ttcagtagctatggcatgcactgggtccgccaggctccaggcaagg 
               
               
                   
                 sequence encoding signal 
                 ggctggagtgggtggcagttatatggtatgaaggaagtaataaata 
               
               
                   
                 peptide 
                 ttatgcagactccgtgaagggccgattcaccatctccagagacaat 
               
               
                   
                 The sequence encoding the 
                 tccaagaacacgctgtatctgcaaatgaacagcctgagagccgagg 
               
               
                   
                 signal peptide is underlined 
                 acacggctgtgtattactgtgcgagaggggggagtatggttcgggg 
               
               
                   
                   
                 ggactactactacggtatggacgtctggggccaagggaccacggtc 
               
               
                   
                   
                 accgtctcctcagctagcaccaagggcccatcggtcttccccctgg 
               
               
                   
                   
                 caccctcctccaagagcacctctgggggcacagcggccctgggctg 
               
               
                   
                   
                 cctggtcaaggactacttccccgaaccggtgacggtgtcgtggaac 
               
               
                   
                   
                 tcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctac 
               
               
                   
                   
                 agtcctcaggactctactccctcagcagcgtggtgaccgtgccctc 
               
               
                   
                   
                 cagcagcttgggcacccagacctacatctgcaacgtgaatcacaag 
               
               
                   
                   
                 cccagcaacaccaaggtggacaagagagttgagcccaaatcttgtg 
               
               
                   
                   
                 acaaaactcacacatgcccaccgtgcccagcacctgaactcctggg 
               
               
                   
                   
                 gggaccgtcagtcttcctcttccccccaaaacccaaggacaccctc 
               
               
                   
                   
                 atgatctcccggacccctgaggtcacatgcgtggtggtggacgtga 
               
               
                   
                   
                 gccacgaagaccctgaggtcaagttcaactggtacgtggacggcgt 
               
               
                   
                   
                 ggaggtgcataatgccaagacaaagccgcgggaggagcagtacaac 
               
               
                   
                   
                 agcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggact 
               
               
                   
                   
                 ggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccct 
               
               
                   
                   
                 cccagcccccatcgagaaaaccatctccaaagccaaagggcagccc 
               
               
                   
                   
                 cgagaaccacaggtgtacaccctgcccccatcccgggaggagatga 
               
               
                   
                   
                 ccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcc 
               
               
                   
                   
                 cagcgacatcgccgtggagtgggagagcaatgggcagccggagaac 
               
               
                   
                   
                 aactacaagaccacgcctcccgtgctggactccgacggctccttct 
               
               
                   
                   
                 tcctctatagcaagctcaccgtggacaagagcaggtggcagcaggg 
               
               
                   
                   
                 gaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccac 
               
               
                   
                   
                 tacacgcagaagagcctctccctgtccccgggttga 
               
               
                   
               
               
                 364 
                 28F3.IgG1.1 (VH + IgG1.1) 
                 
                   atgagggcttggatcttctttctgctctgcctggccgggagagc 
                 
               
               
                   
                 with signal peptide 
                   gctcgca caggtgcagc tggtggagtc tgggggaggc 
               
               
                   
                 nucleotide sequence 
                 gtggtccagc ctgggaggtc cctgagactc tcctgtgcag 
               
               
                   
                 SEQ ID NO: 152 with 
                 cgtctggatt caccttcagt agctatggca tgcactgggt 
               
               
                   
                 sequence encoding signal 
                 ccgccaggct 
               
               
                   
                 peptide 
                 ccaggcaagg ggctggagtg ggtggcagtt atatggtatg 
               
               
                   
                 The sequence encoding the 
                 aaggaagtaa taaatattat gcagactccg tgaagggccg 
               
               
                   
                 signal peptide is underlined 
                 attcaccatc tccagagaca attccaagaa cacgctgtat 
               
               
                   
                   
                 ctgcaaatga acagcctgag agccgaggac acggctgtgt 
               
               
                   
                   
                 attactgtgc gagagggggg agtatggttc ggggggacta 
               
               
                   
                   
                 ctactacggt atggacgtct ggggccaagg gaccacggtc 
               
               
                   
                   
                 accgtctcct cagctagcac caagggccca tcggtcttcc 
               
               
                   
                   
                 ccctggcacc ctcctccaag agcacctctg ggggcacagc 
               
               
                   
                   
                 ggccctgggc tgcctggtca aggactactt ccccgaaccg 
               
               
                   
                   
                 gtgacggtgt cgtggaactc aggcgccctg accagcggcg 
               
               
                   
                   
                 tgcacacctt cccggctgtc ctacagtcct caggactcta 
               
               
                   
                   
                 ctccctcagc agcgtggtga ccgtgccctc cagcagcttg 
               
               
                   
                   
                 ggcacccaga cctacatctg caacgtgaat cacaagccca 
               
               
                   
                   
                 gcaacaccaa ggtggacaag agagttgagc ccaaatcttg 
               
               
                   
                   
                 tgacaaaact cacacatgcc caccgtgccc agcacctgaa 
               
               
                   
                   
                 gccgaagggg ccccgtcagt cttcctcttc cccccaaaac 
               
               
                   
                   
                 ccaaggacac cctcatgatc tcccggaccc ctgaggtcac 
               
               
                   
                   
                 atgcgtggtg gtggacgtga gccacgaaga ccctgaggtc 
               
               
                   
                   
                 aagttcaact ggtacgtgga cggcgtggag gtgcataatg 
               
               
                   
                   
                 ccaagacaaa gccgcgggag gagcagtaca acagcacgta 
               
               
                   
                   
                 ccgtgtggtc agcgtcctca ccgtcctgca ccaggactgg 
               
               
                   
                   
                 ctgaatggca aggagtacaa gtgcaaggtc tccaacaaag 
               
               
                   
                   
                 ccctcccaag cagcatcgag aaaaccatct ccaaagccaa 
               
               
                   
                   
                 agggcagccc cgagaaccac aggtgtacac cctgccccca 
               
               
                   
                   
                 tcccgggagg agatgaccaa gaaccaggtc agcctgacct 
               
               
                   
                   
                 gcctggtcaa aggcttctat cccagcgaca tcgccgtgga 
               
               
                   
                   
                 gtgggagagc aatgggcagc cggagaacaa ctacaagacc 
               
               
                   
                   
                 acgcctcccg tgctggactc cgacggctcc ttcttcctct 
               
               
                   
                   
                 atagcaagct caccgtggac aagagcaggt ggcagcaggg 
               
               
                   
                   
                 gaacgtcttc tcatgctccg tgatgcatga ggctctgcac 
               
               
                   
                   
                 aaccactaca cgcagaagag cctctccctg tccccgggtt ga 
               
               
                   
               
               
                 365 
                 28F3.1gG1 (VL + CL) (SEQ 
                   MRAWIFFLLCLAGRALA AIQLTQSPSSLSASVGDRVTITCRASQ 
               
               
                   
                 ID NO: 19) with signal 
                 GISSALAWYQQKPGKAPKLLIYDASSLESGVPSRFSGSGSGTDF 
               
               
                   
                 peptide 
                 TLTISSLQPEDFATYYCQQFNSYPYTFGQGTKLEIK RTVAAPSV   
               
               
                   
                 The signal peptide and 
                 
                   FIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNS 
                 
               
               
                   
                 constant region are 
                 
                   QESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSS 
                 
               
               
                   
                 underlined 
                 
                   PVTKSFNRGEC 
                 
               
               
                   
               
               
                 366 
                 28F3.1gG1 (VL + CL) with 
                 
                   atgagggcttggatcttctttctgctctgcctggccgggcgcgc 
                 
               
               
                   
                 signal peptide nucleotide 
                   cttggcc gccatccagttgacccagtotccatcctocctgtotgc 
               
               
                   
                 sequence 
                 atctgtaggagacagagtcaccatcacttgccgggcaagtcagggc 
               
               
                   
                 SEQ ID NO: 153 with signal 
                 attagcagtgctttagcctggtatcagcagaaaccagggaaagctc 
               
               
                   
                 sequence 
                 ctaagctcctgatctatgatgcctccagtttggaaagtggggtccc 
               
               
                   
                 The sequence encoding the 
                 atcaaggttcagcggcagtggatctgggacagatttcactctcacc 
               
               
                   
                 signal peptide is underlined 
                 atcagcagcctgcagcctgaagattttgcaacttattactgtcaac 
               
               
                   
                   
                 agtttaatagttacccgtacacttttggccaggggaccaagctgga 
               
               
                   
                   
                 gatcaaacgtacggtggctgcaccatctgtcttcatcttcccgcca 
               
               
                   
                   
                 tctgatgagcagttgaaatctggaactgcctctgttgtgtgcctgc 
               
               
                   
                   
                 tgaataacttctatcccagagaggccaaagtacagtggaaggtgga 
               
               
                   
                   
                 taacgccctccaatcgggtaactcccaggagagtgtcacagagcag 
               
               
                   
                   
                 gacagcaaggacagcacctacagcctcagcagcaccctgacgctga 
               
               
                   
                   
                 gcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcac 
               
               
                   
                   
                 ccatcagggcctgagctcgcccgtcacaaagagcttcaacaggg 
               
               
                   
                   
                 gagagtgttag 
               
               
                   
               
               
                 367 
                 Signal peptide 
                 MRAWIFFLLCLAGRALA 
               
               
                   
               
               
                 368 
                 Signal peptide nucleotide 
                 atgagggcttggatcttctttctgctctgcctggccgg 
               
               
                   
                 sequence 
                 gagagcgctcgca 
               
               
                   
               
               
                 369 
                 Signal peptide nucleotide 
                 atgagggcttggatcttctttctgctctgcctggccgg 
               
               
                   
                 sequence 
                 gcgcgccttggcc 
               
               
                   
               
               
                 370 
                 Human GITR fragment 
                 QRPTGGPGCGPGRLLLGTGTDARCCRVHTTR 
               
               
                   
               
               
                 371 
                 9G7 L1 (full length wild- 
                 EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQ 
               
               
                   
                 type light chain 1) 
                 QKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTI 
               
               
                   
                 The constant region is 
                 SRLEPEDFAVYYCQQYGSSPWTFGQGTKVEIK RTVAAP   
               
               
                   
                 underlined 
                 
                   SVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVD 
                 
               
               
                   
                   
                 
                   NALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKH 
                 
               
               
                   
                   
                 
                   KVYACEVTHQGLSSPVTKSFNRGEC 
                 
               
               
                   
               
               
                 372 
                 degenerate VH CDR1 
                 SYGXH, wherein X is any amino acid 
               
               
                   
               
               
                 373 
                 degenerate VH CDR2 
                 VIWYX 1 GSNKX 2 YADSVKG, wherein X 1  and X 2   
               
               
                   
                   
                 are any amino acids 
               
               
                   
               
               
                 374 
                 degenerate VH CDR2 
                 VIWYX 1 GSNKX 2 YX 3 DSVKG, wherein X 1 , X 2 , 
               
               
                   
                   
                 and X 3  are any amino acids 
               
               
                   
               
               
                 375 
                 degenerate VH CDR3 
                 GGSX 1 VRGDYYYGMDV, wherein X 1  is any 
               
               
                   
                   
                 amino acid 
               
               
                   
               
               
                 376 
                 degenerate VH CDR3 
                 GGSX 1 VRGX 2 YYYGMDV, wherein X 1  and X 2   
               
               
                   
                   
                 are any amino acids 
               
               
                   
               
               
                 377 
                 degenerate VH CDR3 
                 GG (6-7aa) MDVWYYX 1 MDVW, wherein X 1  is 
               
               
                   
                   
                 any amino acid, and the 6-7 amino 
               
               
                   
                   
                 acids are any amino acids 
               
               
                   
               
               
                 378 
                 degenerate VL CDR1 
                 RASQGISSXLA, wherein X is any amino 
               
               
                   
                   
                 acid 
               
               
                   
               
               
                 379 
                 degenerate VL CDR1 
                 RASQG (2-3 aa) SX 1 LA, wherein X1 is 
               
               
                   
                   
                 any amino acid, and the 2-3 amino 
               
               
                   
                   
                 acids are any amino acids 
               
               
                   
               
               
                 380 
                 degenerate VL CDR2 
                 DASSLXS, wherein X is any amino acid 
               
               
                   
               
               
                 381 
                 degenerate VL CDR3 
                 QQXNSYPYT, wherein X is any amino acid 
               
               
                   
               
               
                 382 
                 degenerate VL CDR3 
                 QQX 1 X 2 SX 3 PX 4 T, wherein X 1 , X 2 , X 3 , and X 4   
               
               
                   
                   
                 are any amino acids 
               
               
                   
               
            
           
         
       
     
     Atty. Docket No.: MXI-559US 
     Atty. Docket No.: MXI-559US 
     The Table above provides the sequences of the mature variable regions and heavy and light chains and where indicated, sequences with signal peptides. 
     
       
         
           
               
               
             
               
                 TABLE 3 
               
               
                   
               
               
                 SEQ 
                   
               
               
                 ID 
                   
               
               
                 NO: 
                 SEQUENCE 
               
               
                   
               
             
            
               
                 383 
                 Heavy Chain Variable Region (VH) Amino Acid Sequence 
               
               
                   
                 Anti-PD-L1 mAb (12A4; 12A4 in WO 2007/005874 and U.S. 
               
               
                   
                 Pat. No. 7,943,743) 
               
               
                   
                 QVQLVQSGAEVKKPGSSVKVSCKTSGDTFSTYAISWVRQAPGQGLEWMGGII 
               
               
                   
                 PIFGKAHYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYFCARKFHFVS 
               
               
                   
                 GSPFGMDVWGQGTTVTVSS 
               
               
                   
               
               
                 384 
                 Heavy Chain Variable Region (VH) Nucleotide Sequence 
               
               
                   
                 Anti-PD-L1 mAb (12A4; 12A4 in WO 2007/005874 and U.S. 
               
               
                   
                 Pat. No. 7,943,743) 
               
               
                   
                 cag gtc cag ctg gtg cag tct ggg gct gag gtg aag aag 
               
               
                   
                 cct ggg tcc 
               
               
                   
                 tcg gtg aag gtc tcc tgc aag act tct gga gac acc ttc 
               
               
                   
                 agc acc tat 
               
               
                   
                 gct atc agc tgg gtg cga cag gcc cct gga caa ggg ctt 
               
               
                   
                 gag tgg atg 
               
               
                   
                 gga ggg atc atc cct ata ttt ggt aaa gca cac tac gca 
               
               
                   
                 cag aag ttc 
               
               
                   
                 cag ggc aga gtc acg att acc gcg gac gaa tcc acg agc 
               
               
                   
                 aca gcc tac 
               
               
                   
                 atg gag ctg agc agc ctg aga tct gag gac acg gcc gtg 
               
               
                   
                 tat ttt tgt 
               
               
                   
                 gcg aga aag ttt cac ttt gtt tcg ggg agc ccc ttc ggt 
               
               
                   
                 atg gac gtc 
               
               
                   
                 tgg ggc caa ggg acc acg gtc acc gtc tcc 
               
               
                   
               
               
                 385 
                 Light Chain Variable Region (VL) Amino Acid Sequence 
               
               
                   
                 Anti-PD-L1 mAb (12A4; 12A4 in WO 2007/005874 and U.S. 
               
               
                   
                 Pat. No. 7,943,743) 
               
               
                   
                 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIY 
               
               
                   
                 DASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPTFG 
               
               
                   
                 QGTKVEIK 
               
               
                   
               
               
                 386 
                 Light Chain Variable Region (VL) Nucleotide Sequence 
               
               
                   
                 Anti-PD-L1 mAb (12A4; 12A4 in WO 2007/005874 and U.S. 
               
               
                   
                 Pat. No. 7,943,743) 
               
               
                   
                 gaa att gtg ttg aca cag tct cca gcc acc ctg tct ttg 
               
               
                   
                 tct cca ggg 
               
               
                   
                 gaa aga gcc acc ctc tcc tgc agg gcc agt cag agt gtt 
               
               
                   
                 agc agc tac 
               
               
                   
                 tta gcc tgg tac caa cag aaa cct ggc cag gct ccc agg 
               
               
                   
                 ctc ctc atc 
               
               
                   
                 tat gat gca tcc aac agg gcc act ggc atc cca gcc agg 
               
               
                   
                 ttc agt ggc 
               
               
                   
                 agt ggg tct ggg aca gac ttc act ctc acc atc agc agc 
               
               
                   
                 cta gag cct 
               
               
                   
                 gaa gat ttt gca gtt tat tac tgt cag cag cgt agc aac 
               
               
                   
                 tgg ccg acg 
               
               
                   
                 ttc ggc caa ggg acc aag gtg gaa atc aaa 
               
               
                   
               
               
                 387 
                 Heavy Chain CDR1 Amino Acid Sequence 
               
               
                   
                 Anti-PD-L1 mAb (12A4; 12A4 in WO 2007/005874 and U.S. 
               
               
                   
                 Pat. No. 7,943,743) 
               
               
                   
                 TYAIS 
               
               
                   
               
               
                 388 
                 Heavy Chain CDR2 Amino Acid Sequence 
               
               
                   
                 Anti-PD-L1 mAb (12A4; 12A4 in WO 2007/005874 and U.S. 
               
               
                   
                 Pat. No. 7,943,743) 
               
               
                   
                 GIIPIFGKAHYAQKFQ 
               
               
                   
               
               
                 389 
                 Heavy Chain CDR3 Amino Acid Sequence 
               
               
                   
                 Anti-PD-L1 mAb (12A4; 12A4 in WO 2007/005874 and U.S. 
               
               
                   
                 Pat. No. 7,943,743) 
               
               
                   
                 KFHFVSGSPFGMDV 
               
               
                   
               
               
                 390 
                 Light Chain CDR1 Amino Acid Sequence 
               
               
                   
                 Anti-PD-L1 mAb (12A4; 12A4 in WO 2007/005874 and U.S. 
               
               
                   
                 Pat. No. 7,943,743) 
               
               
                   
                 RASQSVSSYLA 
               
               
                   
               
               
                 391 
                 Light Chain CDR2 Amino Acid Sequence 
               
               
                   
                 Anti-PD-L1 mAb (12A4; 12A4 in WO 2007/005874 and U.S. 
               
               
                   
                 Pat. No. 7,943,743) 
               
               
                   
                 DASNRAT 
               
               
                   
               
               
                 392 
                 Light Chain CDR3 Amino Acid Sequence 
               
               
                   
                 Anti-PD-L1 mAb (12A4; 12A4 in WO 2007/005874 and U.S. 
               
               
                   
                 Pat. No. 7,943,743) 
               
               
                   
                 QQRSNWPT 
               
               
                   
               
               
                 393 
                 Heavy Chain Amino Acid Sequence 
               
               
                   
                 Anti-PD-1 mAb (5C4 in WO 2006/121168) 
               
               
                   
                 (variable region underlined; constant region bold) 
               
               
                   
                 
                   QVQLVESGGGVVQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGL 
                 
               
               
                   
                 
                   EWVAVIWYDGSKRYYADSVKGRFTISRDNSKNTLFLQMNSLRAEDT 
                 
               
               
                   
                 
                   AVYYCATNDDYWGQGTLVTVSS 
                   ASTKGPSVFPLAPCSRSTSESTAA 
                 
               
               
                   
                 
                   LGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVT 
                 
               
               
                   
                 
                   VPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLG 
                 
               
               
                   
                 
                   GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGV 
                 
               
               
                   
                 
                   EVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKG 
                 
               
               
                   
                 
                   LPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPS 
                 
               
               
                   
                 
                   DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNV 
                 
               
               
                   
                 
                   FSCSVMHEALHNHYTQKSLSLSLGK 
                 
               
               
                   
               
               
                 394 
                 Light Chain Amino Acid Sequence 
               
               
                   
                 Anti-PD-1 mAb (5C4 in WO 2006/121168) 
               
               
                   
                 (variable region underlined; constant region bold) 
               
               
                   
                 
                   EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLI 
                 
               
               
                   
                 
                   YDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSSNWPR 
                 
               
               
                   
                 
                   TFGQGTKVEIK 
                   RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREA 
                 
               
               
                   
                 
                   KVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHK 
                 
               
               
                   
                 
                   VYACEVTHQGLSSPVTKSFNRGEC 
                 
               
               
                   
               
               
                 395 
                 Heavy Chain Variable Region (VH) Amino Acid Sequence 
               
               
                   
                 Anti-PD-1 mAb (5C4 in WO 2006/121168) 
               
               
                   
                 (SEQ ID NO: 4 from WO 2006/121168) 
               
               
                   
                 QVQLVESGGGVVQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGLEWVAV 
               
               
                   
                 IWYDGSKRYYADSVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCATND 
               
               
                   
                 DYWGQGTLVTVSS 
               
               
                   
               
               
                 396 
                 Heavy Chain Variable Region (VH) Nucleotide Sequence 
               
               
                   
                 Anti-PD-1 mAb (5C4 in WO 2006/121168) 
               
               
                   
                 (SEQ ID NO: 60 from WO 2006/121168) 
               
               
                   
                 cag gtg cag ctg gtg gag tct ggg gga ggc gtg gtc cag 
               
               
                   
                 cct ggg agg tcc ctg aga ctc gac tgt aaa gcg tct gga 
               
               
                   
                 atc acc 
               
               
                   
                 ttc agt aac tct ggc atg cac tgg gtc cgc cag gct cca 
               
               
                   
                 ggc 
               
               
                   
                 aag ggg ctg gag tgg gtg gca gtt att tgg tat gat gga 
               
               
                   
                 agt aaa aga tac tat gca gac tcc gtg aag ggc cga ttc 
               
               
                   
                 acc atc tcc aga gac aat tcc aag aac acg ctg ttt ctg 
               
               
                   
                 caa atg aac 
               
               
                   
                 agc ctg aga gcc gag gac acg gct gtg tat tac tgt gcg 
               
               
                   
                 aca 
               
               
                   
                 aac gac gac tac tgg ggc cag gga acc ctg gtc acc gtc 
               
               
                   
                 tcc 
               
               
                   
                 tca 
               
               
                   
               
               
                 397 
                 Light Chain Variable Region (VL) Amino Acid Sequence 
               
               
                   
                 Anti-PD-1 mAb (5C4 in WO 2006/121168) 
               
               
                   
                 (SEQ ID NO: 11 from WO 2006/121168) 
               
               
                   
                 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYD 
               
               
                   
                 ASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSSNWPRTFGQ 
               
               
                   
                 GTKVEIK 
               
               
                   
               
               
                 398 
                 Light Chain Variable Region (VL) Nucleotide Sequence 
               
               
                   
                 Anti-PD-1 mAb (5C4 in WO 2006/121168) 
               
               
                   
                 (SEQ ID NO: 67 from WO 2006/121168) 
               
               
                   
                 gaa att gtg ttg aca cag tct cca gcc acc ctg tct ttg 
               
               
                   
                 tct cca ggg gaa aga gcc acc ctc tcc tgc agg gcc agt 
               
               
                   
                 cag agt 
               
               
                   
                 gtt agt agt tac tta gcc tgg tac caa cag aaa cct ggc 
               
               
                   
                 cag 
               
               
                   
                 gct ccc agg ctc ctc atc tat gat gca tcc aac agg gcc 
               
               
                   
                 act ggc atc cca gcc agg ttc agt ggc agt ggg tct ggg 
               
               
                   
                 aca gac 
               
               
                   
                 ttc act ctc acc atc agc agc cta gag cct gaa gat ttt 
               
               
                   
                 gca gtt tat tac tgt cag cag agt agc aac tgg cct cgg 
               
               
                   
                 acg ttc 
               
               
                   
                 ggc caa ggg acc aag gtg gaa atc aaa 
               
               
                   
               
               
                 399 
                 Heavy Chain CDR1 Amino Acid Sequence 
               
               
                   
                 Anti-PD-1 mAb (5C4 in WO 2006/121168) 
               
               
                   
                 (SEQ ID NO: 18 from WO 2006/121168) 
               
               
                   
                 NSGMH 
               
               
                   
               
               
                 400 
                 Heavy Chain CDR2 Amino Acid Sequence 
               
               
                   
                 Anti-PD-1 mAb (5C4 in WO 2006/121168) 
               
               
                   
                 (SEQ ID NO: 25 from WO 2006/121168) 
               
               
                   
                 VIWYDGSKRYYADSVKG 
               
               
                   
               
               
                 401 
                 Heavy Chain CDR3 Amino Acid Sequence 
               
               
                   
                 Anti-PD-1 mAb (5C4 in WO 2006/121168) 
               
               
                   
                 (SEQ ID NO: 32 from WO 2006/121168) 
               
               
                   
                 NDDY 
               
               
                   
               
               
                 402 
                 Light Chain CDR1 Amino Acid Sequence 
               
               
                   
                 Anti-PD-1 mAb (5C4 in WO 2006/121168) 
               
               
                   
                 (SEQ ID NO: 39 from WO 2006/121168) 
               
               
                   
                 RASQSVSSYLA 
               
               
                   
               
               
                 403 
                 Light Chain CDR2 Amino Acid Sequence 
               
               
                   
                 Anti-PD-1 mAb (5C4 in WO 2006/121168) 
               
               
                   
                 (SEQ ID NO: 46 from WO 2006/121168) 
               
               
                   
                 DASNRAT 
               
               
                   
               
               
                 404 
                 Light Chain CDR3 Amino Acid Sequence 
               
               
                   
                 Anti-PD-1 mAb (5C4 in WO 2006/121168) 
               
               
                   
                 (SEQ ID NO: 53 from WO 2006/121168) 
               
               
                   
                 QQSSNWPRT 
               
               
                   
               
               
                 405 
                 Complete PD-1 sequence (GenBank Accession No.: U64863) 
               
               
                   
                 agtttccctt ccgctcacct ccgcctgagc agtggagaag gcggcactct 
               
               
                   
                 ggtggggctg ctccaggcat gcagatccca caggcgccct ggccagtcgt 
               
               
                   
                 ctgggcggtg ctacaactgg gctggcggcc aggatggttc ttagactccc 
               
               
                   
                 cagacaggcc ctggaacccc cccaccttct tcccagccct gctcgtggtg 
               
               
                   
                 accgaagggg acaacgccac cttcacctgc agcttctcca acacatcgga 
               
               
                   
                 gagcttcgtg ctaaactggt accgcatgag ccccagcaac cagacggaca 
               
               
                   
                 agctggccgc cttccccgag gaccgcagcc agcccggcca ggactgccgc 
               
               
                   
                 ttccgtgtca cacaactgcc caacgggcgt gacttccaca tgagcgtggt 
               
               
                   
                 cagggcccgg cgcaatgaca gcggcaccta cctctgtggg gccatctccc 
               
               
                   
                 tggcccccaa ggcgcagatc aaagagagcc tgcgggcaga gctcagggtg 
               
               
                   
                 acagagagaa gggcagaagt gcccacagcc caccccagcc cctcacccag 
               
               
                   
                 gccagccggc cagttccaaa ccctggtggt tggtgtcgtg ggcggcctgc 
               
               
                   
                 tgggcagcct ggtgctgcta gtctgggtcc tggccgtcat ctgctcccgg 
               
               
                   
                 gccgcacgag ggacaatagg agccaggcgc accggccagc ccctgaagga 
               
               
                   
                 ggacccctca gccgtgcctg tgttctctgt ggactatggg gagctggatt 
               
               
                   
                 tccagtggcg agagaagacc ccggagcccc ccgtgccctg tgtccctgag 
               
               
                   
                 cagacggagt atgccaccat tgtctttcct agcggaatgg gcacctcatc 
               
               
                   
                 ccccgcccgc aggggctcag ccgacggccc tcggagtgcc cagccactga 
               
               
                   
                 ggcctgagga tggacactgc tcttggcccc tctgaccggc ttccttggcc 
               
               
                   
                 accagtgttc tgcagaccct ccaccatgag cccgggtcag cgcatttcct 
               
               
                   
                 caggagaagc aggcagggtg caggccattg caggccgtcc aggggctgag 
               
               
                   
                 ctgcctgggg gcgaccgggg ctccagcctg cacctgcacc aggcacagcc 
               
               
                   
                 ccaccacagg actcatgtct caatgcccac agtgagccca ggcagcaggt 
               
               
                   
                 gtcaccgtcc cctacaggga gggccagatg cagtcactgc ttcaggtcct 
               
               
                   
                 gccagcacag agctgcctgc gtccagctcc ctgaatctct gctgctgctg 
               
               
                   
                 ctgctgctgc tgctgctgcc tgcggcccgg ggctgaaggc gccgtggccc 
               
               
                   
                 tgcctgacgc cccggagcct cctgcctgaa cttgggggct ggttggagat 
               
               
                   
                 ggccttggag cagccaaggt gcccctggca gtggcatccc gaaacgccct 
               
               
                   
                 ggacgcaggg cccaagactg ggcacaggag tgggaggtac atggggctgg 
               
               
                   
                 ggactcccca ggagttatct gctccctgca ggcctagaga agtttcaggg 
               
               
                   
                 aaggtcagaa gagctcctgg ctgtggtggg cagggcagga aacccctccc 
               
               
                   
                 acctttacac atgcccaggc agcacctcag gccctttgtg gggcagggaa 
               
               
                   
                 gctgaggcag taagcgggca ggcagagctg gaggcctttc aggccagcca 
               
               
                   
                 gcactctggc ctcctgccgc cgcattccac cccagcccct cacaccactc 
               
               
                   
                 gggagaggga catcctacgg tcccaaggtc aggagggcag ggctggggtt 
               
               
                   
                 gactcaggcc cctcccagct gtggccacct gggtgttggg agggcagaag 
               
               
                   
                 tgcaggcacc tagggccccc catgtgccca ccctgggagc tctccttgga 
               
               
                   
                 acccattcct gaaattattt aaaggggttg gccgggctcc caccagggcc 
               
               
                   
                 tgggtgggaa ggtacaggcg ttcccccggg gcctagtacc cccgcgtggc 
               
               
                   
                 ctatccactc ctcacatcca cacactgcac ccccactcct ggggcagggc 
               
               
                   
                 caccagcatc caggcggcca gcaggcacct gagtggctgg gacaagggat 
               
               
                   
                 cccccttccc tgtggttcta ttatattata attataatta aatatgagag 
               
               
                   
                 catgct 
               
               
                   
               
               
                 406 
                 Human PD-L1 amino acid sequence-isoform a precursor 
               
               
                   
                 (GenBank Accession No. NP_054862.1) 
               
               
                   
                 MRIFAVFIFM TYWHLLNAFT VTVPKDLYVV EYGSNMTIEC KFPVEKQLDL 
               
               
                   
                 AALIVYWEME DKNIIQFVHG EEDLKVQHSS 
               
               
                   
                 YRQRARLLKD QLSLGNAALQ ITDVKLQDAG VYRCMISYGG 
               
               
                   
                 ADYKRITVKV NAPYNKINQR ILVVDPVTSE HELTCQAEGY PKAEVIWTSS 
               
               
                   
                 DHQVLSGKTT TTNSKREEKL FNVTSTLRIN 
               
               
                   
                 TTTNEIFYCT FRRLDPEENH TAELVIPELP LAHPPNERTH 
               
               
                   
                 LVILGAILLC LGVALTFIFR LRKGRMMDVK KCGIQDTNSK KQSDTHLEET 
               
               
                   
               
               
                 407 
                 Human PD-L1 amino acid sequence-isoform b precursor 
               
               
                   
                 (GenBank Accession No. NP_001254635.1) 
               
               
                   
                 MRIFAVFIFM TYWHLLNAPY NKINQRILVV DPVTSEHELT CQAEGYPKAE 
               
               
                   
                 VIWTSSDHQV LSGKTTTTNS KREEKLFNVT 
               
               
                   
                 STLRINTTTN EIFYCTFRRL DPEENHTAEL VIPELPLAHP 
               
               
                   
                 PNERTHLVIL GAILLCLGVA LTFIFRLRKG RMMDVKKCGI QDTNSKKQSD 
               
               
                   
                 THLEET 
               
               
                   
               
            
           
         
       
     
     The present disclosure is further illustrated by the following examples, which should not be construed as further limiting. The contents of all figures and all references, Genbank sequences, patents and published patent applications cited throughout this application are expressly incorporated herein by reference. In particular, the disclosures of PCT publications WO 09/045957, WO 09/073533, WO 09/073546, WO 09/054863, PCT/US2013/072918, WO16168716, PCT/US2015/033991 (W015/187,835), WO16081746, WO16196792, WO17087678, U.S. Pat. No. 9,228,016 (application Ser. No. 14/732,082) and U.S. Patent Publication No. 2011/0150892 are expressly incorporated herein by reference. 
     EXAMPLES 
     Example 1: Anti-GITR Agonist Abs for Treatment of Advanced Solid Tumors 
     Anti-GITR agonist Ab 28F3.IgG1 will be administered to subjects with advanced solid tumors to determine safety, tolerability and efficacy. When referring to administration of an anti-GITR Ab in this and the next Examples, the anti-GITR Ab is Ab 28F3.IgG1 (i.e., having full length heavy chain and light chain amino acid sequences of SEQ ID NOs: 17 and 19 (Table 2), respectively). A Phase ½a dose escalation and cohort expansion study for safety, tolerability, and efficacy of anti-GITR agonist Ab 28F3.IgG1 administered alone and in combination with nivolumab (BMS-936558; anti-PD-1 monoclonal antibody) in advanced solid tumors. ORR, duration of response and progression free survival rate (PFSF) will be measured at 24 weeks based on tumor measurements every 8 weeks during treatment, response and survival in follow up periods. 
     Each subject will be administered IV doses of 28F3.IgG1 at dose levels of 10, 30, 100, 240, or 800 mg once every 2 weeks, in 8-week cycles, for up to 3 cycles of study therapy. Certain patients will receive a combination therapy including 10, 30, 100, 240, or 800 mg of 28F3.IgG1 once every 2 weeks in combination with nivolumab which will be administered at a dose of 240 mg once every 2 weeks, in 8-week cycles, for up to 3 cycles of study therapy. 1 mg and 3 mg of 28F3.IgG1 may also be given. 
     Additional cycles of treatment beyond 3 cycles (for up to a total of 6 cycles) or re-treatment with monotherapy or combination therapy during the follow-up period within 12 months of the last dose of study therapy, at the dose and regimen assigned at study entry, may be administered. 
     28F3.IgG1 will be administered in 2 disease-restricted populations: (i) NSCLC subjects with progressive or recurrent disease during or after prior platinum doublet-based chemotherapy, followed by recurrent or progressive disease (per RECIST v1.1) during or after subsequent anti-PD-1 or anti-PD-L1 therapy, and (ii) persistent, recurrent or metastatic cervical cancer. 
     28F3.IgG1 will be administered in disease-restricted populations as follows: (i) NSCLC subjects with progressive or recurrent disease during or after prior platinum doublet-based chemotherapy followed by progressive or recurrent disease (per RECIST v1.1) during or after subsequent anti-PD-1 or anti-PD-L1 therapy, (ii) NSCLC subjects with progressive or recurrent disease during or after platinum doublet-based chemotherapy with no prior anti-PD-1 or anti-PD-L1 therapy, and (iii) persistent, recurrent or metastatic cervical cancer. 
     28F3.IgG1 and nivolumab will be administered as an IV infusion over 60 minutes every 2 weeks. Treatment periods will consist of up to three, 8-week treatment cycles. Each treatment cycle will comprise 4 doses of 28F3.IgG1 administered every 2 weeks on Days 1, 15, 29, and 43 of the treatment cycle. In treatments with nivolumab, each treatment cycle will comprise 4 doses of 28F3.IgG1 (administered on Days 1, 15, 29 and 43) in combination with 4 doses of nivolumab administered on Days 1, 15, 29, and 43 of the treatment cycle. When both 28F3.IgG1 and nivolumab will be given, nivolumab will be given first followed by 28F3.IgG1 at least 30 minutes after completion of the infusion of nivolumab. 
     The following combinations will be administered to patients having advanced solid tumors: 
     
       
         
           
               
               
             
               
                 TABLE 4 
               
               
                   
               
               
                 28F3.IgG1 
                 Nivolumab 
               
               
                   
               
             
            
               
                  1 mg 
                 240 mg IV q 2 weeks 
               
               
                  3 mg 
                 240 mg IV q 2 weeks 
               
               
                  10 mg 
                 240 mg IV q 2 weeks 
               
               
                  30 mg 
                 240 mg IV q 2 weeks 
               
               
                 100 mg 
                 240 mg IV q 2 weeks 
               
               
                 240 mg 
                 240 mg IV q 2 weeks 
               
               
                 800 mg 
                 240 mg IV q 2 weeks 
               
               
                   
               
            
           
         
       
     
     Intermediate or lower doses, or less frequent dosing of 28F3.IgG1 may be tested if none of the planned doses/schedules are found to be tolerated as monotherapy or in combination with nivolumab. 
     For certain treatments, subjects must have one of the following tumor types to be eligible: post-chemotherapy NSCLC or advanced/metastatic cervical cancer. 
     The following inclusion and exclusion criteria will be used: 
     Inclusion Criteria: 
     
         
         1. Consent for tumor biopsy samples 
         2. Should have ECOG performance status of ≤1 
         3. Presence of at least one lesion with measurable disease as defined by RECIST v1.1 for solid tumors for response assessment. Subjects with lesions in a previously irradiated field as the sole site of measurable disease will be permitted to enroll provided the lesion(s) have demonstrated clear progression and can be measured accurately 
         4. Subjects with prior exposure to therapy with any agent specifically targeting checkpoint pathway inhibition (such as anti-PD-1, anti-PD-L1, anti-PDL-2, anti-LAG-3, anti-CTLA-4 antibody) are permitted after a washout period of any time greater than 4 weeks from the last treatment. 
         5. Subjects with prior therapy with any agent specifically targeting T-cell co-stimulation pathways except anti-GITR antibody, such as anti-CD137, anti-OX40 antibody, are permitted after a washout period of any time greater than 4 weeks from the last treatment 
         6. Prior palliative radiotherapy must have been completed at least 2 weeks prior to first dose of study drug. Subjects with symptomatic tumor lesions at baseline that may require palliative radiotherapy within 4 weeks of first dose of study drug are strongly encouraged to receive palliative radiotherapy prior to enrollment 
         7. Subjects must consent to allow the acquisition of fresh tumor biopsy or existing formalin-fixed paraffin-embedded (FFPE) material, either a block or at least 15-20 unstained slides, for performance of correlative studies 
         8. Adequate organ function for subjects with solid tumor histologies as defined by the following:
       a. WBC≥2000/μL (stable off any growth factor within 4 weeks of first study drug administration)   b. Neutrophils≥1500/μL (stable off any growth factor within 4 weeks of first study drug administration)   c. Platelets≥100×10 3 /μL (transfusion to achieve this level is not permitted within 2 weeks of first study drug administration)   d. Hemoglobin≥8.5 g/dL (transfusion to achieve this level is not permitted within 2 weeks of first study drug administration)   e. ALT and AST≥3× ULN   f. Total bilirubin≤1.5× ULN (except subjects with Gilbert&#39;s Syndrome who must have normal direct bilirubin)   g. Normal thyroid function, subclinical hypothyroidism (TSH&lt;10 mIU/mL) or have controlled hypothyroidism on appropriate thyroid supplementation   h. Serum creatinine≤1.5× ULN or creatinine clearance (CrCl)≥40 ml/min (measured using the Cockcroft-Gault)   
     
         9. Ability to comply with treatment, PK and PD sample collection, and required study follow-up. 
         10. Dose Escalation:
       a. Subjects must have received, and then progressed or been intolerant to, at least one standard treatment regimen in the advanced or metastatic setting, if such a therapy exists. Subjects who refuse or are ineligible for standard therapy will be allowed to enroll provided their refusal/ineligibility is documented in medical records.   b. All solid tumor histologies will be permitted except for subjects with primary CNS tumors, or with CNS metastases as the only site of active disease.   
     
         11. Dose Expansion:
       a. Non-Small Cell Lung Cancer (NSCLC)
           i. All subjects must have had progressive or recurrent disease during or after platinum doublet-based chemotherapy.   ii. All subjects with non-squamous histology must have known EGFR and ALK status.   iii. Subjects with an activating EGFR mutation must have received an EGFR tyrosine kinase inhibitor.   iv. Subjects with an ALK translocation must have received an ALK inhibitor   
           b. Cervical Cancer
           i. Persistent, recurrent or metastatic cervical cancer with documented disease progression   ii. Squamous, adenosquamous or adenocarcinoma histology—confirmation of the original primary tumor is required   iii. Must have had one prior systemic chemotherapeutic regimen (e.g. paclitaxel/cisplatin, paclitaxel/cisplatin/bevacizumab) for persistent, recurrent, or metastatic disease. Chemotherapy administered concurrently with primary radiation (e.g. weekly cisplatin), adjuvant chemotherapy given following completion of radiation therapy or as concurrent chemotherapy and radiation therapy (e.g. paclitaxel and carboplatin for up to 4 cycles) is not counted as a systemic chemotherapy regimen   iv. Confirmation of tumor HPV status: Prior testing results are acceptable if known. If tumor HPV status is unknown, subjects must consent to allow their submitted archived tumor tissue sample in the form of block or unstained slides to be tested for confirmation of tumor HPV status   
           
     
       
    
     Exclusion Criteria: 
     
         
         1. Subjects with known or suspected central nervous system (CNS) metastases, untreated CNS metastases, or with the CNS as the only site of disease are excluded. However, subjects with controlled brain metastases will be allowed to enroll. Controlled brain metastases are defined as no radiographic progression for at least 4 weeks following radiation and/or surgical treatment (or 4 weeks of observation if no intervention is clinically indicated), and off of steroids for at least 2 weeks, and no new or progressive neurological signs and symptoms.
       a. Subjects with carcinomatous meningitis   b. Participation in any prior clinical study with nivolumab, including subjects in comparator arms, in which overall survival is listed as the primary or co-primary endpoint and which has not completed analysis based on the primary endpoint.   
     
         2. Subjects with a prior malignancy are excluded (except non-melanoma skin cancers, and in situ cancers such as the following: bladder, colon, cervical/dysplasia, melanoma, or breast). Subjects with other second malignancies diagnosed more than 2 years ago who have received therapy with curative intent with no evidence of disease during the interval who are considered by the investigator to present a low risk for recurrence will be eligible. 
         3. Other active malignancy requiring concurrent intervention 
         4. Prior organ allograft 
         5. Any anti-cancer therapy (e.g., chemotherapy, biologics, vaccines, or hormonal treatment) including investigational drugs within 4 weeks prior to the first dose of study drug administration, with the exception of GnRH agonist therapy for subjects with prostate cancer and anti-cancer therapies with half-life &lt;4 weeks (e.g. prior use of EGFR TKI (completed at least two weeks prior to first dose of study drug is acceptable). 
         6. Prior therapy with anti-GITR antibody 
         7. Subjects with active, known or suspected autoimmune disease. Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, euthyroid patients with a history of Grave&#39;s disease (subjects with suspected autoimmune thyroid disorders must be negative for thyroglobulin and thyroid peroxidase antibodies and thyroid stimulating immunoglobulin prior to first dose of study drug), psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll. 
         8. Subjects with interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity 
         9. Chronic Obstructive Pulmonary Disease requiring recurrent steroids bursts or chronic steroids at doses greater than 10 mg/day of prednisone or the equivalent 
         10. Subjects with a condition requiring systemic treatment with either corticosteroids (&gt;10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration except for adrenal replacement steroid doses &gt;10 mg daily prednisone equivalent in the absence of active autoimmune disease. Treatment with a short course of steroids (&lt;5 days) up to 7 days prior to initiating study drug is permitted. 
         11. Uncontrolled or significant cardiovascular disease including, but not limited to any of the following:
       a. myocardial infarction or stroke/TIA within the past 6 months   b. uncontrolled angina within the past 3 months   c. any history of clinically significant arrhythmias (such as ventricular tachycardia, ventricular fibrillation or torsades de pointes)   d. QTcF prolongation&gt;480 msec   e. history of other clinically significant heart disease (e.g., cardiomyopathy, congestive heart failure with NYHA functional classification III-IV, pericarditis, significant pericardial effusion)   f. requirement for daily supplemental oxygen therapy   
     
         12. History of any chronic hepatitis as evidenced by:
       a. Positive test for hepatitis B surface antigen (HBsAg)   b. Positive test for qualitative hepatitis C viral load (by PCR)   
     
         13. Any major surgery within 4 weeks of study drug administration. Subjects must have recovered from the effects of major surgery or significant traumatic injury at least 14 days before the first dose of study drug 
         14. Use of non-oncology vaccines containing live virus for prevention of infectious diseases within 12 weeks prior to study drug. The use of inactivated seasonal influenza vaccines e.g. Fluzone® will be permitted on study without restriction. 
         15. Use of pRBC or platelet transfusion within 2 weeks prior to the first dose of study drug. 
       
    
     Example 2: Phase ½a Study of 28F3.IgG1 Given Alone and in Combination with Nivolumab in Subjects with Advanced Solid Tumors 
     Purpose 
     The purpose of this study is to evaluate the safety, tolerability pharmacokinetics, pharmacodynamics, immunogenicity and preliminary anti-tumor activity of 28F3.IgG1 when administered alone and in combination with nivolumab in subjects with advanced solid tumors. 
     
       
         
           
               
               
               
             
               
                 TABLE 5 
               
               
                   
               
               
                 Condition 
                 Intervention 
                 Phase 
               
               
                   
               
             
            
               
                 Cervical Cancer 
                 Drug: 28F3.IgG1 
                 Phase 1/Phase 2 
               
               
                 Non-Small Cell Lung Cancer 
                 Drug: Nivolumab 
               
               
                   
               
            
           
         
       
     
     Study Type: Interventional 
     Study Design: Treatment, Parallel Assignment, Open Label, Non-Randomized, Safety/Efficacy Study 
     Official Title: A Phase 1/2a Dose Escalation and Cohort Expansion Study for Safety, Tolerability, and Efficacy of Anti-GITR Monoclonal Antibody (28F3.IgG1) Administered Alone and in Combination With Nivolumab (BMS-936558, Anti PD-1 Monoclonal Antibody) in Advanced Solid Tumors. 
     Further Study Details: 
     Primary Outcome Measure: 
     
         
         
           
             Safety of 28F3.IgG1 based on number of incidence of adverse events (AEs), serious adverse events (SAEs), adverse events leading to discontinuation and deaths in addition to clinical laboratory test abnormalities [Time Frame: Up to 30 days after the last dose of study drug] 
           
         
       
    
     Secondary Outcome Measures: 
     
         
         
           
             Objective response rate (ORR) [Time Frame: Every 8 weeks during treatment]ORR is defined as the proportion of all treated subjects whose best overall response is either a complete response (CR) or partial response (PR) 
             Progression free survival rate (PFSR) [Time Frame: Every 8 weeks during treatment] The proportion of treated subjects remaining progression free and surviving at 24 weeks. The proportion will be calculated by the K-M estimate which takes into account censored data 
             Duration of response [Time Frame: Every 8 weeks during treatment] Duration of response is defined as the time between the date of first response and the date of disease progression or death, whichever occurs first 
             Maximum observed concentration (Cmax) of 28F3.IgG1 [Time Frame: Day 1 to 56 days] 
             Time of maximum observed concentration (Tmax) of 28F3.1gG1 [Time Frame: Day 1 to 56 days] 
             Area under the concentration-time curve in one dosing interval (AUC [TAU]) of 28F3.1gG1 [Time Frame: Day 1 to 56 days] 
             Area under the plasma concentration-time curve from time zero to time of last quantifiable concentration (AUC(0-T) of 28F3.1gG1 [Time Frame: Day 1 to 56 days] 
             Anti-drug antibody (ADA) response to 28F3.1gG1 [Time Frame: Day 1 to 56 days] 
             Anti-drug antibody response to 28F3.IgGland Nivolumab [Time Frame: Day 1 to 56 days] 
           
         
       
    
     
       
         
           
               
               
             
               
                 TABLE 6 
               
               
                   
               
               
                 Arms 
                 Assigned Interventions 
               
               
                   
               
             
            
               
                 Experimental: Mono therapy - 28F3.IgG1 
                 Drug: 28F3.IgG1 
               
               
                 (Dose Escalation) 28F3.IgG1 dose as specified 
               
               
                 Experimental: Combination therapy - 
                 Drug: 28F3.IgG1 
               
               
                 28F3.IgG1 + Nivolumab (Dose Escalation) 
                 Drug: Nivolumab 
               
               
                 28F3.IgG1 + Nivolumab dose as specified 
               
               
                 Experimental: Mono therapy - 
                 Drug: 28F3.IgG1 
               
               
                 28F3.IgG1 (Dose Expansion) 28F3.IgG1 
               
               
                 dose as specified 
               
               
                 Experimental: Combination therapy - 
                 Drug: 28F3.IgG1 
               
               
                 28F3.IgG1 + Nivolumab (Dose Expansion) 
                 Drug: Nivolumab 
               
               
                 28F3.IgG1 + Nivolumab dose as specified 
               
               
                   
               
            
           
         
       
     
     Eligibility: 
     Ages Eligible for Study: 18 Years and older 
     Genders Eligible for Study: Both 
     Inclusion Criteria: 
     
         
         
           
             For Dose Escalation:
           i) Subjects with any previously treated advanced (metastatic or refractory) solid tumor   
         
             For Cohort Expansion:
           i) Subjects must have a previously treated advanced solid tumor to be eligible   
         
             Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 
             Willing and able to provide pre-treatment and on-treatment fresh tumor biopsy 
             Women of child-bearing potential and men must use an acceptable method of contraception during treatment and for 23 weeks after treatment for women and 31 weeks for men 
           
         
       
    
     Exclusion Criteria: 
     
         
         
           
             Known central nervous system metastases or central nervous system as the only source of disease 
             Other concomitant malignancies (with some exceptions per protocol) 
             Active, known or suspected autoimmune disease 
             Uncontrolled or significant cardiovascular disease 
             History of chronic hepatitis 
             History of active hepatitis (B or C) 
             Impaired liver or bone marrow function 
             Major surgery less than 1 month before start of the study. 
           
         
       
    
     Example 3: Preliminary Results of a Phase ½a Study of 28F3.IgG1 (Glucocorticoid-Induced Tumor Necrosis Factor Receptor-Related Gene [GITR] Agonist), Alone and in Combination with Nivolumab in Patients with Advanced Solid Tumors 
     Background: 28F3.IgG1 is a fully human IgG1 agonist mAb that binds GITR and promotes T effector cell activation and possible reduction/inactivation of T regulatory cells. Preclinical data show enhanced antitumor T-cell activity with anti-GITR +anti-programmed death-1 (PD-1). Here we describe preliminary dose escalation data from a phase ½a study of 28F3.IgG1±nivolumab (anti-PD-1 mAb) in patients with advanced solid tumors. Methods: During dose escalation, patients received 28F3.IgG1 (10-800 mg) or 28F3.IgG1 (30-800 mg)+nivolumab (240 mg) every 2 weeks ( FIG. 1 ). Objectives included safety (primary), immunogenicity, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy. 
     Results: As of Dec 12, 2016, 66 patients were treated with 28F3.IgG1 (n=29) or 28F3.IgG1+nivolumab (n=37). No dose-limiting toxicities (DLTs) were reported during dose escalation. The most common treatment-related adverse events reported with 28F3.IgG1/28F3.IgG1+nivolumab included pyrexia (21%/30%), chills (10%/16%), and fatigue (14%/14%); events were G½ in all patients except for 4 patients (6%) treated with the combination (G3 lipase [n=1], G3 lung infection [n=1], G3 fatigue [n=1], and G3 aspartate aminotransferase with G4 creatine phosphokinase [n=1; leading to discontinuation of treatment]). Preliminary data indicate that the incidence of immunogenicity to 28F3.IgG1 was low when 28F3.IgG1±nivolumab was administered. Preliminary data also indicate that 28F3.IgG1±nivolumab exhibits linear PK with dose proportionality after a single dose, and 28F3.IgG1±nivolumab is biologically active in PD analyses in peripheral blood. Initial antitumor activity has been observed in several patients treated with the combination. 
     Conclusions: This is the first report of clinical data with an anti-GITR mAb±a PD-1 inhibitor. 28F3.IgG1±nivolumab was well tolerated, with no DLTs and low immunogenicity. Antitumor activity was observed with 28F3.IgG1+nivolumab at doses predicted to be biologically active. Further evaluation of this combination in patients with advanced solid tumors is ongoing. 
     Example 4: Baseline Demographics, Prior Therapy, and Treatment Exposure 
     Table 7 provides information on the patients involved in the clinical trial described in Examples 1 to 3. 
     
       
         
           
               
             
               
                 TABLE 7 
               
             
            
               
                   
               
               
                 Baseline demographics, prior therapy, and treatment exposure 
               
            
           
           
               
               
               
            
               
                   
                   
                 GITR Ab + 
               
               
                   
                 GITR Ab 
                 Nivolumab 
               
               
                   
                 All Mono (n = 29) 
                 All Combo (n = 37) 
               
               
                   
                   
               
            
           
           
               
               
               
            
               
                 Median age (range), years 
                 56 (28-74) 
                 59 (21-87) 
               
               
                 ECOG performance status, n 
               
               
                 0 
                 14 
                 13  
               
               
                 1 
                 15 
                 24  
               
               
                 Tumor type, n 
               
               
                 Melanoma 
                 6 
                 1 
               
               
                 Cervical 
                 3 
                 4 
               
               
                 Colon 
                 3 
                 2 
               
               
                 Breast 
                 2 
                 2 
               
               
                 Cholangiocarcinoma 
                 2 
                 1 
               
               
                 Renal 
                 1 
                 2 
               
               
                 Pancreatic 
                 1 
                  2 a   
               
               
                 Ovarian 
                 0 
                 3 
               
               
                 Other (≤2 patients) 
                 14 
                 23  
               
               
                 Number of prior therapies, n 
               
               
                 1 
                 12 
                 15  
               
               
                 2 
                 5 
                 2 
               
               
                 ≥3 
                 9 
                 17  
               
               
                 Prior anti-PD-1/PD-L1, n 
                 7 
                 5 
               
               
                   
               
               
                   a Includes 1 patient with adenocarcinoma of the ampulla of Vater. 
               
            
           
         
       
     
     Median duration of treatment ranged from 7 to 15.5 weeks with 28F3.IgG1 monotherapy and 8 to 18 weeks with 28F3.IgG1+nivolumab (duration was longer with the 240/240 mg and 800/240 mg doses). 
     Example 5: 28F3.IgG1 ±Nivolumab is Well Tolerated 
     This Example describes any adverse events observed during the clinical trial described in Examples 1-4. 
     No Dose Related Toxicities (DLTs) or treatment-related deaths were observed, and safety with 28F3.IgG1+nivolumab is consistent with that observed in prior studies of nivolumab monotherapy. The presence or absence of treatment Related Adverse Events (TRAEs) of all patients are listed in Table 8. 
     
       
         
           
               
             
               
                 TABLE 8 
               
             
            
               
                   
               
               
                 Treatment related adverse events 
               
            
           
           
               
               
               
               
            
               
                   
                 GITR Ab 
                   
                 GITR Ab + Nivolumab 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                 All Mono 
                 All Mono 
                 30/240 mg 
                 100/240 mg 
                 240/240 mg 
                 800/240 mg 
               
               
                   
                 n = 29 
                 n = 37 
                 n = 3 
                 n = 9 
                 n = 14 
                 n = 11 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 Any treatment-related 
                 17(59) 
                 26(70) 
                 2(67) 
                 6(67) 
                 9(64) 
                 9(82) 
               
               
                 AE (TRAE), n (%) 
               
               
                 Grade 1 or 2 TRAEs 
               
               
                 in &gt;2 patients in either 
               
               
                 regimen, n 
               
               
                 Pyrexia 
                 6 
                 12 
                 2 
                 2 
                 3 
                 5 
               
               
                 Chills 
                 3 
                 7 
                 0 
                 2 
                 3 
                 2 
               
               
                 Fatigue 
                 3 
                 6 
                 0 
                 1 
                 2 
                 3 
               
               
                 Nausea 
                 5 
                 3 
                 0 
                 1 
                 1 
                 1 
               
               
                 Myalgia 
                 1 
                 6 
                 0 
                 2 
                 2 
                 2 
               
               
                 Arthralgia 
                 2 
                 4 
                 0 
                 1 
                 2 
                 1 
               
               
                 Diarrhea 
                 2 
                 3 
                 0 
                 0 
                 1 
                 2 
               
               
                 Decreased appetite 
                 1 
                 3 
                 1 
                 0 
                 0 
                 2 
               
               
                 Infusion-related reaction 
                 1 
                 3 
                 0 
                 1 
                 0 
                 2 
               
               
                 Any grade 3 or 4 TRAE, n 
               
               
                 Blood CPK increased   
                 0 
                 1 
                 0 
                 0 
                 0 
                 1 
               
               
                 Colitis d   
                 0 
                 1 
                 0 
                 0 
                 1 
                 0 
               
               
                 Dehydration   
                 0 
                 1 
                 1 
                 0 
                 0 
                 0 
               
               
                 Fatigue 
                 0 
                 1 
                 0 
                 0 
                 1 
                 0 
               
               
                 Hepatic enzyme increased   
                 0 
                 1 
                 0 
                 0 
                 0 
                 1 
               
               
                 Lipase increased 
                 0 
                 1 
                 0 
                 1 
                 0 
                 0 
               
               
                 Lung Infection 
                 0 
                 1 
                 0 
                 1 
                 0 
                 0 
               
               
                   
               
               
                   a Serious TRAE. Other serious TRAEs were grade 2 pneumonitis (800 mg) and grade 2 nephritis (100/240 mg). 
               
               
                   b Events occurred in same patient. 
               
               
                   c Grade 4 TRAE. 
               
               
                   d Discontinued due to TRAE. 
               
               
                     indicates data missing or illegible when filed 
               
            
           
         
       
     
     Safety with 28F3.IgG1+nivolumab is consistent with that observed in prior studies of nivolumab monotherapy (Brahmer J et al.  New Engl J Med.  2015;373:123-135. Motzer R J et al.  New Engl J Med.  2015;373:1803-1813. Ferris R L et al.  New Engl J Med.  2016;375:1856-1867). 
     Example 6: 28F3.IgG1±Nivolumab Demonstrates Linear PK and Low Immunogenicity 
     This Example provides PK and immunogenicity data from patients involved in the clinical trial described in Examples 1 to 5. 
       FIG. 2  shows the GITR Ab (28F3.IgG1) concentration (μg/ml) at various times (in days) following administration of the first dose in patients treated with the GITR Ab or GITR Ab and nivolumab. The plots in  FIG. 2  show that:
         PK is linear and not affected by combination with 240 mg nivolumab;   240 mg-dose (±nivolumab; steady state levels) exceeds the concentration estimated to be biologically active in preclinical studies (13 μg/mL; dotted line); and   Immunogenicity was low and no patients had persistent positive anti-drug antibodies.       

     In addition, the PK of GITR Ab monotherapy is linear at dose range 10-800 mg, and the half-life of the antibody is 9-12 days. 
     Example 7: 28F3.IgG1±Nivolumab Increases Proliferating (Ki67+) NK and CD8 Cells in Peripheral Blood 
     This Example provides PD data from patients involved in the clinical trial described in Examples 1 to 6. 
     At day 8 following administration of the first dose of GITR Ab or GITR Ab and nivolumab to patients, GITR Ab with or without nivolumab increases proliferating (Ki67+) NK and CD8 cells in the peripheral blood of patients (see  FIG. 3 ). Proliferating CD8+T cell levels were determined by measuring the level of CD45+CD3+CD4-CD8+Ki67+cells. Ki67 positive cells were detected with the anti-Ki-67 antibody PerCP5.5 (clone B56; Cat#561284, BD Biosciences). 
     The following protocol was used for flow cytometric analysis of proliferating NK cells. Blood samples were collected by direct vein puncture and collected in Streck Cytochex BCT tubes. Collection of the blood in these tubes allows the samples to be accurately analyzed up to 72 hour post blood collection. An aliquot was taken for TBNK (BD biosciences) analysis for downstream calculation of absolute counts of discreet cell populations. The remainder of the sample was subjected to lysing of the red blood cells using the standard BD pharmlyse procedure. The cells were then stained using fluorescently labeled antibodies specific for surface antigens CD45-ApC-H7 (2D1, BD biosciences), CD3-AF700 (SK7, Biolegend), CD16-BV510 (3G8, BD biosciences), CD27-BV605 (0323, Biolegend), CD56-AF647 (HCD56, Biolegend), CD94-FITC (DX22, Biolegend), NKp46-BV421 (9E2, BD biosciences), HLA-DR-BV650 (G46-6, BD biosciences), TIM-3-PE (344823, R&amp;D systems), NKG2D-PE-CF594 (1D11, BD biosciences), and CD57-PE-Cy7 (TB01, ebiosciences). After surface staining, the samples were fixed and permeablized using the standard protocol for BD biosciences Cytofix/Cytoperm reagent. The presence of Ki67 was measured using a specific anti-Ki67 antibody labeled with PerCP5.5 (B56, BD biosciences). The samples were then acquired on a Beckman Coulter Cytoflex S flow cytometer, and the resulting data was analyzed using FlowJo software (TreeStar). Antibodies used are set forth in the following table: 
     
       
         
           
               
               
               
               
               
             
               
                 TABLE 9 
               
               
                   
               
               
                 Antigen 
                 Clone 
                 Label 
                 Cat # 
                 Supplier 
               
               
                   
               
             
            
               
                 CD94 
                 DX22 
                 FITC 
                 305504 
                 Biolegend 
               
               
                 Ki-67 
                 B56 
                 PerCP5.5 
                 561284 
                 BD biosciences 
               
               
                 CD56 
                 HCD56 
                 AF647 
                 318314 
                 Biolegend 
               
               
                 CD3 
                 SK7 
                 AF700 
                 344822 
                 Biolegend 
               
               
                 CD45 
                 2D1 
                 APC-H7 
                 560178 
                 BD biosciences 
               
               
                 NKp46 
                 9E2 
                 BV421 
                 564065 
                 BD biosciences 
               
               
                 CD16 
                 3G8 
                 BV510 
                 563830 
                 BD biosciences 
               
               
                 CD27 
                 O323 
                 BV605 
                 302830 
                 Biolegend 
               
               
                 HLA-DR 
                 G46-6 
                 BV650 
                 564231 
                 BD biosciences 
               
               
                 TIM-3 
                 344823 
                 PE 
                 FAB2365P 
                 R&amp;D Systems 
               
               
                 NKG2D 
                 1D11 
                 PE-CF594 
                 562498 
                 BD biosciences 
               
               
                 CD57 
                 TB01 
                 PE Cy-7 
                 25-0577-42 
                 ebioscience 
               
               
                   
               
               
                 Proliferating NK cells are CD45 + CD3 − CD56 + Ki67+. 
               
            
           
         
       
     
     The following protocol was used for flow cytometric analysis of proliferating CD8 cells. Blood samples were collected by direct vein puncture and collected in Streck Cytochex BCT tubes. Collection of the blood in these tubes allows the samples to be accurately analyzed up to 72 hour post blood collection. An aliquot was taken for TBNK (BD biosciences) analysis for downstream calculation of absolute counts of discreet cell populations. The remainder of the sample was subjected to lysing of the red blood cells using the standard BD pharmlyse procedure. The cells were then stained using fluorescently labeled antibodies specific for surface antigens CD45-ApC-H7 (2D1, BD biosciences), CD3-AF700 (SK7, Biolegend), CD4-BV510 (OKT4, Biolegend), CD8a-BV605 (RPA-T8, BD biosciences), CD27-AF647 (0323, Biolegend), CD45RA-BB515 (HI100, BD biosciences), CD197-BV421 (G043H7, Biolegend), HLA-DR-BV650 (G46-6, BD biosciences), PD-1-PE (MIH4, eBiosciences), CD38-PE Dazzle 594 (HB7, Biolegend), and CD152-PE-Cy7 (BNI3, BD biosciences). After surface staining, the samples were fixed and permeablized using the standard protocol for BD biosciences Cytofix/Cytoperm reagent. The presence of Ki67 was measured using a specific anti-Ki67 antibody labeled with PerCP5.5 (B56, BD biosciences). The samples were then acquired on a Beckman Coulter Cytoflex S flow cytometer, and the resulting data was analyzed using FlowJo software (TreeStar). Antibodies used are set forth in the following table: 
     
       
         
           
               
               
               
               
               
             
               
                 TABLE 10 
               
               
                   
               
               
                 Antigen 
                 Clone 
                 Label 
                 Cat # 
                 Supplier 
               
               
                   
               
             
            
               
                 CD45RA 
                 HI100 
                 BB515 
                 564552 
                 BD Biosciences 
               
               
                 Ki-67 
                 B56 
                 PerCP5.5 
                 561284 
                 BD Biosciences 
               
               
                 CD197 
                 GO43H7 
                 BV421 
                 353208 
                 Biolegend 
               
               
                 CD4 
                 OKT4 
                 BV510 
                 300546 
                 Biolegend 
               
               
                 CD8a 
                 RPA-T8 
                 BV605 
                 563821 
                 BD Biosciences 
               
               
                 HLA-DR 
                 G46-6 
                 BV650 
                 563965 
                 BD Biosciences 
               
               
                 CD27 
                 O323 
                 AF647 
                 302812 
                 Biolegend 
               
               
                 CD3 
                 SK7 
                 AF700 
                 344822 
                 Biolegend 
               
               
                 CD45 
                 2D1 
                 APC-H7 
                 560178 
                 BD Biosciences 
               
               
                 PD1 
                 MIH4 
                 PE 
                 12-9969-42 
                 eBiosciences 
               
               
                 CD38 
                 HB7 
                 PE Dazzle 594 
                 331226 
                 Biolegend 
               
               
                   
                   
                 (TR) 
               
               
                 CD152 
                 BNI3 
                 PE-Cy7 
                 560651 
                 BD Biosciences 
               
               
                   
               
               
                 CD8 Proliferating CD8+ cells are CD45 + CD3 + CD4 − CD8 + Ki67+. 
               
            
           
         
       
     
     The results show that GITR Ab is biologically active at 30 mg-240 mg alone and in combination with nivolumab. 
     Example 8: 28F3.IgG1+Nivolumab Increases Proliferation and Activation of CD8 Memory Cells 
     This Example provides PD data from patients involved in the clinical trial described in Examples 1 to 7. 
     Immunophenotyping of expansion phase patients shows increased proliferation and activation of CD8 effector memory cells and central memory cells (see  FIG. 4 ). Transient increases were observed between day 8 and pre-dose on day 15. Similar results were observed with CD4 cells. 
     For flow cytometric analysis, blood samples were collected by direct vein puncture and collected in Streck Cytochex BCT tubes. Collection of the blood in these tubes allows the samples to be accurately analyzed up to 72 hour post blood collection. An aliquot was taken for TBNK (BD biosciences) analysis for downstream calculation of absolute counts of discreet cell populations. The remainder of the sample was subjected to lysing of the red blood cells using the standard BD pharmlyse procedure. The cells were then stained using fluorescently labeled antibodies specific for surface antigens CD45-ApC-H7 (2D1, BD biosciences), CD3-AF700 (SK7, Biolegend), CD4-BV510 (OKT4, Biolegend), CD8a-BV605 (RPA-T8, BD biosciences), CD27-AF647 (0323, Biolegend), CD45RA-BB515 (HI100, BD biosciences), CD197-BV421 (G043H7, Biolegend), HLA-DR-BV650 (G46-6, BD biosciences), PD-1-PE (MIH4, eBiosciences), CD38-PE Dazzle 594 (HB7, Biolegend), and CD152-PE-Cy7 (BNI3, BD biosciences). After surface staining, the samples were fixed and permeabilized using the standard protocol for BD biosciences Cytofix/Cytoperm reagent. The presence of Ki67 was measured using a specific anti-Ki67 antibody labeled with PerCP5.5 (B56, BD biosciences). The samples were then acquired on a Beckman Coulter Cytoflex S flow cytometer, and the resulting data was analyzed using FlowJo software (TreeStar). Antibodies used are set forth in the following table: 
     
       
         
           
               
               
               
               
               
             
               
                 TABLE 11 
               
               
                   
               
               
                 Antigen 
                 Clone 
                 Label 
                 Cat # 
                 Supplier 
               
               
                   
               
             
            
               
                 CD45RA 
                 HI100 
                 BB515 
                 564552 
                 BD Biosciences 
               
               
                 Ki-67 
                 B56 
                 PerCP5.5 
                 561284 
                 BD Biosciences 
               
               
                 CD197 
                 GO43H7 
                 BV421 
                 353208 
                 Biolegend 
               
               
                 CD4 
                 OKT4 
                 BV510 
                 300546 
                 Biolegend 
               
               
                 CD8a 
                 RPA-T8 
                 BV605 
                 563821 
                 BD Biosciences 
               
               
                 HLA-DR 
                 G46-6 
                 BV650 
                 563965 
                 BD Biosciences 
               
               
                 CD27 
                 O323 
                 AF647 
                 302812 
                 Biolegend 
               
               
                 CD3 
                 SK7 
                 AF700 
                 344822 
                 Biolegend 
               
               
                 CD45 
                 2D1 
                 APC-H7 
                 560178 
                 BD Biosciences 
               
               
                 PD1 
                 MIH4 
                 PE 
                 12-9969-42 
                 eBiosciences 
               
               
                 CD38 
                 HB7 
                 PE Dazzle 594 
                 331226 
                 Biolegend 
               
               
                   
                   
                 (TR) 
               
               
                 CD152 
                 BNI3 
                 PE-Cy7 
                 560651 
                 BD Biosciences 
               
               
                   
               
            
           
         
       
     
     The following markers were used to quantify the different types of cells:
     CD8 Effector memory: CD45+CD3+CD4-CD8+CD197-CD45RA−   CD8 effector memory activated: CD45+CD3+CD4-CD8+CD197-CD45RA-HLA-DR+   CD8 effector memory proliferating: CD45+CD3+CD4-CD8+CD197-CD45RA-Ki67+   CD8 Central memory: CD45+CD3+CD4-CD8+CD197+CD45RA−   CD8 central memory activated: CD45+CD3+CD4-CD8+CD197+CD45RA-HLA-DR+   CD8 central memory proliferating: CD45+CD3+CD4-CD8+CD197+CD45RA-Ki67+   CD4 Effector memory: CD45+CD3+CD4+CD8-CD197-CD45RA−   CD4 Effector memory Activated: CD45+CD3+CD4+CD8-CD197-CD45RA-HLA-DR+   CD4 Effector memory Proliferating: CD45+CD3+CD4+CD8-CD197-CD45RA- Ki67+   CD4 Central memory: CD45+CD3+CD4+CD8-CD197+CD45RA−   CD4 Central memory Activated: CD45+CD3+CD4+CD8-CD197+CD45RA-HLA-DR+   CD4 Central memory Proliferating: CD45+CD3+CD4+CD8-CD197+CD45RA-Ki67+   

     Example 9: Response in a Tumor Type Known to Have High GITR Expression: Response to 28F3.IgG1 +Nivolumab in a Patient with Cervical Cancer 
     Cervical cancer has been associated with high GITR expression (Padovani C T J et al.  Rev Soc Bras Med Trop.  2013;46:288-292. 2 and Visser J et al.  Clin Exp Immunol.  2007; 150:199-209). A 44 year old patient with metastatic cervical cancer who had 3 prior lines of therapy (chemotherapy±VEGF inhibitor) was treated with a combination of GITR Ab at 240 mg and nivolumab at 240 mg. About 9 months later, the patient showed a partial response, with a best change in tumor burden of −62% ( FIG. 5 ). The duration of response at data cutoff was 8 weeks, and the response is still ongoing. 
     Example 10: Response in a Tumor Type Not Typically JO Responsive: 28F3.IgG1+Nivolumab in a Patient with Adenocarcinoma of the Ampulla of Vater 
     A 69 year old patient with adenocarcinoma of the ampulla of Vater who had 3 prior lines of chemotherapy was treated with a combination of GITR Ab at 240 mg and nivolumab at 240 mg. A partial response was observed, with a best change in tumor burden of −38% ( FIG. 6 ). The duration of response at data cutoff was 16 weeks; and the response is still ongoing. 
     Example 11: Response After Progression on Anti-PD-1 Therapy: 28F3.IgG1+Nivolumab in a Patient with Melanoma 
     A 59 year old patient with metastatic melanoma who had 3 prior lines of therapy (BRAF inhibitor, PD-1 inhibitor [pembrolizumab for 3 months (February to May 2014); best response was progressive disease], and BRAF+MEK inhibitor) was treated with a combination of GITR Ab at 100 mg and nivolumab at 240 mg. A partial response was observed, with a best change in tumor burden of −41% ( FIG. 7 ). The duration of response at data cutoff was 24 weeks; and the response is still ongoing. 
     Example 12: Response After Progression on Anti-PD-1 Therapy: 28F3.IgG1+Nivolumab in a Patient With Nasopharyngeal Cancer 
     A 32 year old patient with nasopharyngeal cancer who had 3 prior lines of therapy (chemotherapy, PD-1 inhibitor [pembrolizumab for 6 months (July 2014 to January 2015); best response was partial response, with subsequent progression], FGFR+PI3K inhibitor) was treated with a combination of GITR Ab at 240 mg and nivolumab at 240 mg. A partial response was observed, with a best change in tumor burden of −43% ( FIG. 8 ). The duration of response at data cutoff was 17 weeks; and the response is still ongoing. 
     Thus, based at least on the results described in Examples 10 and 11, patients who progressed on/after prior anti-PD1 therapy can be treated with a combination of an anti-GITR antibody and an anti-PD-1 or PD-L1 antagonist. 
     Thus, the Examples show a first clinical report of an anti-GITR mAb +PD-1 inhibitor. The combination treatment demonstrated:
         Linear PK with dose-related increase in exposure and low incidence of immunogenicity;   Well-tolerated safety profile consistent with that of nivolumab monotherapy; and   Biologic activity with increased proliferation of NK and CD8 cells in peripheral blood and increased proliferation and activation of effector and central memory cells.       

     In addition, clinical responses were observed with 28F3.IgG1+nivolumab at biologically active doses and including patients who progressed on or after prior anti-PD1 therapy. 
     Example 13. Model-Based PK/PD Integration for First-in-Human Starting Dose Selection 
     This Example describes how the first in human (FIH) starting dose for 28F3.IgG1 used in the clinical trial described in the previous Examples was determined. 
     It is important to select a FIH starting dose of protein therapeutics for cancer immunotherapy, and this is particularly challenging for a cancer immunotherapy agonist, e.g., a 
     GITR agonist. Immune-mediated adverse effects (irAEs) is one of the key challenges in early development of cancer immunotherapeutics. irAEs are mostly on-target toxicities due to exaggerated pharmacology. FIH starting dose selection has evolved from mostly toxicology-based approach to an integrated pharmacology-based method. The starting dose selection for cancer patients is aimed to balance the safety and efficacy in FIH studies. PK/PD modeling plays an important role in nonclinical PK and pharmacology data integration. 
     Approaches for FIH safe starting dose selection for novel immunomodulatory protein therapeutics is shown in  FIG. 9 . 
       28 F3.IgG1 is a fully human agonist antibody that increases Teff survival and reduces Treg-mediated suppression. FcγR mediated ADCC activity leads to preferential depletion of intratumoral GITR high expression Tregs. A minimum anticipated biological effect level (MABEL) approach was employed for selecting FIH starting dose due to the agonistic mechanism on a novel target with unknown clinical safety information. A diagram of the 28F3.IgG1 FIH starting dose selection is provided in  FIG. 10 . DTA-mIgG2a and G2b are anti-mGITR surrogate antibodies with either mIgG2a or mIgG2b Fc. The data analysis method is shown in  FIG. 11 . The criteria of MABEL were the following:
         In vitro activities/PD responses: to have &gt;50% chance to be significantly different (P&lt;0.05) from the control group.   Anti-tumor efficacy: 20% of the maximum efficacy       

     Table 12 shows the in vitro potencies of 28F3.IgG1 and its mouse surrogates (DTA1-mIgG2a and G2b). The affinities of all three antibodies for CD4+ T cells and CD8+ T cells were similar. 
     
       
         
           
               
               
             
               
                   
                 TABLE 12 
               
             
            
               
                   
                   
               
               
                   
                 In vitro binding EC50 (nM) on activated T cells 
               
            
           
           
               
               
               
               
            
               
                   
                 28F3.IgG1 
                 DTA1-mIgG2a 
                 DTA1-mIgG2b 
               
               
                   
                   
               
            
           
           
               
               
               
               
            
               
                 CD4+ T cells 
                 0.37 (human) 
                 0.14 (mouse) 
                 0.33 (mouse) 
               
               
                 CD8+ T cells 
                 0.44 (human) 
                 0.17 (mouse) 
                 0.33 (mouse  
               
               
                   
               
            
           
         
       
     
     The effects of 28F3.IgG1 on in vitro cytokine release and lymphocyte activation in human whole blood PBMCs was determined. As shown in  FIG. 12 , there was:
         no cytokine release or increased expression of activation markers on human T or B cells;   NK cell activation (high CD69+ and CD25+), consistent with constitutive low level GITR expression on NK cells; and   NK cell activation with a minimum increase at 1 μg/mL.       

     In vivo efficacy of the mouse surrogate antibody DTA1-mIgG2a in a syngeneic mouse CT26 tumor model (CT26 cell implantation into Balb/C mice) was determined. The dosing schedule is shown in  FIG. 13 , with antibody being dosed on days 7, 14, and 21 after cell implantation. PD was determined in tumor (%CD8+ T cells, %Tregs, CD8+ T cell/Treg ratio) and blood (% Ki67 and % Ki67+CD25+ among CD8+ T cells) on day 12. As shown in  FIG. 14 , a dose between 0.3-1 mg/kg achieved minimum increases in proliferating CD8+ T cells in blood. In tumors, a similar minimum increase in CD8+ T cell/Treg ratio was observed at 0.3-1 mg/kg, similar to that seen in blood ( FIG. 15 ). 
     With respect to anti-tumor efficacy, the minimum efficacy was observed at 0.2 mg/kg with DTA1-mIgG2a. The minimum efficacy observed for DTA1-mIgG2b was at 0.6 mg/kg. As shown in  FIG. 16 , exposure of the antibody to achieve 20% survival was equivalent to the exposure at a single 0.2 mg/kg dose. 
     The data discussed above were used to project the MABEL dose of 28F3.IgG1. As shown in Table 13, the projected dose was determined to be 2.4-13.6 mg flat dose, or 0.03-0.17 mg/kg of the antibody. 
     
       
         
           
               
               
               
               
             
               
                   
                 TABLE 13 
               
               
                   
                   
               
             
            
               
                   
                   
                   
                 28F3.IgG1 MABEL 
               
               
                   
                 In vitro studies 
                 28F3.IgG1 
                 in humans 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 NK cell CD25 and 
                 1 μg/mL 
                 3.2 
                 mg 
               
               
                   
                 CD69 activation 
                   
                 (0.04 
                 mg/kg) 
               
               
                   
                 biomarker 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
            
               
                 In vivo CT26 mouse 
                 DTA1- 
                 DTA1- 
                   
                   
               
               
                 model 
                 mIgG2a 
                 mIgG2b 
               
               
                   
               
               
                 Blood % Ki67+ of 
                 0.3-1 mg/kg     
                 0.3-1 mg/kg 
                 2.4-13.6 
                 mg 
               
               
                 CD8+ T cells 
                   
                   
                 (0.03-0.17 
                 mg/kg) 
               
               
                 Tumor infiltrating 
                 0.3 mg/kg 
                 0.3-1 mg/kg 
               
               
                 lymphocytes 
               
               
                 CD8+ T 
               
               
                 cell/Treg ratio 
               
               
                 Antitumor efficacy 
                 0.2 mg/kg 
                     0.6 mg/kg 
               
               
                   
               
            
           
         
       
     
     The human efficacious dose was determined by projections based on mouse efficacy data, as shown in  FIG. 17 . The projected human efficacious dose was determined to be 0.7-1.4 mg/kg iv at Q2W, targeting an average steady state concentration (Css_ave) of 13 μg/mL. Some uncertainties in the model include: the relevance of the mouse tumor model; mouse surrogate antibody was used in the study; and mIgG2a versus huIgG1 may have different depletion potencies. 
     In conclusion, a Model-based nonclinical PK/PD data integration facilitates early clinical development. A phase I starting dose of 10 mg (within 2.4-13.6 mg MABEL dose range) was selected to balance pharmacologic activity and safety. This dose was about 100-fold lower than the maximum recommended starting dose (992 mg or 12 mg/kg) projected from IND toxicity studies in monkeys, and about 10-fold lower than the projected human efficacious dose (0.7-1.4 mg/kg). 
     As further described herein, a Phase 1 dose escalation of 10, 30, 100, 240, and 800 mg was well tolerated; 240 mg Css_trough exceeds concentration of 13 μg/mL; in combinations with nivolumab at 240 mg for each Q2W, an increase in proliferating NK and CD8 cells was observed in peripheral blood. 
     Equivalents: 
     Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents of the specific embodiments disclosed herein. Such equivalents are intended to be encompassed by the following claims.