Patent Publication Number: US-2022235143-A1

Title: Humanized antibodies to mucin-16 and methods of use thereof

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This application is a U.S. National Stage Application under 35 U.S.C. § 371 of International Patent Application No. PCT/US2020/031886, filed on May 7, 2020, which claims the benefit of and priority to U.S. Provisional Patent Application No. 62/845,065, filed May 8, 2019, the entire contents of each of which are incorporated herein by reference. 
    
    
     STATEMENT OF GOVERNMENT SUPPORT 
     This invention was made with government support under P01 CA190174-01, P01 CA190174-02, and P01 CA190174-03, awarded by the National Institutes of Health. The government has certain rights in the invention. 
    
    
     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 Jun. 12, 2020, is named 115872-0832_SL.txt and is 545,591 bytes in size. 
     BACKGROUND 
     Mucins are important biomolecules for cellular homeostasis and protection of epithelial surfaces. Changes in expression of mucins in cancers, such as ovarian cancer, are useful as a biomarker for diagnosis, prognosis and treatment (Singh A P, et al.,  Lancet Oncol  2008; 9(11): 1076-85). MUC16 is a mucin that is over expressed on most ovarian carcinoma cells and is an established surrogate serum marker (CA-125) for the detection and progression of ovarian cancers (Badgwell D, et al.,  Dis Markers  23(5-6):397410 (2007); Bast RC, Jr, et al.,  Int J Gynecol Cancer  15 Suppl 3:274-81 (2005); Fritsche H A, et al.,  Clin Chem  44(7): 1379-80 (1998); and Krivak T C et al.,  Gynecol Oncol  115(1):81-5 (2009)). 
     MUC16 is a highly glycosylated mucin composed of a large extracellular domain (CA-125), which is cleaved and released, and a retained domain (MUC-CD) ( FIG. 1 ). MUC-CD comprises a non-repeating extracellular domain (MUC16 ectodomain) proximal to a cleavage site, a transmembrane domain, and a cytoplasmic tail with potential phosphorylation sites. Distal to the cleavage site, the released extracellular domain (CA-125) contains 16-20 tandem repeats of 156 amino acids, each with many potential glycosylation sites (O&#39;Brien T J, et al.,  Tumor Biol  22(6):348-66 (2001)). Since the MUC16 antigen is otherwise expressed only at low levels in normal tissues of the uterus, endometrium, fallopian tubes, ovaries, and serosa of the abdominal and thoracic cavities, MUC16 is a potentially attractive target for immune-based therapies, including the targeting and treatment of cancer. 
     A significant portion of the extracellular domain of MUC16 is cleaved and secreted (i.e., CA-125), which limits the utility of this portion of MUC16 to be used as a target antigen on ovarian carcinomas. Many reported MUC16 monoclonal antibodies bind to epitopes present on the large secreted CA-125 fraction of the glycoprotein, and not to the retained MUC16 ectodomain (Bellone S  Am J Obstet Gynecol  200(1):75 el-10 (2009), Berek J S.  Expert Opin Biol Ther.  4(7): 1159-65 (2004); O&#39;Brien T J, et al.,  Int J Biol Markers  13(4): 188-95 (1998)). Thus, the generation of new antibodies to the region of MUC16 that is not shed are needed for diagnostic and therapeutic purposes. 
     SUMMARY OF THE PRESENT TECHNOLOGY 
     Provided herein are compositions, methods, and uses of anti-Mucin 16 (MUC16) constructs that comprise antibody moieties that immunospecifically bind to Mucin 16 (MUC16), and modulate expression and/or activity of MUC16 for managing or treating MUC16-mediated disorders, such as cancer. 
     Provided herein, in certain embodiments, are anti-mucin 16 (MUC16) constructs comprising an antibody moiety that immunospecifically recognizes a mucin 16 (MUC16) polypeptide, wherein the antibody moiety comprises a humanized heavy chain variable domain and a humanized light chain variable domain of a 4H11 or 18C6 murine monoclonal antibody. In some embodiments, the antibody moiety comprises (a) (i) a variable heavy (VH) chain comprising a heavy chain complementarity determining region 1 (HC-CDR1), HC-CDR2, and HC-CDR3 of SEQ ID NOS: 17, 18, and 19, respectively, and a heavy chain framework region 1 (HC-FW1), HC-FW2, and HC-FW3 of SEQ ID NOS: 136, 137, and 138, respectively, wherein one or more amino acids selected from amino acid positions 1, 3, 5, 11 and 19 of SEQ ID NO: 136, amino acid positions 5, 7, 8, and 9 of SEQ ID NO: 137, and amino acid positions 12, 14, 18, 22, and 23 of SEQ ID NO: 138 is humanized relative to a mouse HC-FW1, HC-FW2, and HC-FW3 of SEQ ID NOS: 124, 125, and 126, respectively; (ii) a variable light (VL) chain comprising a light chain complementarity determining region 1 (LC-CDR1), LC-CDR2, and LC-CDR3 of SEQ ID NOS: 14, 15, and 16, respectively, and a light chain framework region 1 (LC-FW1), LC-FW2, LC-FW3, and LC-FW4 of SEQ ID NOS: 120, 121, 122, and 123, respectively, wherein one or more amino acids selected from positions 3, 9, 15, 18, and 22 of SEQ ID NO: 120, amino acid positions 7 and 27 of SEQ ID NO: 122, and amino acid positions 3 and 9 of SEQ ID NO: 123, is humanized relative to a mouse LC-FW1, LC-FW2, LC-FW3, and LC-FW4 of SEQ ID NOS: 104, 105, 106 and 107, respectively; or (b)(i) a variable heavy (VH) chain comprising SEQ ID NO: 4 or 5; and (ii) a variable light (VL) chain comprising SEQ ID NO: 2 or 3; or (c) (i) a variable heavy (VH) chain comprising a heavy chain complementarity determining region 1 (HC-CDR1), HC-CDR2, and HC-CDR3 of SEQ ID NOS: 35, 36, and 37, respectively, and a heavy chain framework region 1 (HC-FW1), HC-FW2, HC-FW3, and HC-FW4 of SEQ ID NOS: 175, 176, 177 and 178, respectively, wherein one or more amino acids selected from amino acid positions 10, 11, 12, 13, 15, 19, and 23 of SEQ ID NO: 175, amino acid positions 5, 14, 16, 18, 22, and 23 of SEQ ID NO: 177, and amino acid position 6 of SEQ ID NO: 178 is humanized relative to a mouse HC-FW1, HC-FW2, HC-FW3, and HC-FW4 of SEQ ID NOS: 159, 160, 161, and 162, respectively; and (ii) a variable light (VL) chain comprising a light chain complementarity determining region 1 (LC-CDR1), LC-CDR2, and LC-CDR3 of SEQ ID NOS: 32, 33, and 34, respectively, and a light chain framework region 1 (LC-FW1), LC-FW2, LC-FW3, and LC-FW4 of SEQ ID NOS: 155, 156, 157, and 158, respectively, wherein one or more amino acids selected from positions 7, 9, 11, and 18 of SEQ ID NO: 155, amino acid position 5 of SEQ ID NO: 156, and amino acid positions 9 and 18 of SEQ ID NO: 157, is humanized relative to a mouse LC-FW1, LC-FW2, LC-FW3, and LC-FW4 of SEQ ID NOS: 139, 140, 141, and 142, respectively; or (d) (i) a variable heavy (VH) chain comprising SEQ ID NO: 22 or 23; and (ii) a variable light (VL) chain comprising SEQ ID NO: 20 or 21. 
     In some embodiments, the HC-FW1 of (a)(i) comprises SEQ ID NO: 130; the HC-FW2 of (a)(i) comprises SEQ ID NO: 131; the HC-FW3 of (a)(i) comprises SEQ ID NO: 132; the LC-FW1 of (a)(ii) comprises SEQ ID NO: 112; the LC-FW2 of (a)(ii) comprises SEQ ID NO: 113; the LC-FW3 of (a)(ii) comprises SEQ ID NO: 114; and/or the LC-FW4 of (a)(ii) comprises SEQ ID NO: 115. In some embodiments, the HC-FW1 of (a)(i) comprises SEQ ID NO: 133; the HC-FW2 of (a)(i) comprises SEQ ID NO: 134; the HC-FW3 of (a)(i) comprises SEQ ID NO: 135; the LC-FW1 of (a)(ii) comprises SEQ ID NO: 116; the LC-FW2 of (a)(ii) comprises SEQ ID NO: 117; the LC-FW3 of (a)(ii) comprises SEQ ID NO: 118; and/or the LC-FW4 of (a)(ii) comprises SEQ ID NO: 119. 
     In some embodiments, the HC-FW1 of (c)(i) comprises SEQ ID NO: 167; the HC-FW2 of (c)(i) comprises SEQ ID NO: 168; the HC-FW3 of (c)(i) comprises SEQ ID NO: 169; the HC-FW4 of (c)(i) comprises SEQ ID NO: 170; the LC-FW1 of (c)(ii) comprises SEQ ID NO: 147; the LC-FW2 of (c)(ii) comprises SEQ ID NO: 148; the LC-FW3 of (c)(ii) comprises SEQ ID NO: 149; and/or the LC-FW4 of (c)(ii) comprises SEQ ID NO: 150. In some embodiments, the HC-FW1 of (c)(i) comprises SEQ ID NO: 171; the HC-FW2 of (c)(i) comprises SEQ ID NO: 172; the HC-FW3 of (c)(i) comprises SEQ ID NO: 173; the HC-FW4 of (c)(i) comprises SEQ ID NO: 174; the LC-FW1 of (c)(ii) comprises SEQ ID NO: 151; the LC-FW2 of (c)(ii) comprises SEQ ID NO: 152; the LC-FW3 of (c)(ii) comprises SEQ ID NO: 153; and/or the LC-FW4 of (c)(ii) comprises SEQ ID NO: 154. 
     In some embodiments, the antibody moiety immunospecifically recognizes a human MUC16. In some embodiments, the antibody moiety immunospecifically recognizes a human MUC16 peptide of SEQ ID NO: 53. In some embodiments, the antibody moiety immunospecifically binds to a MUC16 c114 polypeptide comprising the amino acid sequence of SEQ ID NO: 44 or 180. In some embodiments, the MUC16 is glycosylated. In some embodiments, the MUC16 is N-glycosylated at Asnl800 or Asn1806. In some embodiments, the antibody moiety of the anti-mucin 16 (MUC16) constructs provided herein comprises (a)(i) a heavy chain comprising SEQ ID NO: 12 or 13 and (ii) a light chain comprising SEQ ID NO: 10 or 11; or (b)(i) a heavy chain comprising SEQ ID NO: 30 or 31 and (ii) a light chain comprising SEQ ID NO: 28 or 29. 
     In some embodiments, the antibody moiety of the anti-mucin 16 (MUC16) constructs provided herein immunospecifically binds to the ectodomain of MUC16. In some embodiments, the antibody moiety is a full-length antibody, a Fab, a Fab′, a F(ab′)2, an Fv, or a single chain Fv (scFv). In some embodiments, the antibody moiety is a single chain Fv (scFv), and the scFv comprises any one of SEQ ID NOs: 53-68. In some embodiments, the VH chain and the VL chain are human VH chain and VL chain. In some embodiments, the antibody moiety is a monoclonal antibody. 
     In some embodiments, the anti-MUC16 constructs provided herein inhibit in vitro invasion of a tumor cell that expresses MUC16 in a Matrigel invasion assay. In some embodiments, the tumor cell is an ovarian tumor cell. 
     In some embodiments, the antibody moiety comprises human-derived heavy and light chain constant regions. In some embodiments, the heavy chain constant region has an isotype selected from the group consisting of gamma 1, gamma 2, gamma 3, and gamma 4. In some embodiments, the light chain constant region has an isotype selected from the group consisting of kappa and lambda. In some embodiments, the antibody moiety is an immunoglobulin comprising two identical heavy chains and two identical light chains. In some embodiments, the immunoglobulin is an IgG. 
     In some embodiments, the anti-MUC16 construct provided herein is monospecific. In some embodiments, the anti-MUC16 construct provided herein is multispecific. In some embodiments, the anti-MUC16 construct provided herein is bispecific. In some embodiments, the anti-MUC16 construct provided herein is a tandem scFv, a diabody (db), a single chain diabody (scDb), a dual-affinity retargeting (DART) antibody, a F(ab′)2, a dual variable domain (DVD) antibody, a knob-into-hole (KiH) antibody, a dock and lock (DNL) antibody, a chemically cross-linked antibody, a heteromultimeric antibody, or a heteroconjugate antibody. In some embodiments, the anti-MUC16 construct provided herein is a tandem scFv comprising two scFvs linked by a peptide linker. In some embodiments, the antibody moiety that immunospecifically recognizes MUC16 is a first antibody moiety, and wherein the anti-MUC16 construct further comprises a second antibody moiety that immunospecifically recognizes a second antigen. In some embodiments, the second antigen is an antigen on the surface of a T cell. In some embodiments, the second antigen is a CD3. In some embodiments, the second antigen is selected from the group consisting of CD3γ, CD3δ, CD3ε, and CD3ζ. In some embodiments, the second antigen is CD3ε. In some embodiments, a multispecific or bispecific anti-MUC16 construct comprises an anti-CD3 antibody moiety. In some embodiments, a multispecific or bispecific anti-MUC16 construct comprises any one of SEQ ID NOS: 42, 69-75, and 88-95. 
     In some embodiments, the anti-MUC16 construct provided herein is a chimeric antigen receptor (CAR). In some embodiments, the CAR comprises a co-stimulatory domain. In some embodiments, the CAR comprises a CD3 zeta (ζ) chain cytoplasmic signaling domain. In some embodiments, the CAR comprises an scFv of any one of SEQ ID NOS: 53-68. In some embodiments, the CAR comprises any one of SEQ ID NOS: 80-87 and 97-103. 
     In some embodiments, the anti-MUC16 construct provided herein is further conjugated to a peptide agent, a detection agent, an imaging agent, a therapeutic agent, or a cytotoxic agent. 
     Also provided herein, in certain embodiments, are polypeptides comprising an amino acid sequence of one or more of SEQ ID NOs: 2-5, 10-13, 20-23 and 28-31, or an amino acid of an anti-MUC16 construct provided herein. 
     Also provided herein, in certain embodiments, are polynucleotides comprising a nucleic acid sequence encoding one or more polypeptides comprising an amino acid sequence of one or more of SEQ ID NOs: 2-5, 10-13, 20-23 and 28-31, or an amino acid of an anti-MUC16 construct provided herein. Provided herein, in certain embodiments, are vectors comprising the polynucleotide provided herein operably linked to a promoter. 
     Also provided herein, in certain embodiments, are cells comprising the anti-MUC16 construct provided herein, a polypeptide provided herein, a polynucleotide provided herein, or a vector provided herein. In some embodiments, the cell is a mammalian cell. In some embodiments, the cell is an immune cell. In some embodiments, the cell is a lymphocyte. In some embodiments, the cell is a T cell or a B cell. 
     Also provided herein, in certain embodiments, are pharmaceutical compositions comprising: a therapeutically effective amount of the anti-MUC16 construct provided herein, a polypeptide provided herein, polynucleotide provided herein, or a vector provided herein; and a pharmaceutically acceptable carrier. 
     Also provided herein, in certain embodiments, are methods of treating a MUC16-associated disease or disorder in a patient in need thereof, comprising administering to said patient a pharmaceutical composition comprising a therapeutically effective amount of the anti-MUC16 construct provided herein, a polypeptide provided herein, polynucleotide provided herein, or a vector provided herein. In some embodiments, the MUC16-associated disease or disorder is a cancer. In some embodiments, the cancer is a cancer of the ovary, lung, pancreas, breast, uterine, fallopian tube, or primary peritoneum. In some embodiments, the cancer is a metastatic cancer. In some embodiments, the pharmaceutical composition inhibits or reduces metastasis in the patient. In some embodiments, the patient is a human patient. 
     Also provided herein, in certain embodiments, are methods for producing an effector cell, comprising genetically modifying a cell with one or more nucleic acids encoding the anti-MUC16 construct provided herein. 
     Also provided herein, in certain embodiments, are methods of comprising introducing one or more nucleic acids encoding the anti-MUC16 construct provided herein into one or more primary cells isolated from a patient and administering cells comprising the one or more nucleic acids to the patient. In some embodiments, the method further comprises expanding the cells prior to administering the cells to the patient. In some embodiments, the primary cells are lymphocytes. In some embodiments, the primary cells are T cells. 
     In some embodiments, the methods of treatment provided herein further comprises administering a therapeutically effective amount of an additional therapeutic agent to the patient. In some embodiments, the therapeutic agent is an anti-cancer agent. In some embodiments, the therapeutic agent is a chemotherapeutic agent. 
     Also provided herein, in certain embodiments, are methods of detecting MUC16 in a sample, comprising: (a) contacting the sample with the anti-MUC16 construct provided herein; and (b) detecting the binding, directly or indirectly, between the anti-MUC16 construct and MUC16 that is present in the sample. In some embodiments, the anti-MUC16 construct is conjugated to a detectable label. In some embodiments, the detectable label is a chromogenic, enzymatic, radioisotopic, isotopic, fluorescent, toxic, chemiluminescent, nuclear magnetic resonance contrast agent. In some embodiments, the binding between the anti-MUC16 construct and any MUC16 in the sample is detected directly by detecting the detectable label. In some embodiments, the binding between the anti-MUC16 construct and any MUC16 in the sample is detected indirectly using a secondary antibody. 
     Also provided herein, in certain embodiments, are methods of diagnosing an individual suspected of having a MUC16-associated disease or disorder, comprising a) administering an effective amount of the anti-MUC16 construct provided herein to the individual; and b) determining the level of the binding, directly or indirectly, between the anti-MUC16 construct and any MUC16 in the individual, wherein a level of the binding above a threshold level indicates that the individual has the MUC16-associated disease or disorder. In some embodiments, the anti-MUC16 construct is conjugated to a detectable label. In some embodiments, the detectable label is a chromogenic, enzymatic, radioisotopic, isotopic, fluorescent, toxic, chemiluminescent, nuclear magnetic resonance contrast agent. In some embodiments, the binding between the anti-MUC16 construct and any MUC16 in the sample is detected directly by detecting the detectable label. In some embodiments, the binding between the anti-MUC16 construct and any MUC16 in the sample is detected indirectly using a secondary antibody. 
     A method of diagnosing an individual suspected of having a MUC16-associated disease or disorder, comprising a) contacting a sample comprising cells derived from the individual with the anti-MUC16 construct provided herein; and b) determining the number of cells in the sample bound to the anti-MUC16 construct, wherein a value for the number of cells bound to the anti-MUC16 construct above a threshold level indicates that the individual has the MUC16-associated disease or disorder. In some embodiments, the anti-MUC16 construct is conjugated to a detectable label. In some embodiments, the detectable label is a chromogenic, enzymatic, radioisotopic, isotopic, fluorescent, toxic, chemiluminescent, nuclear magnetic resonance contrast agent. In some embodiments, the binding between the anti-MUC16 construct and any MUC16 in the sample is detected directly by detecting the detectable label. In some embodiments, the binding between the anti-MUC16 construct and any MUC16 in the sample is detected indirectly using a secondary antibody. 
     Also provided herein, in certain embodiments, are uses of anti-MUC16 constructs, anti-MUC16 polypeptides, polynucleotides encoding anti-MUC16 constructs or anti-MUC16 polypeptides, vectors comprising the polynucleotides, or cells comprising any the polypeptides and polynucleotides thereof provided herein for the treatment of a disease or disorder associated with positive MUC16 expression. In some embodiments, the disease or disorder associated with positive MUC16 expression is a cancer. 
     Also provided herein, in certain embodiments, are uses of the anti-MUC16 constructs, anti-MUC16 polypeptides, polynucleotides encoding anti-MUC16 constructs or anti-MUC16 polypeptides, vectors comprising the polynucleotides, or cells comprising any the polypeptides and polynucleotides thereof provided herein in the manufacture of a medicament for the treatment of a disease or disorder associated with positive MUC16 expression. In some embodiments, the disease or disorder associated with positive MUC16 expression is a cancer. 
     Also provided herein, in certain embodiments, are uses of anti-MUC16 constructs, anti-MUC16 polypeptides, polynucleotides encoding anti-MUC16 constructs or anti-MUC16 polypeptides, vectors comprising the polynucleotides, or cells comprising any the polypeptides and polynucleotides thereof provided herein for the diagnosis of a disease or disorder associated with positive MUC16 expression. In some embodiments, the disease or disorder associated with positive MUC16 expression is a cancer 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG. 1A  shows a schematic illustration of the structure of MUC16.  FIG. 1B  shows schematic and amino acid sequence of the truncated form of MUC16, called MUC16 c114 (SEQ ID NO: 44), which includes the 58 amino acid ectodomain, the 25 amino acid transmembrane domain, and the 31 amino acid cytoplasmic tail. Numbering in figure is based on original publication identifying Muc16, Yin and Lloyd (2001)  J Biol Chem  276: 27371-27375. 
         FIG. 2  shows an amino acid alignment between wildtype MUC16-C114 (SEQ ID NO: 180) and the N30 mutant MUC16-C114 (SEQ ID NO: 181) ectodomains. Figure also discloses SEQ ID NO: 182. 
         FIGS. 3A-3E  illustrate the in vitro characterization of antibodies that bind to the MUC16 carboxy-terminus.  FIG. 3A  shows a cartoon representation of the molecular layout of the MUC16 superstructure highlighting the 4 distinct regions: N-terminal domain, tandem repeat [TR] region, SEA (Sperm protein, Enterokinase and Agrin) domains, and carboxy-terminus domain including the juxtamembrane [JM] region or ectodomain and the transmembrane [TM] region. The sequence of MUC16 peptide-2 (SEQ ID NO: 183), which is found within the ectodomain region and is the target-binding site for antibodies tested in this study, is shown.  FIG. 3B  provides graphs showing results from the saturation binding assays for radiolabeled variants of the two lead antibody candidates. The binding affinity curves for [ 89 Zr]Zr-DFO-9C9 (left) and [ 89 Zr]Zr-DFO-4H11 (right) (solid lines) versus control antibodies (dashes) are shown.  FIG. 3C  illustrates the cellular internalization profiles of [ 89 Zr]Zr-DFO-4H11 versus [ 89 Zr]Zr-DFO-9C9 showing minimum uptake of either antibody at 4° C., but relatively rapid uptake of [ 89 Zr]Zr-DFO-4H11 at 37° C. compared to the slow uptake of [ 89 Zr]Zr-DFO-9C9 in SKOV3 c114  cells;  FIG. 3D  provides a graphic representation showing comparable in vitro serum stability of [ 89 Zr]Zr-DFO-4H11 versus [ 89 Zr]Zr-DFO-9C9.  FIG. 3E  provides a graphic representation showing blockade of [ 89 Zr]Zr-DFO-4H11 binding to biotinylated MUC16 peptide-2 captured on a streptavidin-functionalized magnetic beads in presence of an excess of unlabeled 9C9 antibody (compare Unblocked (middle bar) to Blocked (right bar); control sample without MUC16 peptide-2 is also shown (left bar)). 
         FIGS. 4A-4D  illustrates in vivo characterization of the radiopharmacologic profiles of [ 89 Zr]Zr-DFO-9C9 and [ 89 Zr]Zr-DFO-4H11.  FIG. 4A  provides representative serial PET images [top: coronal slice; bottom: maximum intensity projection (MIP)] of [ 89 Zr]Zr-DFO-9C9 (170-200 μCi; 6.29-7.4 MBq suspended in 200 μL of chelex-treated PBS injected via the lateral tail vein) in SKOV3 c114  xenografts showing tumor (T) delineation at 24 h post-injection (p.i.) and progressively increasing uptake of activity in the tumor up to 96 h p.i. High concentrations of activity visible in the liver (L) and kidneys (K) at early time points, but gradually reduced at later time points.  FIG. 4B  provides representative serial PET images [top: coronal slice; bottom: maximum intensity projection (MIP)] of [ 89 Zr]Zr-DFO-4H11 (170-200 μCi; 6.29-7.4 MBq suspended in 200 μL of chelex-treated PBS injected via the lateral tail vein) in SKOV3 c114  xenografts delineating the tumor (T) and lymph nodes (LN) at 24 h post-injection (p.i.), with the PET signal intensity in the tumor increasing progressively up to 96 h p.i. High contrast PET images were obtained with [ 89 Zr]Zr-DFO-4H11 and liver (L) and lymph nodes (LN) were the only non-tumor tissues displaying background activity at later time points.  FIG. 4C  provides a graphical representation of the in vivo biodistribution of [ 89 Zr]Zr-DFO-9C9 and [ 89 Zr]Zr-DFO-4H11 in SKOV3 c114  xenografts showing high and comparable tumoral uptake of activity associated with both the radioimmunoconjugates. The uptake of [ 89 Zr]Zr-DFO-9C9 and [ 89 Zr]Zr-DFO-4H11 in SKOV3 c114  tumors could be blocked in the presence of an excess of the unlabeled antibody co-injected with the respective radiolabeled variants of the antibody, and was significantly higher than that of the isotype control. Differences between the in vivo activity concentrations in non-tumor tissues were most notable between the kidneys and axillary lymph nodes (LN). [ 89 Zr]Zr-DFO-9C9 displayed significantly higher activity concentration in the kidney than [ 89 Zr]Zr-DFO-4H11 and the isotype control whereas [ 89 Zr]Zr-DFO-4H11 displayed significantly higher activity concentration in the LN of mice injected with [ 89 Zr]Zr-DFO-9C9 or isotype control. ** indicates p-value ≤0.005; *** indicates p-value ≤0.0005; *** indicates p-value ≤0.00005.  FIG. 4D  provides a bar graph displaying a comparison between the in vivo radiopharmacologic profiles of [ 89 Zr]Zr-DFO-9C9 versus [ 89 Zr]Zr-DFO-4H11 as evaluated from the tumor-to-background (T:B) ratios of the activity concentration in vital organs of interest. 
         FIGS. 5A-5E  illustrate in vitro characterization of humanized 4H11 antibody.  FIG. 5A  provides a cartoon representation of DFO-conjugated humanized 4H11 antibody (DFO-hu4H11).  FIG. 5B  provides a histogram from flow cytometry analysis showing the binding of DFO-hu4H11 to SKOV3 c114  cells (or SKOV3+ cells, solid lines) versus lack of binding to SKOV3 cells (dotted lines);  FIG. 5C  provides a cartoon representation of  89 Zr-labeled hu4H11 antibody ([ 89 Zr]Zr-DFO-hu4H11).  FIG. 5D  provides a quality control of [ 89 Zr]Zr-DFO-hu4H11 showing high radiochemical purity on instant thin layer chromatograph analysis of crude labeling reaction versus size-exclusion purified radioimmunoconjugate;  FIG. 5E  provides a graphical representation of the low non-specific binding and high (&gt;90%) immunoreactive fraction of [ 89 Zr]Zr-DFO-hu4H11 to biotinylated MUC16 peptide-2 captured on streptavidin-functionalized DynaBeads. Specificity of target-binding was established by virtue of blockade of [ 89 Zr]Zr-DFO-hu4H11 binding to MUC16 peptide-2 on magnetic beads in presence of a huge excess of unlabeled DFO-hu4H11. 
         FIGS. 6A-6C  illustrate in vivo characterization of the radiopharmacologic profile of humanized 4H11 antibody.  FIG. 6A  provides representative serial PET images [top: coronal slices; bottom: maximum intensity projection (MIP)] of [ 89 Zr]Zr-DFO-hu4H11 (200 μCi; 7.4 MBq suspended in 200 μL of chelex-treated PBS injected via the lateral tail vein) in SKOV3 c114  xenografts showing clear delineation of the tumor (T) at 36 h followed by the gradual accretion of a vast majority of injected activity in the tumor at 96 h p.i.;  FIG. 6B  illustrates in vivo biodistribution of [ 89 Zr]Zr-DFO-hu4H11 showing high activity concentration in the tumor, with most non-tumor background organs having 8% ID/g except the bone and axillary lymph nodes. The tumoral uptake of activity could be blocked by co-injection of a 40-fold excess of unlabeled DFO-hu4H11. ** indicates p-value ≤0.005;  FIG. 6C  provides a bar graph displaying the in vivo radiopharmacologic profile of [ 89 Zr]Zr-DFO-hu4H11 as evaluated from the tumor-to-background (T:B) ratios of the activity concentration in vital organs of interest. 
         FIGS. 7A-7D  illustrate in vivo and ex vivo analyses of the biodistribution of [ 89 Zr]Zr-DFO-hu4H11.  FIG. 7A  provides representative serial PET images [top: coronal slices; middle: transverse slice; bottom: PET-CT overlay of the maximum intensity projection (MIP)] of [ 89 Zr]Zr-DFO-hu4H11 (250 μCi; 9.25 MBq suspended in 200 μL of chelex-treated PBS injected via the lateral tail vein) in bilateral xenografts (left shoulder: SKOV3 c114  tumor; right shoulder: SKOV3 tumor) showing preferential and targeted uptake in SKOV3 c114  tumors.  FIG. 7B  provides representative autoradiography images from the ex vivo analysis of the harvested bilateral tumors (from mouse shown in  7 A) revealing higher and heterogeneous distribution of signal in SKOV3 c114  tumor (dashed circle: high activity hot spot dashed triangle: low-no activity cold spot) in comparison to a near absence of any signal in the SKOV3 tumor exposed for autoradiography in the same cassette.  FIG. 7C  provides hematoxylin and eosin (H&amp;E) staining of the tumor sections (shown in  7 B) revealing areas of necrosis (dashed triangle) versus areas with nests of actively dividing tumor cells (dashed circle).  FIG. 7D  provides comparative H&amp;E staining of formalin-fixed paraffin-embedded SKOV3 c114  (left) versus SKOV3 (right) tumors showing distinct differences in the tumor architecture and morphology of cells comprising the tumors. 
         FIGS. 8A-8B  illustrate PET imaging of [ 89 Zr]Zr-DFO-hu4H11 in a MUC16-expressing cell line and HGSOC patient-derived xenograft model.  FIG. 8A  provides representative PET image [left: coronal slice; right maximum intensity projection (MIP)] of [ 89 Zr]Zr-DFO-hu4H11 (150 μCi; 5.55 MBq suspended in 200 μL of chelex-treated PBS injected via the lateral tail vein) at 72 h p.i. in nude mice bearing subcutaneously xenografted MUC16-positive OVCAR3 tumor on the right shoulder.  FIG. 8B  provides representative PET images [MIPs] of [ 89 Zr]Zr-DFO-hu4H11 (150 μCi; 5.55 MBq suspended in 200 μL of chelex-treated PBS injected via the lateral tail vein) at 72 h p.i. in two mice bearing PDXs of HGSOC tumor on the right shoulder and showing high activity concentration in the tumors (T) and some persistent activity in the blood pool (BP) including the heart and descending aorta. 
         FIGS. 9A-9D  illustrate in vitro binding of 4H11 and 18C6 mouse mAbs and humanized antibodies to a MUC16+ OVCAR3 cell line and transfectant cell lines expressing MUC16 c344 and c114 peptides but not to control MUC16 −  A2780 and SKOV3 cell line by FACS analysis.  FIG. 9A  shows mean fluorescence for binding of the 4H11 and 18C6 mouse mAbs antibodies to the assayed cell lines.  FIG. 9B  shows fluorescence percentage positive cells for binding of the 4H11 and 18C6 mouse mAbs antibodies to the assayed cell lines.  FIG. 9C  shows mean fluorescence for binding of the 4H11 and 18C6 humanized antibodies to the assayed cell lines.  FIG. 9D  shows fluorescence percentage positive cells for binding of the 4H11 and 18C6 humanized antibodies to the assayed cell lines. 
         FIGS. 10A and 10B  illustrate in vitro binding of 4H11 humanized antibodies to a MUC16+ OVCAR3 cell line and transfectant SKOV3 cell lines expressing MUC16 c344 and c114 peptides but not to control MUC16 −  SKOV3 cell line by FACS analysis. 
         FIG. 11  illustrates 4H11 humanized antibodies inhibit invasion of MUC16+ OVCAR3, OVCA-433 and CAOV3 cell lines as compared to untreated cells in a Matrigel invasion assay. 
         FIG. 12  illustrates 4H11 humanized antibodies inhibit invasion of transfectant SKOV3 cell lines expressing MUC16 c344 and c114 peptides as compared to untreated cells in a Matrigel invasion assay. SKOV3 cell lines expressing the mutant MUC16 peptide N123mut c114 was employed as a negative control for invasion. 
     
    
    
     DETAILED DESCRIPTION 
     The present application in one aspect provides anti-MUC16 antibody agents, such as anti-MUC16 constructs that comprise an antibody moiety that specifically recognizes an epitope of MUC16, such as an epitope of the retained extracellular domain of MUC16 (MUC16 ectodomain). 
     Using phage display technology, scFvs that are specific for the retained extracellular domain of human MUC16 were identified. Flow cytometry assays demonstrated that these antibodies recognize MUC16-expressing cancer cell lines. The present application thus provides anti-MUC16 antibody agents, such as anti-MUC16 constructs that comprise an antibody moiety that immunospecifically binds MUC16. The anti-MUC16 antibody agents include, for example, anti-MUC16 antibodies, e.g., full-length anti-MUC16 antibodies and antigen-binding fragments thereof, anti-MUC16 scFvs, anti-MUC16 antibody fusion proteins (e.g., anti-MUC16 Fc fusion proteins and chimeric antigen receptors (CAR)), multi-specific antibodies, e.g., bispecific antibodies, and anti-MUC16 antibody conjugates (i.e., anti-MUC16 immunoconjugates) thereof. 
     In another aspect, provided are nucleic acids encoding the anti-MUC16 antibody agents, such as anti-MUC16 antibodies, e.g., full-length anti-MUC16 antibodies and antigen-binding fragments thereof, anti-MUC16 scFvs, anti-MUC16 antibody fusion proteins (e.g., anti-MUC16 Fc fusion proteins and chimeric antigen receptors (CAR)), multi-specific antibodies, e.g., bispecific antibodies, and anti-MUC16 antibody conjugates (i.e., anti-MUC16 immunoconjugates) thereof. 
     In another aspect, provided are compositions, such as pharmaceutical compositions, comprising an anti-MUC16 antibody agent, such as full-length anti-MUC16 antibodies and antigen-binding fragments thereof, anti-MUC16 scFvs, anti-MUC16 antibody fusion proteins (e.g., anti-MUC16 Fc fusion proteins and chimeric antigen receptors (CAR)), multi-specific antibodies, e.g., bispecific antibodies, and anti-MUC16 antibody conjugates (i.e., anti-MUC16 immunoconjugates) thereof. 
     Also provided are methods of making and using the anti-MUC16 antibody agents and antibodies, such as for treating cancer, as well as kits and articles of manufacture useful for such methods. 
     Also disclosed herein are kits for the detection and/or treatment of MUC16-associated pathologies, comprising at least one anti-MUC16 antibody agent of the present technology, or a functional variant (e.g., substitutional variant) thereof and instructions for use. In certain embodiments, the anti-MUC16 antibody agent is coupled to one or more detectable labels. In one embodiment, the one or more detectable labels comprise a radioactive label, a fluorescent label, or a chromogenic label. 
     Additionally or alternatively, in some embodiments, the kit further comprises a secondary antibody that specifically binds to an anti-MUC16 antibody agent described herein. In some embodiments, the secondary antibody is coupled to at least one detectable label selected from the group consisting of a radioactive label, a fluorescent label, or a chromogenic label. 
     Definitions 
     Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by a person skilled in the art to which this disclosure belongs. The following references provide one of skill with a general definition of many of the terms used in the present technology: Singleton et al., Dictionary of Microbiology and Molecular Biology (2nd ed. 1994); The Cambridge Dictionary of Science and Technology (Walker ed., 1988); The Glossary of Genetics, 5th Ed., R. Rieger et al., (eds.), Springer Verlag (1991); and Hale &amp; Marham, The Harper Collins Dictionary of Biology (1991). As used herein, the following terms have the meanings ascribed to them below, unless specified otherwise. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the disclosure. 
     As used herein, the term “MUC16” or “MUC16 polypeptide” or “MUC16 peptide” refers to the MUC16 tethered mucin protein as described in Yin B W and Lloyd K O, 2001 , J Biol Chem.  276(29):27371-5. GenBank™ accession number NP_078966.2 (SEQ ID NO: 1) provides an exemplary human MUC16 nucleic acid sequence. GenBank™ accession number NP 078966.2 (SEQ ID NO: 1) provides an exemplary human MUC16 amino acid sequence. Native MUC16 comprises an intracellular domain, a transmembrane domain, an ectodomain proximal to the putative cleavage site, and a large, heavily glycosylated region of 12-20 repeats, each 156 amino acids long ( FIG. 1A ). “Immature” MUC16 refers to SEQ ID NO: 1, which comprises the MUC16 signal sequence (amino acid residues 1-60 of SEQ ID NO: 1). “Mature MUC16” refers to native MUC16 as expressed on the cell surface, i.e., where the signal sequence has been removed by cellular processing, for example, SEQ ID NO: 51, where the first 60 amino acid residues of SEQ ID NO: 1 have been removed (i.e., SEQ ID NO: 1 is the “immature” form of MUC16). 
     The polypeptide represented by the amino acid sequence of SEQ ID NO: 44 or 180 is referred to herein as MUC16 C114 and consists of the C-terminal 114 amino acid residues of mature MUC16 (SEQ ID NO: 51 being the sequence of mature MUC16). MUC16 C114 comprises a 58 amino acid ectodomain, a 25 amino acid transmembrane domain and a 31 amino acid cytoplasmic tail ( FIG. 1B ). MUC16c114 is capable of being N-glycosylated at the asparagine amino acid residues at positions 1, 24, and 30 of SEQ ID NO: 44 or 180 (also referred to as amino acid positions Asn1777, Asn1800, and Asn1806 according the original MUC16 publication Yin B W and Lloyd K O, 2001 , J Biol Chem.  276(29):27371-5). 
     As used herein, the singular forms “a”, “an” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise. 
     As used herein, the terms “about” when used to modify a numeric value or numeric range, indicate that deviations of 5% to 10% above and 5% to 10% below the value or range remain within the intended meaning of the recited value or range. 
     As used herein, the term “administration” of an agent to a subject includes any route of introducing or delivering the agent to a subject to perform its intended function. Administration can be carried out by any suitable route, including, but not limited to, intravenously, intramuscularly, intraperitoneally, subcutaneously, and other suitable routes as described herein. Administration includes self-administration and the administration by another. 
     The term “amino acid” refers to naturally occurring and non-naturally occurring amino acids, as well as amino acid analogs and amino acid mimetics that function in a manner similar to the naturally occurring amino acids. Naturally encoded amino acids are the 20 common amino acids (alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine) and pyrolysine and selenocysteine. Amino acid analogs refer to agents that have the same basic chemical structure as a naturally occurring amino acid, i.e., an α carbon that is bound to a hydrogen, a carboxyl group, an amino group, and an R group, such as, homoserine, norleucine, methionine sulfoxide, methionine methyl sulfonium. Such analogs have modified R groups (such as norleucine) or modified peptide backbones, but retain the same basic chemical structure as a naturally occurring amino acid. In some embodiments, amino acids forming a polypeptide are in the D form. In some embodiments, the amino acids forming a polypeptide are in the L form. In some embodiments, a first plurality of amino acids forming a polypeptide are in the D form and a second plurality are in the L form. 
     Amino acids are referred to herein by either their commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission. Nucleotides, likewise, are referred to by their commonly accepted single-letter code. 
     The terms “polypeptide,” “peptide,” and “protein” are used interchangeably herein to refer to a polymer of amino acid residues. The terms apply to naturally occurring amino acid polymers as well as amino acid polymers in which one or more amino acid residues is a non-naturally occurring amino acid, e.g., an amino acid analog. The terms encompass amino acid chains of any length, including full length proteins, wherein the amino acid residues are linked by covalent peptide bonds. 
     As used herein, the term “antibody” means not only intact antibody molecules, but also fragments of antibody molecules that retain immunogen-binding ability. Such fragments are also well known in the art and are regularly employed both in vitro and in vivo. Accordingly, as used herein, the term “antibody” means not only intact immunoglobulin molecules but also the well-known active fragments F(ab′) 2 , and Fab. F(ab′) 2 , and Fab fragments that lack the Fc fragment of intact antibody, clear more rapidly from the circulation, and may have less non-specific tissue binding of an intact antibody (Wahl et al.,  J. Nucl. Med.  24:316-325 (1983)). The antibodies of the present technology comprise whole native antibodies, monoclonal antibodies, human antibodies, humanized antibodies, camelised antibodies, multispecific antibodies, bispecific antibodies, chimeric antibodies, Fab, Fab′, single chain V region fragments (scFv), single domain antibodies (e.g., nanobodies and single domain camelid antibodies), V NAR  fragments, Bi-specific T-cell engager antibodies, minibodies, disulfide-linked Fvs (sdFv), and anti-idiotypic (anti-Id) antibodies, intrabodies, fusion polypeptides, unconventional antibodies and antigen-binding fragments of any of the above. In particular, antibodies include immunoglobulin molecules and immunologically active fragments of immunoglobulin molecules, i.e., molecules that contain an antigen-binding site. Immunoglobulin molecules can be of any type (e.g., IgG, IgE, IgM, IgD, IgA and IgY), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2) or subclass. 
     In certain embodiments, an antibody is a glycoprotein comprising at least two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds. Each heavy chain is comprised of a heavy chain variable region (abbreviated herein as V H ) and a heavy chain constant (C H ) region. The heavy chain constant region is comprised of three domains, CH1, CH2 and CH3. Each light chain is comprised of a light chain variable region (abbreviated herein as V L ) and a light chain constant C L  region. The light chain constant region is comprised of one domain, C L . 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 (Cl q) of the classical complement system. As used herein interchangeably, the terms “antigen-binding portion”, “antigen-binding fragment”, or “antigen-binding region” of an antibody, refer to the region or portion of an antibody that binds to the antigen and which confers antigen specificity to the antibody; fragments of antigen-binding proteins, for example, antibodies includes one or more fragments of an antibody that retain the ability to specifically bind to an antigen (e.g., an peptide/HLA complex). It has been shown that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody. Examples of antigen-binding portions encompassed within the term “antibody fragments” of an antibody include a Fab fragment, a monovalent fragment consisting of the V L , V H , C L  and CHI domains; a F(ab) 2  fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; a Fd fragment consisting of the V H  and CHI domains; a Fv fragment consisting of the V L  and V H  domains of a single arm of an antibody; a dAb fragment (Ward et al.,  Nature  341: 544-546 (1989)), which consists of a VH domain; and an isolated complementarity determining region (CDR). 
     Antibodies and antibody fragments can be wholly or partially derived from mammals (e.g., humans, non-human primates, goats, guinea pigs, hamsters, horses, mice, rats, rabbits and sheep) or non-mammalian antibody producing animals (e.g., chickens, ducks, geese, snakes, urodele amphibians). The antibodies and antibody fragments can be produced in animals or produced outside of animals, such as from yeast or phage (e.g., as a single antibody or antibody fragment or as part of an antibody library). 
     Furthermore, although the two domains of the Fv fragment, V L  and V H , are coded for by separate genes, they can be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the V L  and V H  regions pair to form monovalent molecules. These are known as single chain Fv (scFv); see e.g., Bird et al.,  Science  242:423-426 (1988); and Huston et al.,  Proc. Natl. Acad. Sci.  85: 5879-5883 (1988). These antibody fragments are obtained using conventional techniques known to those of ordinary skill in the art, and the fragments are screened for utility in the same manner as are intact antibodies. 
     An “isolated antibody” or “isolated antigen-binding protein” is one which has been identified and separated and/or recovered from a component of its natural environment. “Synthetic antibodies” or “recombinant antibodies” are generally generated using recombinant technology or using peptide synthetic techniques known to those of skill in the art. 
     As used herein, the term “single-chain variable fragment” or “scFv” is a fusion protein of the variable regions of the heavy (V H ) and light chains (V L ) of an immunoglobulin (e.g., mouse or human) covalently linked to form a V H :V L  heterodimer. The heavy (V H ) and light chains (V L ) are either joined directly or joined by a peptide-encoding linker (e.g., about 10, 15, 20, 25 amino acids), which connects the N-terminus of the V H  with the C-terminus of the V L , or the C-terminus of the V H  with the N-terminus of the V L . The linker is usually rich in glycine for flexibility, as well as serine or threonine for solubility. The linker can link the heavy chain variable region and the light chain variable region of the extracellular antigen-binding domain. 
     Despite removal of the constant regions and the introduction of a linker, scFv proteins retain the specificity of the original immunoglobulin. Single chain Fv polypeptide antibodies can be expressed from a nucleic acid comprising V H - and V L -encoding sequences as described by Huston, et al.,  Proc. Nat. Acad. Sci. USA,  85:5879-5883 (1988)). See, also, U.S. Pat. Nos. 5,091,513, 5,132,405 and 4,956,778; and U.S. Patent Publication Nos. 20050196754 and 20050196754. Antagonistic scFvs having inhibitory activity have been described (see, e.g., Zhao et al.,  Hybridoma  (Larchmt) 27(6):455-51 (2008); Peter et al.,  J Cachexia Sarcopenia Muscle  (2012); Shieh et al.,  J Imunol  183(4):2277-85 (2009); Giomarelli et al.,  Thromb Haemost  97(6):955-63 (2007); Fife et al.,  J Clin Invst  116(8):2252-61 (2006); Brocks et al.,  Immunotechnology  3(3): 173-84 (1997); Moosmayer et al.,  Ther Immunol  2(10):31-40 (1995) Agonistic scFvs having stimulatory activity have been described (see, e.g., Peter et al.,  J Biol Chem  25278(38):36740-7 (2003); Xie et al.,  Nat Biotech  15(8):768-71 (1997); Ledbetter et al.,  Crit Rev Immunol  17 (5-6):427-55 (1997); Ho et al.,  Bio Chim Biophys Acta  1638(3):257-66 (2003)). 
     As used herein, an “antigen” refers to a molecule to which an antibody (or antigen binding fragment thereof) can selectively bind. The target antigen may be a protein, carbohydrate, nucleic acid, lipid, hapten, or other naturally occurring or synthetic compound. In some embodiments, the target antigen may be a polypeptide (e.g., a MUC16 polypeptide). An antigen may also be administered to an animal to generate an immune response in the animal. 
     The term “antigen binding fragment” refers to a fragment of the whole immunoglobulin structure which possesses a part of a polypeptide responsible for binding to antigen. Examples of the antigen binding fragment useful in the present technology include scFv, (scFv) 2 , scFvFc, Fab, Fab′ and F(ab′) 2 , but are not limited thereto. 
     As used herein, the term “biological sample” or “sample” means sample material derived from living cells. Biological samples may include tissues, cells, protein or membrane extracts of cells, and biological fluids (e.g., ascites fluid or cerebrospinal fluid (CSF)) isolated from a subject, as well as tissues, cells and fluids present within a subject. Biological samples of the present technology include, but are not limited to, samples taken from breast tissue, renal tissue, the uterine cervix, the endometrium, the head or neck, the gallbladder, parotid tissue, the prostate, the brain, the pituitary gland, kidney tissue, muscle, the esophagus, the stomach, the small intestine, the colon, the liver, the spleen, the pancreas, thyroid tissue, heart tissue, lung tissue, the bladder, adipose tissue, lymph node tissue, the uterus, ovarian tissue, adrenal tissue, testis tissue, the tonsils, thymus, blood, hair, buccal, skin, serum, plasma, CSF, semen, prostate fluid, seminal fluid, urine, feces, sweat, saliva, sputum, mucus, bone marrow, lymph, and tears. Biological samples can also be obtained from biopsies of internal organs or from cancers. Biological samples can be obtained from subjects for diagnosis or research or can be obtained from non-diseased individuals, as controls or for basic research. Samples may be obtained by standard methods including, e.g., venous puncture and surgical biopsy. In certain embodiments, the biological sample is a tissue sample obtained by needle biopsy. 
     “Bispecific antibody” or “BsAb”, as used herein, refers to an antibody that can bind simultaneously to two targets that have a distinct structure, e.g., two different target antigens, or two different epitopes on the same target antigen. A variety of different bispecific antibody structures are known in the art. In some embodiments, each antigen binding moiety in a bispecific antibody includes V H  and/or V L  regions; in some such embodiments, the V H  and/or V L  regions are those found in a particular monoclonal antibody. In some embodiments, the bispecific antibody contains two antigen binding moieties, each including V H  and/or V L  regions from different monoclonal antibodies. In some embodiments, the bispecific antibody contains two antigen binding moieties, wherein one of the two antigen binding moieties includes an immunoglobulin molecule having V H  and/or V L  regions that contain CDRs from a first monoclonal antibody, and the other antigen binding moiety includes an antibody fragment (e.g., Fab, F(ab′), F(ab′) 2 , Fd, Fv, dAB, scFv, etc.) having V H  and/or V L  regions that contain CDRs from a second monoclonal antibody. 
     As used herein, the term “conjugated” refers to the association of two molecules by any method known to those in the art. Suitable types of associations include chemical bonds and physical bonds. Chemical bonds include, for example, covalent bonds and coordinate bonds. Physical bonds include, for instance, hydrogen bonds, dipolar interactions, van der Waal forces, electrostatic interactions, hydrophobic interactions and aromatic stacking. 
     As used herein, a “control” is an alternative sample used in an experiment for comparison purpose. A control can be “positive” or “negative.” For example, where the purpose of the experiment is to determine a correlation of the efficacy of a therapeutic agent for the treatment for a particular type of disease, a positive control (a composition known to exhibit the desired therapeutic effect) and a negative control (a subject or a sample that does not receive the therapy or receives a placebo) are typically employed. 
     As used herein, the term “consensus FR” means a framework (FR) antibody region in a consensus immunoglobulin sequence. The FR regions of an antibody do not contact the antigen. 
     As used herein, the term “effective amount” refers to a quantity sufficient to achieve a desired therapeutic and/or prophylactic effect, e.g., an amount which results in the prevention of, or a decrease in a disease or condition described herein or one or more signs or symptoms associated with a disease or condition described herein. In the context of therapeutic or prophylactic applications, the amount of a composition administered to the subject will vary depending on the composition, the degree, type, and severity of the disease and on the characteristics of the individual, such as general health, age, sex, body weight and tolerance to drugs. The skilled artisan will be able to determine appropriate dosages depending on these and other factors. The compositions can also be administered in combination with one or more additional therapeutic compounds. In the methods described herein, the therapeutic compositions may be administered to a subject having one or more signs or symptoms of a disease or condition described herein. As used herein, a “therapeutically effective amount” of a composition refers to composition levels in which the physiological effects of a disease or condition are ameliorated or eliminated. A therapeutically effective amount can be given in one or more administrations. 
     As used herein, the term “expression” refers to the process by which polynucleotides are transcribed into mRNA and/or the process by which the transcribed mRNA is subsequently being translated into peptides, polypeptides, or proteins. If the polynucleotide is derived from genomic DNA, expression can include splicing of the mRNA in a eukaryotic cell. The expression level of a gene can be determined by measuring the amount of mRNA or protein in a cell or tissue sample. In one aspect, the expression level of a gene from one sample can be directly compared to the expression level of that gene from a control or reference sample. In another aspect, the expression level of a gene from one sample can be directly compared to the expression level of that gene from the same sample following administration of the compositions disclosed herein. The term “expression” also refers to one or more of the following events: (1) production of an RNA template from a DNA sequence (e.g., by transcription) within a cell; (2) processing of an RNA transcript (e.g., by splicing, editing, 5′ cap formation, and/or 3′ end formation) within a cell; (3) translation of an RNA sequence into a polypeptide or protein within a cell; (4) post-translational modification of a polypeptide or protein within a cell; (5) presentation of a polypeptide or protein on the cell surface; and (6) secretion or presentation or release of a polypeptide or protein from a cell. 
     The term “linker” refers to synthetic sequences (e.g., amino acid sequences) that connect or link two sequences, e.g., that link two polypeptide domains. In some embodiments, the linker contains 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 of amino acid sequences. 
     As used herein, “humanized” forms of non-human (e.g., murine) antibodies are chimeric antibodies which contain minimal sequence derived from non-human immunoglobulin. For the most part, humanized antibodies are human immunoglobulins in which hypervariable region residues of the recipient are replaced by hypervariable region residues from a non-human species (donor antibody) such as mouse, rat, rabbit or nonhuman primate having the desired specificity, affinity, and capacity. In some embodiments, Fv framework region (FR) residues of the human immunoglobulin are replaced by corresponding non-human residues. Furthermore, humanized antibodies may comprise residues which are not found in the recipient antibody or in the donor antibody. These modifications are made to further refine antibody performance such as binding affinity. Generally, the humanized antibody will comprise substantially all of at least one, and typically two, variable domains (e.g., Fab, Fab′, F(ab′) 2 , or Fv), in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin and all or substantially all of the FR regions are those of a human immunoglobulin consensus FR sequence although the FR regions may include one or more amino acid substitutions that improve binding affinity. The number of these amino acid substitutions in the FR are typically no more than 6 in the H chain, and in the L chain, no more than 3. The humanized antibody optionally may also comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. For further details, see Jones et al.,  Nature  321:522-525 (1986); Reichmann et al.,  Nature  332:323-329 (1988); and Presta,  Curr. Op. Struct. Biol.  2:593-596 (1992). See e.g., Ahmed &amp; Cheung,  FEBS Letters  588(2):288-297 (2014). 
     As used herein, the term “hypervariable region” refers to the amino acid residues of an antibody which are responsible for antigen-binding. The hypervariable region generally comprises amino acid residues from a “complementarity determining region” or “CDR” (e.g., around about residues 24-34 (L1), 50-56 (L2) and 89-97 (L3) in the V L , and around about 31-35B (H1), 50-65 (H2) and 95-102 (H3) in the V H  (Kabat et al.,  Sequences of Proteins of Immunological Interest,  5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991)) and/or those residues from a “hypervariable loop” (e.g., residues 26-32 (L1), 50-52 (L2) and 91-96 (L3) in the V L , and 26-32 (H1), 52A-55 (H2) and 96-101 (H3) in the V H  (Chothia and Leski.  Mol. Biol.  196:901-917 (1987)). 
     As used herein, “F(ab)” refers to a fragment of an antibody structure that binds to an antigen but is monovalent and does not have a Fc portion, for example, an antibody digested by the enzyme papain yields two F(ab) fragments and an Fc fragment (e.g., a heavy (H) chain constant region; Fc region that does not bind to an antigen). 
     As used herein, “F(ab′) 2 ” refers to an antibody fragment generated by pepsin digestion of whole IgG antibodies, wherein this fragment has two antigen binding (ab′) (bivalent) regions, wherein each (ab 1 ) region comprises two separate amino acid chains, a part of a H chain and a light (L) chain linked by an S—S bond for binding an antigen and where the remaining H chain portions are linked together. A “F(ab′) 2 ” fragment can be split into two individual Fab′ fragments. 
     As used herein, “CDRs” are defined as the complementarity determining region amino acid sequences of an antibody which are the hypervariable regions of immunoglobulin heavy and light chains. See, e.g., Kabat et al., Sequences of Proteins of Immunological Interest, 4th U. S. Department of Health and Human Services, National Institutes of Health (1987). Generally, antibodies comprise three heavy chain and three light chain CDRs or CDR regions in the variable region. CDRs provide the majority of contact residues for the binding of the antibody to the antigen or epitope. In certain embodiments, the CDRs regions are delineated using the Kabat system (Kabat, E. A., et al., Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242(1991)). 
     As used herein, the term “constant region” or “constant domain” is interchangeable and has its meaning common in the art. The constant region is an antibody portion, e.g., a carboxyl terminal portion of a light and/or heavy chain which is not directly involved in binding of an antibody to antigen but which can exhibit various effector functions, such as interaction with the Fc receptor. The constant region of an immunoglobulin molecule generally has a more conserved amino acid sequence relative to an immunoglobulin variable domain. 
     As used herein, an “epitope” is a term in the art and can refer to a localized region of an antigen to which an antibody can immunospecifically bind. An epitope can be, e.g., contiguous amino acids of a polypeptide (linear or contiguous epitope) or an epitope can, e.g., come together from two or more noncontiguous regions of a polypeptide or polypeptides (conformational, non-linear, discontinuous, or non-contiguous epitope). 
     As used herein, the term “ligand” refers to a molecule that binds to a receptor. In particular, the ligand binds a receptor on another cell, allowing for cell-to-cell recognition and/or interaction. 
     As used herein, the term “affinity” is meant a measure of binding strength. Without being bound to theory, affinity depends on the closeness of stereochemical fit between antibody combining sites and antigen determinants, on the size of the area of contact between them, and on the distribution of charged and hydrophobic groups. Affinity also includes the term “avidity,” which refers to the strength of the antigen-antibody bond after formation of reversible complexes (e.g., either monovalent or multivalent). Methods for calculating the affinity of an antibody for an antigen are known in the art, comprising use of binding experiments to calculate affinity. Antibody activity in functional assays (e.g., flow cytometry assay) is also reflective of antibody affinity. Antibodies and affinities can be phenotypically characterized and compared using functional assays (e.g., flow cytometry assay). Nucleic acid molecules useful in the presently disclosed subject matter include any nucleic acid molecule that encodes a polypeptide or a fragment thereof. In certain embodiments, nucleic acid molecules useful in the presently disclosed subject matter include nucleic acid molecules that encode an antibody or an antigen-binding portion thereof. Such nucleic acid molecules need not be 100% identical with an endogenous nucleic acid sequence, but will typically exhibit substantial identity. Polynucleotides having “substantial homology” or “substantial identity” to an endogenous sequence are typically capable of hybridizing with at least one strand of a double-stranded nucleic acid molecule. By “hybridize” is meant pair to form a double-stranded molecule between complementary polynucleotide sequences (e.g., a gene described herein), or portions thereof, under various conditions of stringency. (See, e.g., Wahl, G. M. and S. L. Berger,  Methods Enzymol.  152:399 (1987); Kimmel, A. R.,  Methods Enzymol.  152:507 (1987)). 
     As used herein, the terms “immunospecifically binds,” “immunospecifically recognizes,” “specifically binds,” and “specifically recognizes” are analogous terms in the context of antibodies and refer to antibodies and antigen-binding fragments thereof that bind to an antigen (e.g., epitope or immune complex) via the antigen-binding sites as understood by one skilled in the art, and does not exclude cross-reactivity of the antibody or antigen-binding fragment with other antigens. 
     The terms “substantially homologous” or “substantially identical” mean a polypeptide or nucleic acid molecule that exhibits at least 50% or greater homology or identity to a reference amino acid sequence (for example, any one of the amino acid sequences described herein) or nucleic acid sequence (for example, any one of the nucleic acid sequences described herein). For example, such a sequence is at least about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95% or about 99% homologous or identical at the amino acid level or nucleic acid to the sequence used for comparison (e.g., a wild-type, or native, sequence). In some embodiments, a substantially homologous or substantially identical polypeptide contains one or more amino acid amino acid substitutions, insertions, or deletions relative to the sequence used for comparison. In some embodiments, a substantially homologous or substantially identical polypeptide contains one or more non-natural amino acids or amino acid analogs, including, D-amino acids and retroinverso amino acids, to replace homologous sequences. 
     Sequence homology or sequence identity is typically measured using sequence analysis software (for example, Sequence Analysis Software Package of the Genetics Computer Group, University of Wisconsin Biotechnology Center, 1710 University Avenue, Madison, Wis. 53705, BLAST, BESTFIT, GAP, or PILEUP/PRETTYBOX programs). Such software matches identical or similar sequences by assigning degrees of homology to various substitutions, deletions, and/or other modifications. In an exemplary approach to determining the degree of identity, a BLAST program may be used, with a probability score between e −3  and  e-100  indicating a closely related sequence. 
     As used herein, the term “analog” refers to a structurally related polypeptide or nucleic acid molecule having the function of a reference polypeptide or nucleic acid molecule. 
     As used herein, the term “a conservative sequence modification” refers to an amino acid modification that does not significantly affect or alter the binding characteristics of the presently disclosed anti-MUC16 antibody agent or an antigen-binding fragment thereof comprising the amino acid sequence. Conservative modifications can include amino acid substitutions, additions and deletions. Modifications can be introduced into the human scFv of the presently disclosed anti-MUC16 antibody or an antigen-binding fragment thereof by standard techniques known in the art, such as site-directed mutagenesis and PCR-mediated mutagenesis. Amino acids can be classified into groups according to their physicochemical properties such as charge and polarity. Conservative amino acid substitutions are ones in which the amino acid residue is replaced with an amino acid within the same group. For example, amino acids can be classified by charge: positively-charged amino acids include lysine, arginine, and histidine; negatively-charged amino acids include aspartic acid and glutamic acid; neutral charge amino acids include alanine, asparagine, cysteine, glutamine, glycine, isoleucine, leucine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In addition, amino acids can be classified by polarity: polar amino acids include arginine (basic polar), asparagine, and aspartic acid (acidic polar), glutamic acid (acidic polar), glutamine, histidine (basic polar), lysine (basic polar), serine, threonine, and tyrosine; non-polar amino acids include alanine, cysteine, glycine, isoleucine, leucine, methionine, phenylalanine, proline, tryptophan, and valine. Thus, one or more amino acid residues within a CDR region can be replaced with other amino acid residues from the same group and the altered antibody can be tested for retained function (i.e., the functions set forth in (c) through (1) above) using the functional assays described herein. In certain embodiments, no more than one, no more than two, no more than three, no more than four, no more than five residues within a specified sequence or a CDR region are altered. 
     As used herein, the term “heterologous nucleic acid molecule or polypeptide” refers to a nucleic acid molecule (e.g., a cDNA, DNA or RNA molecule) or polypeptide that is not normally present in a cell or sample obtained from a cell. This nucleic acid may be from another organism, or it may be, for example, an mRNA molecule that is not normally expressed in a cell or sample. 
     As used herein, the term “modulate” refers positively or negatively alter. Exemplary modulations include an about 1%, about 2%, about 5%, about 10%, about 25%, about 50%, about 75%, or about 100% change. 
     As used herein, the term “increase” refers to alter positively by at least about 5%, including, but not limited to, alter positively by about 5%, by about 10%, by about 25%, by about 30%, by about 50%, by about 75%, or by about 100%. 
     As used herein, the term “reduce” refers to alter negatively by at least about 5% including, but not limited to, alter negatively by about 5%, by about 10%, by about 25%, by about 30%, by about 50%, by about 75%, or by about 100%. 
     As used herein, an “isolated” polynucleotide or nucleic acid molecule is one which is separated from other nucleic acid molecules which are present in the natural source (e.g., in a mouse or a human) of the nucleic acid molecule. Moreover, an “isolated” nucleic acid molecule, such as a cDNA molecule, can be substantially free of other cellular material, or culture medium when produced by recombinant techniques, or substantially free of chemical precursors or other chemicals when chemically synthesized. For example, the language “substantially free” includes preparations of polynucleotide or nucleic acid molecule having less than about 15%, 10%, 5%, 2%), 1%), 0.5%), or 0.1%) of other material, e.g., cellular material, culture medium, other nucleic acid molecules, chemical precursors and/or other chemicals. 
     As used herein, the term “isolated cell” refers to a cell that is separated from the molecular and/or cellular components that naturally accompany the cell. 
     As used herein, the term “neoplasia” refers to a disease characterized by the pathological proliferation of a cell or tissue and its subsequent migration to or invasion of other tissues or organs. Neoplasia growth is typically uncontrolled and progressive, and occurs under conditions that would not elicit, or would cause cessation of, multiplication of normal cells. Neoplasia can affect a variety of cell types, tissues, or organs, including but not limited to an organ selected from the group consisting of bladder, colon, bone, brain, breast, cartilage, glia, esophagus, fallopian tube, gallbladder, heart, intestines, kidney, liver, lung, lymph node, nervous tissue, ovaries, pleura, pancreas, prostate, skeletal muscle, skin, spinal cord, spleen, stomach, testes, thymus, thyroid, trachea, urogenital tract, ureter, urethra, uterus, and vagina, or a tissue or cell type thereof. Neoplasia include cancers, such as sarcomas, carcinomas, or plasmacytomas (malignant tumor of the plasma cells). 
     As used herein, the term “pharmaceutically acceptable carrier” is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal compounds, isotonic and absorption delaying compounds, and the like, compatible with pharmaceutical administration. Pharmaceutically acceptable carriers and their formulations are known to one skilled in the art and are described, for example, in Remington&#39;s Pharmaceutical Sciences (20 th  edition, ed. A. Gennaro, 2000, Lippincott, Williams &amp; Wilkins, Philadelphia, Pa.). 
     As used herein, the term “recombinant” when used with reference, e.g., to a cell, or nucleic acid, protein, or vector, indicates that the cell, nucleic acid, protein or vector, has been modified by the introduction of a heterologous nucleic acid or protein or the alteration of a native nucleic acid or protein, or that the material is derived from a cell so modified. Thus, for example, recombinant cells express genes that are not found within the native (non-recombinant) form of the cell or express native genes that are otherwise abnormally expressed, under expressed or not expressed at all. 
     As used herein, the term “separate” therapeutic use refers to an administration of at least two active ingredients at the same time or at substantially the same time by different routes. 
     As used herein, the term “sequential” therapeutic use refers to administration of at least two active ingredients at different times, the administration route being identical or different. More particularly, sequential use refers to the whole administration of one of the active ingredients before administration of the other or others commences. It is thus possible to administer one of the active ingredients over several minutes, hours, or days before administering the other active ingredient or ingredients. There is no simultaneous treatment in this case. 
     As used herein, the term “simultaneous” therapeutic use refers to the administration of at least two active ingredients by the same route and at the same time or at substantially the same time. 
     As used herein, the terms “subject,” “individual”, or “patient” can be an individual organism, a vertebrate, a mammal, or a human. In some embodiments, the individual, patient or subject is a human. 
     “Treating” or “treatment” as used herein covers the treatment of a disease or disorder described herein, in a subject, such as a human, and includes: (i) inhibiting a disease or disorder, i.e., arresting its development; (ii) relieving a disease or disorder, i.e., causing regression of the disorder; (iii) slowing progression of the disorder; and/or (iv) inhibiting, relieving, or slowing progression of one or more symptoms of the disease or disorder. In some embodiments, treatment means that the symptoms associated with the disease are, e.g., alleviated, reduced, cured, or placed in a state of remission. 
     It is also to be appreciated that the various modes of treatment of disorders as described herein are intended to mean “substantial,” which includes total but also less than total treatment, and wherein some biologically or medically relevant result is achieved. The treatment may be a continuous prolonged treatment for a chronic disease or a single, or few time administrations for the treatment of an acute condition. 
     Anti-MUC16 Antibody Agents 
     Provided herein are anti-MUC16 antibody agents that immunospecifically bind to MUC16. In some embodiments, the anti-MUC16 antibody agent immunospecifically binds to the retained extracellular domain of MUC16. In some embodiments, the anti-MUC16 antibody agent is an anti-MUC16 construct that comprises an antibody moiety that immunospecifically binds to MUC16. In some embodiments, the anti-MUC16 antibody agent is an anti-MUC16 antibody (e.g., a full-length anti-MUC16 antibody or an antigen binding fragment thereof). In some embodiments, the anti-MUC16 antibody agent binds to an MUC16-expressing cell (e.g., an MUC16-expressing cancer cell). 
     Anti-MUC16 antibody agents, such as anti-MUC16 antibodies or antigen-binding fragments thereof, can include, e.g., monoclonal antibodies, polyclonal antibodies, recombinantly produced antibodies, monospecific antibodies, multispecific antibodies (including bispecific antibodies (BsAb)), human antibodies, humanized antibodies, chimeric antibodies, immunoglobulins, synthetic antibodies, tetrameric antibodies comprising two heavy chain and two light chain molecules, an antibody light chain monomer, an antibody heavy chain monomer, an antibody light chain dimer, an antibody heavy chain dimer, an antibody light chain-antibody heavy chain pair, intrabodies, single domain antibodies, monovalent antibodies, single chain antibodies or single-chain variable fragments (scFv), camelized antibodies, affybodies, and disulfide-linked Fvs (dsFv), Fc fusion proteins, immunoconjugates, or fragments thereof. Such antibodies and antigen-binding fragments can be made by methods known in the art. 
     In some embodiments, the anti-MUC16 antibody agent is a full-length antibody (e.g., full-length IgG) or antigen-binding fragment thereof, which specifically binds to MUC16. 
     In some embodiments, reference to an antibody agent that immunospecifically binds to MUC16 means that the antibody agent binds to MUC16 with an affinity that is at least about 10 times (including for example at least about any of 10, 10 2 , 10 3 , 10 4 , 10 5 , 10 6 , or 10 7  times) its binding affinity for non-target. In some embodiments, the non-target is an antigen that is not MUC16. Binding affinity can be determined by methods known in the art, such as ELISA, fluorescence activated cell sorting (FACS) analysis, or radioimmunoprecipitation assay (RIA). K d  can be determined by methods known in the art, such as surface plasmon resonance (SPR) assay utilizing, for example, Biacore instruments, or kinetic exclusion assay (KinExA) utilizing, for example, Sapidyne instruments. 
     Although anti-MUC16 antibody agents containing human sequences (e.g., human heavy and light chain variable domain sequences comprising human CDR sequences) are extensively discussed herein, non-human anti-MUC16 antibody agents are also contemplated. In some embodiments, non-human anti-MUC16 antibody agents comprise human CDR sequences from an anti-MUC16 antibody agent as described herein and non-human framework sequences. Non-human framework sequences include, in some embodiments, any sequence that can be used for generating synthetic heavy and/or light chain variable domains using one or more human CDR sequences as described herein, including, e.g., mammals, e.g., mouse, rat, rabbit, pig, bovine (e.g., cow, bull, buffalo), deer, sheep, goat, chicken, cat, dog, ferret, primate (e.g., marmoset, rhesus monkey), etc. In some embodiments, a non-human anti-MUC16 antibody agent includes an anti-MUC16 antibody agent generated by grafting one or more human CDR sequences as described herein onto a non-human framework sequence (e.g., a mouse or chicken framework sequence). 
     The complete amino acid sequence of an exemplary human MUC16 comprises or consists of the amino acid sequence of SEQ ID NO: 1. In some embodiments, the anti-MUC16 antibody agent described herein specifically recognizes an epitope within human MUC16. In some embodiments, the anti-MUC16 antibody agent described herein specifically recognizes an epitope within the retained extracellular domain of human MUC16. In some embodiments, the anti-MUC16 antibody agent described herein immunospecifically binds to that MUC16 ectodomain ( FIG. 1 ). In some embodiments, the anti-MUC16 antibody agent described herein immunospecifically binds to a cell expressing human MUC16. In some embodiments, the anti-MUC16 antibody agent described herein immunospecifically binds to a cell expressing a recombinant MUC16 polypeptide. In some embodiments, the MUC16 polypeptide is MUC16-c344 having the amino acid sequence set forth in SEQ ID NO: 43. In some embodiments, the MUC16 polypeptide is MUC16-c114 having the amino acid sequence set forth in SEQ ID NO: 44 or 180. 
     In some embodiments, the anti-MUC16 antibody agent cross-reacts with MUC16 polypeptide from a species other than human. In some embodiments, the anti-MUC16 antibody agent is completely specific for human MUC16 and does not exhibit species or other types of non-human cross-reactivity. 
     In some embodiments, the anti-MUC16 antibody agent specifically recognizes MUC16 expressed on the cell surface of a cancer cell (such as solid tumor). In some embodiments, the anti-MUC16 antibody agent specifically recognizes MUC16 expressed on the cell surface of one or more of ovarian cancer cells, breast cancer cells, prostate cancer cells, colon cancer cells, lung cancer cells, brain cancer cells, pancreatic cancer cells, kidney cancer cells, fallopian tube cancer cells, uterine (e.g., endometrial) cancer cells, primary peritoneum cancer cells or cancer cells of any other tissue that expresses MUC16. In some embodiments, the anti-MUC16 antibody agent specifically recognizes MUC16 expressed on the cell surface of a cancer cell line, e.g. ovarian cancer cell lines, such as OVCAR3, OVCA-432, OVCA-433 and CAOV3. 
     In some embodiments, the anti-MUC16 antibody agent cross-reacts with at least one allelic variant of the MUC16 protein, or fragments thereof. In some embodiments, the allelic variant has up to about 30, such as about any of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, or 30, amino acid substitutions, such as a conservative amino acid substitution, when compared to the naturally occurring MUC16, or fragments thereof. In some embodiments, the anti-MUC16 antibody agent does not cross-react with any allelic variant of the MUC16 protein, or fragments thereof. 
     In some embodiments, the anti-MUC16 antibody agent cross-reacts with at least one interspecies variant of the MUC16 protein. In some embodiments, for example, the MUC16 protein, or fragments thereof is human MUC16 and the interspecies variant of the MUC16 protein, or fragments thereof, is a mouse or rat variant thereof. In some embodiments, the anti-MUC16 antibody agent does not cross-react with any interspecies variant of the MUC16 protein. 
     In some embodiments, according to any of the anti-MUC16 antibody agents described herein, the anti-MUC16 antibody agent comprises an anti-MUC16 antibody moiety that specifically binds to MUC16. 
     In some embodiments, the anti-MUC16 antibody moiety comprises an antibody heavy chain variable domain and an antibody light chain variable domain. In some embodiments, the anti-MUC16 antibody moiety comprises an antibody heavy chain variable domain and/or an antibody light chain variable domain of a humanized 18C6 anti-MUC16 antibody. 
     Humanized 4H11 Anti-MUC16 Antibody Agents 
     In some embodiments, an anti-MUC16 antibody agent described herein comprises an antibody heavy chain variable domain and/or an antibody light chain variable domain of a 4H11 anti-MUC16 antibody (PCT Pub. No. WO2011/119979), where one or more amino acid residues of one or more framework regions of the 4H11 anti-MUC16 heavy chain variable domain and/or an antibody light chain variable domain are modified to a corresponding amino acid in a human antibody heavy chain framework region (HC-FW) or a light chain framework region (LC-FW). 
     In some embodiments, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or more amino acid residues of the framework regions of the mouse 4H11 anti-MUC16 heavy chain variable domain and/or an antibody light chain variable domain are modified to a corresponding amino acid in a human antibody HC-FW and/or LC-FW. In some embodiments, the human LC-FW is from an Immunoglobulin Kappa Variable 4-1 (IGKV4-1) gene or an Immunoglobulin Kappa Joining 2 (IGKJ2) gene. In some embodiments, the human HC-FW is from an Immunoglobulin Heavy Variable 3-21 (IGHV3-21) gene. In some embodiments, the anti-MUC16 antibody agent described herein is more mouse-like, meaning that about 10 or fewer amino acid residues the framework regions of the mouse 4H11 anti-MUC16 heavy chain variable domain and/or an antibody light chain variable domain are modified to a corresponding amino acid in a human antibody HC-FW or LC-FW. In some embodiments, the anti-MUC16 antibody agent described herein is more human-like, meaning that 10 or more amino acid residues the framework regions of the mouse 4H11 anti-MUC16 heavy chain variable domain and/or an antibody light chain variable domain are modified to a corresponding amino acid in a human antibody HC-FW or LC-FW. In some embodiments, the more human amino acid substitutions that are made with respect to the mouse 4H11 anti-MUC16 antibody sequence, a lower the immunogenicity is expected for the anti-MUC16 antibody agent when administered to a human. In some embodiments, one or more amino acids are may be unmodified with respect to the mouse sequence in order to maintain structure and/or activity of the antibody. 
     In some embodiments, the anti-MUC16 antibody moiety comprises a heavy chain variable domain comprising one, two or three HC-CDRs of SEQ ID NO: 4 or 5. In some embodiments, the anti-MUC16 antibody moiety comprises a heavy chain variable domain comprising HC-CDR1, HC-CDR2 and HC-CDR3 of the heavy chain variable domain of SEQ ID NOS: 4 or 5. In some embodiments, the anti-MUC16 antibody moiety comprises a heavy chain variable domain comprising a HC-CDR1, HC-CDR2 and HC-CDR3 set forth in SEQ ID NOS: 17, 18, and 19, respectively. 
     In some embodiments, the anti-MUC16 antibody moiety comprises a heavy chain variable domain comprising a heavy chain framework region 1 (HC-FW1), HC-FW2, and HC-FW3 set forth in SEQ ID NOS: 124, 125, and 126, respectively, where one or more amino acid residues in the HC-FW1, HC-FW2, and/or HC-FW3 are modified to a corresponding amino acid in a human HC-FW1, HC-FW2, and/or HC-FW3, respectively. In some embodiments, the anti-MUC16 antibody moiety comprises a heavy chain variable domain comprising a heavy chain framework region 1 (HC-FW1), HC-FW2, and HC-FW3 of SEQ ID NOS: 124, 125, and 126, respectively, where one or more amino acid residues in the HC-FW1, HC-FW2, and/or HC-FW3 are modified to a corresponding amino acid in a human HC-FW1, HC-FW2, and/or HC-FW3 set forth in SEQ ID NOS: 127, 128, and 129, respectively. 
     Additionally or alternatively, in some embodiments, the anti-MUC16 antibody moiety comprises a heavy chain variable domain comprising a HC-FW1, HC-FW2, and HC-FW3 set forth in SEQ ID NOS: 136, 137, and 138, respectively, where X at position 1 of SEQ ID NO: 136 is S or E, X at position 3 of SEQ ID NO: 136 is K or Q, X at position 5 of SEQ ID NO: 136 is Q or V, X at position 11 of SEQ ID NO: 136 is F or L, X at position 19 of SEQ ID NO: 136 is K or R; X at position 5 of SEQ ID NO: 137 is S or A, X at position 7 of SEQ ID NO: 137 is E or G, X at position 8 of SEQ ID NO: 137 is M or K, X at position 9 of SEQ ID NO: 137 is R or G; X at position 12 of SEQ ID NO: 138 is T or S, X at position 14 of SEQ ID NO: 138 is H or Y, X at position 18 of SEQ ID NO: 138 is G or N, X at position 22 of SEQ ID NO: 138 is S or A, and/or X at position 23 of SEQ ID NO: 138 is G or E. 
     In some embodiments, the anti-MUC16 antibody moiety comprises a heavy chain variable domain comprising a HC-FW1, HC-FW2, and HC-FW3 of SEQ ID NOS: 130, 131, and 132, respectively. In some embodiments, the anti-MUC16 antibody moiety comprises a heavy chain variable domain comprising a HC-FW1, HC-FW2, and HC-FW3 of SEQ ID NOS: 130, 131, and 132, respectively, or variants thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions or having at least about 95% (for example at least about any of 96%, 97%, 98%, or 99%) sequence identity to SEQ ID NOS: 130, 131, and 132. In some embodiments, the anti-MUC16 antibody moiety comprises a heavy chain variable domain comprising a HC-FW1, HC-FW2, and HC-FW3 of SEQ ID NOS: 133, 134, and 135, respectively. In some embodiments, the anti-MUC16 antibody moiety comprises a heavy chain variable domain comprising a HC-FW1, HC-FW2, and HC-FW3 of SEQ ID NOS: 133, 134, and 135, respectively, or variants thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions or having at least about 95% (for example at least about any of 96%, 97%, 98%, or 99%) sequence identity to SEQ ID NOS: 133, 134, and 135. 
     In some embodiments, the anti-MUC16 antibody moiety comprises a heavy chain variable domain comprising SEQ ID NO: 4 or 5. In some embodiments, the anti-MUC16 antibody moiety comprises a heavy chain variable domain set forth in SEQ ID NO: 4 or 5. 
     In some embodiments, the anti-MUC16 antibody moiety comprises a light chain variable domain comprising one, two or three LC-CDRs of SEQ ID NO: 2 or 3. In some embodiments, the anti-MUC16 antibody moiety comprises a light chain variable domain comprising LC-CDR1, LC-CDR2 and LC-CDR3 of the light chain variable domain of SEQ ID NO: 2 or 3. In some embodiments, the anti-MUC16 antibody moiety comprises a light chain variable domain comprising a LC-CDR1, LC-CDR2 and LC-CDR3 set forth in SEQ ID NOS: 14, 15, and 16, respectively. In some embodiments, the anti-MUC16 antibody moiety comprises a light chain variable domain comprising SEQ ID NO: 2 or 3. In some embodiments, the anti-MUC16 antibody moiety comprises a light chain variable domain set forth in SEQ ID NO: 2 or 3. 
     In some embodiments, the anti-MUC16 antibody moiety comprises a light chain variable domain comprising a light chain framework region 1 (LC-FW1), LC-FW2, LC-FW3, and LC-FW4 set forth in SEQ ID NOS: 104, 105, 106, and 107, respectively, where one or more amino acid residues in the LC-FW1, LC-FW2, LC-FW3, and/or LC-FW4 are modified to a corresponding amino acid in a human LC-FW1, LC-FW2, LC-FW3, and/or LC-FW4, respectively. In some embodiments, the anti-MUC16 antibody moiety comprises a light chain variable domain comprising a LC-FW1, LC-FW2, LC-FW3, and LC-FW4 of SEQ ID NOS: 104, 105, 106, and 107, respectively, where one or more amino acid residues in the LC-FW1, LC-FW2, LC-FW3, and/or LC-FW4 are modified to a corresponding amino acid in a human LC-FW1, LC-FW2, LC-FW3, and/or LC-FW4 set forth in SEQ ID NOS: 108, 109, 110, and 111, respectively. 
     In some embodiments, the anti-MUC16 antibody moiety comprises a light chain variable domain comprising a LC-FW1, LC-FW2, LC-FW3, and LC-FW4 set forth in SEQ ID NOS: 120, 121, 122, and 123, respectively, where X at position 3 of SEQ ID NO: 120 is E or V, X at position 9 of SEQ ID NO: 120 is S or D, X at position 15 of SEQ ID NO: 120 is A or L, X at position 18 of SEQ ID NO: 120 is K or R, X at position 22 of SEQ ID NO: 120 is S or N; X at position 7 of SEQ ID NO: 122 is T or S, X at position 27 of SEQ ID NO: 122 is L or V, X at position 3 of SEQ ID NO: 123 is P or Q, and/or X at position 9 of SEQ ID NO: 123 is V or I. 
     In some embodiments, the anti-MUC16 antibody moiety comprises a light chain variable domain comprising a LC-FW1, LC-FW2, LC-FW3, and LC-FW4 of SEQ ID NOS: 112, 113, 114 and 115, respectively. In some embodiments, the anti-MUC16 antibody moiety comprises a light chain variable domain comprising a LC-FW1, LC-FW2, LC-FW3, and LC-FW4 of SEQ ID NOS: 112, 113, 114 and 115, respectively, or variants thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions or having at least about 95% (for example at least about any of 96%, 97%, 98%, or 99%) sequence identity to SEQ ID NOS: 112, 113, 114 and 115. In some embodiments, the anti-MUC16 antibody moiety comprises a light chain variable domain comprising a LC-FW1, LC-FW2, LC-FW3, and LC-FW4 of SEQ ID NOS: 116, 117, 118 and 119, respectively. In some embodiments, the anti-MUC16 antibody moiety comprises a light chain variable domain comprising a LC-FW1, LC-FW2, LC-FW3, and LC-FW4 of SEQ ID NOS: 116, 117, 118 and 119, respectively, or variants thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions or having at least about 95% (for example at least about any of 96%, 97%, 98%, or 99%) sequence identity to SEQ ID NOS: 116, 117, 118 and 119. 
     In some embodiments, the anti-MUC16 antibody moiety comprises a heavy chain variable domain comprising HC-CDR1, HC-CDR2 and HC-CDR3 of the heavy chain variable domain of SEQ ID NO: 4 or 5, and a light chain variable domain comprising LC-CDR1, LC-CDR2 and LC-CDR3 of the light chain variable domain of SEQ ID NO: 2 or 3. In some embodiments, the anti-MUC16 antibody moiety comprises a heavy chain variable domain comprising HC-CDR1, HC-CDR2 and HC-CDR3 set forth in SEQ ID NOS: 17, 18, and 19, respectively, and a light chain variable domain comprising LC-CDR1, LC-CDR2 and LC-CDR3 set forth in SEQ ID NOS: 14, 15, and 16, respectively. In some embodiments, the anti-MUC16 antibody moiety comprises a heavy chain variable domain comprising SEQ ID NO: 4 or 5, and a light chain variable domain comprising SEQ ID NO: 2 or 3. In some embodiments, the anti-MUC16 antibody moiety comprises a heavy chain variable domain set forth in SEQ ID NO: 4 or 5, and a light chain variable domain set forth in SEQ ID NO: 2 or 3. 
     In some embodiments, the anti-MUC16 antibody moiety comprises a heavy chain variable domain comprising a HC-FW1 set forth in SEQ ID NO: 130, a HC-FW2 set forth in SEQ ID NO: 131, a HC-FW3 set forth in SEQ ID NO: 132, a LC-FW1 set forth in SEQ ID NO: 112, a LC-FW2 set forth in SEQ ID NO: 113, a LC-FW3 set forth in SEQ ID NO: 114, and/or a LC-FW4 set forth in SEQ ID NO: 115. 
     In some embodiments, the anti-MUC16 antibody moiety comprises a heavy chain variable domain comprising a HC-FW1 set forth in SEQ ID NO: 133, a HC-FW2 set forth in SEQ ID NO: 134, a HC-FW3 set forth in SEQ ID NO: 135, a LC-FW1 set forth in SEQ ID NO: 116, a LC-FW2 set forth in SEQ ID NO: 117, a LC-FW3 set forth in SEQ ID NO: 118, and/or a LC-FW4 set forth in SEQ ID NO: 119. 
     In some embodiments, the anti-MUC16 antibody moiety comprises a heavy chain variable domain comprising HC-CDR1, HC-CDR2, and HC-CDR3 set forth in SEQ ID NOS: 17, 18, and 19, respectively, and a HC-FW1, HC-FW2, and HC-FW3, set forth in SEQ ID NOS: 130, 131, and 132, respectively; and a light chain variable domain comprising LC-CDR1, LC-CDR2 and LC-CDR3 set forth in SEQ ID NOS: 14, 15, and 16, respectively, and a LC-FW1, LC-FW2, LC-FW3, and a LC-FW4 set forth in SEQ ID NOS: 112, 113, 114, and 115, respectively. 
     In some embodiments, the anti-MUC16 antibody moiety comprises a heavy chain variable domain comprising HC-CDR1, HC-CDR2, and HC-CDR3 set forth in SEQ ID NOS: 17, 18, and 19, respectively, and a HC-FW1, HC-FW2, and HC-FW3, set forth in SEQ ID NOS: 133, 134, and 135, respectively; and a light chain variable domain comprising LC-CDR1, LC-CDR2 and LC-CDR3 set forth in SEQ ID NOS: 14, 15, and 16, respectively, and a LC-FW1, LC-FW2, LC-FW3, and a LC-FW4 set forth in SEQ ID NOS: 116, 117, 118, and 119, respectively. 
     In some embodiments, the antibody heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 4 or 5, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions or having at least about 95% (for example at least about any of 96%, 97%, 98%, or 99%) sequence identity to SEQ ID NO: 4 or 5. In some embodiments, the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 2 or 3, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions or having at least about 95% (for example at least about any of 96%, 97%, 98%, or 99%) sequence identity to SEQ ID NO: 2 or 3. 
     Humanized 18C6 Anti-MUC16 Antibody Agents 
     In some embodiments, an anti-MUC16 antibody agent described herein comprises an antibody heavy chain variable domain and/or an antibody light chain variable domain of a 18C6 anti-MUC16 antibody (PCT Pub. No. WO2016/149368), where one or more amino acid residues of one or more framework regions of the 18C6 anti-MUC16 heavy chain variable domain and/or an antibody light chain variable domain are modified to a corresponding amino acid in a human antibody heavy chain framework region (HC-FW) or a light chain framework region (LC-FW). 
     In some embodiments, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or more amino acid residues of the framework regions of the mouse 18C6 anti-MUC16 heavy chain variable domain and/or an antibody light chain variable domain are modified to a corresponding amino acid in a human antibody HC-FW and/or LC-FW. In some embodiments, the human LC-FW is from an Immunoglobulin Kappa Variable 2-28 (IGKV2-28) gene or an Immunoglobulin Kappa Joining 4 (IGKJ4) gene. In some embodiments, the human HC-FW is from an Immunoglobulin Heavy Variable 2-5 (IGHV2-5) gene. In some embodiments, the anti-MUC16 antibody agent described herein is more mouse-like, meaning that about 10 or fewer amino acid residues the framework regions of the mouse 18C6 anti-MUC16 heavy chain variable domain and/or an antibody light chain variable domain are modified to a corresponding amino acid in a human antibody HC-FW or LC-FW. In some embodiments, the anti-MUC16 antibody agent described herein is more human-like, meaning that 10 or more amino acid residues the framework regions of the mouse 18C6 anti-MUC16 heavy chain variable domain and/or an antibody light chain variable domain are modified to a corresponding amino acid in a human antibody HC-FW or LC-FW. In some embodiments, the more human amino acid substitutions that are made with respect to the mouse 18C6 anti-MUC16 antibody sequence, a lower the immunogenicity is expected for the anti-MUC16 antibody agent when administered to a human. In some embodiments, one or more amino acids are may be unmodified with respect to the mouse sequence in order to maintain structure and/or activity of the antibody. 
     In some embodiments, the anti-MUC16 antibody moiety comprises a heavy chain variable domain comprising one, two or three HC-CDRs of SEQ ID NO: 22 or 23. In some embodiments, the anti-MUC16 antibody moiety comprises a heavy chain variable domain comprising HC-CDR1, HC-CDR2 and HC-CDR3 of the heavy chain variable domain of SEQ ID NO: 22 or 23. In some embodiments, the anti-MUC16 antibody moiety comprises a heavy chain variable domain comprising a HC-CDR1, HC-CDR2 and HC-CDR3 set forth in SEQ ID NOS: 35, 36, and 37, respectively. 
     In some embodiments, the anti-MUC16 antibody moiety comprises a heavy chain variable domain comprising a heavy chain framework region 1 (HC-FW1), HC-FW2, HC-FW3 and HC-FW4 set forth in SEQ ID NOS: 159, 160, 161, and 162, respectively, where one or more amino acid residues in the HC-FW1, HC-FW2, HC-FW3 and/or HC-FW4 are modified to a corresponding amino acid in a human HC-FW1, HC-FW2, HC-FW3 and/or HC-FW4, respectively. In some embodiments, the anti-MUC16 antibody moiety comprises a heavy chain variable domain comprising a heavy chain framework region 1 (HC-FW1), HC-FW2, HC-FW3 and HC-FW4 of SEQ ID NOS: 159, 160, 161, and 162, respectively, where one or more amino acid residues in the HC-FW1, HC-FW2, HC-FW3 and/or HC-FW4 are modified to a corresponding amino acid in a human HC-FW1, HC-FW2, HC-FW3 and/or HC-FW4 set forth in SEQ ID NOS: 163, 164, 165, and 166, respectively. 
     In some embodiments, the anti-MUC16 antibody moiety comprises a heavy chain variable domain comprising a heavy chain framework region 1 (HC-FW1), HC-FW2, HC-FW3 and HC-FW4 set forth in SEQ ID NOS: 175, 176, 177 and 178, respectively, where X at position 10 of SEQ ID NO: 175 is G or T, X at position 11 of SEQ ID NO: 175 is I or L, X at position 12 of SEQ ID NO: 175 is L or V, X at position 13 of SEQ ID NO: 175 is Q or K, X at position 15 of SEQ ID NO: 175 is S or T, X at position 19 of SEQ ID NO: 175 is S or T, X at position 23 of SEQ ID NO: 175 is S or T; X at position 5 of SEQ ID NO: 177 is S or T, X at position 14 of SEQ ID NO: 177 is F or V, X at position 16 of SEQ ID NO: 177 is K or T, X at position 18 of SEQ ID NO: 177 is A or T, X at position 22 of SEQ ID NO: 177 is T or P, X at position 23 of SEQ ID NO: 177 is A or V; and/or X at position 6 of SEQ ID NO: 178 is S or L. 
     In some embodiments, the anti-MUC16 antibody moiety comprises a heavy chain variable domain comprising a HC-FW1, HC-FW2, HC-FW3 and HC-FW4 of SEQ ID NOS: 167, 168, 169, and 170, respectively. In some embodiments, the anti-MUC16 antibody moiety comprises a heavy chain variable domain comprising a HC-FW1, HC-FW2, HC-FW3 and HC-FW4 of SEQ ID NOS: 167, 168, 169, and 170, respectively, or variants thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions or having at least about 95% (for example at least about any of 96%, 97%, 98%, or 99%) sequence identity to SEQ ID NOS: 167, 168, 169, and 170. In some embodiments, the anti-MUC16 antibody moiety comprises a heavy chain variable domain comprising a HC-FW1, HC-FW2, HC-FW3 and HC-FW4 of SEQ ID NOS: 171, 172, 173 and 174, respectively. In some embodiments, the anti-MUC16 antibody moiety comprises a heavy chain variable domain comprising a HC-FW1, HC-FW2, HC-FW3 and HC-FW4 of SEQ ID NOS: 171, 172, 173 and 174, respectively, or variants thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions or having at least about 95% (for example at least about any of 96%, 97%, 98%, or 99%) sequence identity to SEQ ID NOS: 171, 172, 173 and 174. 
     In some embodiments, the anti-MUC16 antibody moiety comprises a heavy chain variable domain comprising SEQ ID NO: 22 or 23. In some embodiments, the anti-MUC16 antibody moiety comprises a heavy chain variable domain set forth in SEQ ID NO: 22 or 23. 
     In some embodiments, the anti-MUC16 antibody moiety comprises a light chain variable domain comprising one, two or three LC-CDRs of SEQ ID NO: 20 or 21. In some embodiments, the anti-MUC16 antibody moiety comprises a light chain variable domain comprising LC-CDR1, LC-CDR2 and LC-CDR3 of the light chain variable domain of SEQ ID NO: 20 or 21. In some embodiments, the anti-MUC16 antibody moiety comprises a light chain variable domain comprising a LC-CDR1, LC-CDR2 and LC-CDR3 set forth in SEQ ID NOS: 32, 33, and 34, respectively. In some embodiments, the anti-MUC16 antibody moiety comprises a light chain variable domain comprising SEQ ID NO: 20 or 21. In some embodiments, the anti-MUC16 antibody moiety comprises a light chain variable domain set forth in SEQ ID NO: 20 or 21. 
     In some embodiments, the anti-MUC16 antibody moiety comprises a light chain variable domain comprising a light chain framework region 1 (LC-FW1), LC-FW2, LC-FW3, and LC-FW4 set forth in SEQ ID NOS: 139, 140, 141, and 142, respectively, where one or more amino acid residues in the LC-FW1, LC-FW2, LC-FW3, and/or LC-FW4 are modified to a corresponding amino acid in a human LC-FW1, LC-FW2, LC-FW3, and/or LC-FW4, respectively. In some embodiments, the anti-MUC16 antibody moiety comprises a light chain variable domain comprising a LC-FW1, LC-FW2, LC-FW3, and LC-FW4 of SEQ ID NOS: 139, 140, 141, and 142, respectively, where one or more amino acid residues in the LC-FW1, LC-FW2, LC-FW3, and/or LC-FW4 are modified to a corresponding amino acid in a human LC-FW1, LC-FW2, LC-FW3, and/or LC-FW4 set forth in SEQ ID NOS: 143, 144, 145, and 146, respectively. 
     In some embodiments, the anti-MUC16 antibody moiety comprises a light chain variable domain comprising a LC-FW1, LC-FW2, LC-FW3, and LC-FW4 set forth in SEQ ID NOS: 155, 156, 157, and 158, respectively, where X at position 7 of SEQ ID NO: 155 is A or S, X at position 9 of SEQ ID NO: 155 is P or L, X at position 11 of SEQ ID NO: 155 is V or L, X at position 18 of SEQ ID NO: 155 is S or P, X at position 5 of SEQ ID NO: 156 is R or K, X at position 9 of SEQ ID NO: 157 is R or S, and/or X at position 18 of SEQ ID NO: 157 is R or K. 
     In some embodiments, the anti-MUC16 antibody moiety comprises a light chain variable domain comprising a LC-FW1, LC-FW2, LC-FW3, and LC-FW4 of SEQ ID NOS: 147, 148, 149 and 150, respectively. In some embodiments, the anti-MUC16 antibody moiety comprises a light chain variable domain comprising a LC-FW1, LC-FW2, LC-FW3, and LC-FW4 of SEQ ID NOS: 147, 148, 149 and 150, respectively, or variants thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions or having at least about 95% (for example at least about any of 96%, 97%, 98%, or 99%) sequence identity to SEQ ID NOS: 147, 148, 149 and 150. In some embodiments, the anti-MUC16 antibody moiety comprises a light chain variable domain comprising a LC-FW1, LC-FW2, LC-FW3, and LC-FW4 of SEQ ID NOS: 151, 152, 153 and 154, respectively. In some embodiments, the anti-MUC16 antibody moiety comprises a light chain variable domain comprising a LC-FW1, LC-FW2, LC-FW3, and LC-FW4 of SEQ ID NOS: 151, 152, 153 and 154, respectively, or variants thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions or having at least about 95% (for example at least about any of 96%, 97%, 98%, or 99%) sequence identity to SEQ ID NOS: 151, 152, 153 and 154. 
     In some embodiments, the anti-MUC16 antibody moiety comprises a heavy chain variable domain comprising HC-CDR1, HC-CDR2 and HC-CDR3 of the heavy chain variable domain of SEQ ID NO: 22 or 23, and a light chain variable domain comprising LC-CDR1, LC-CDR2 and LC-CDR3 of the light chain variable domain of SEQ ID NO: 20 or 21. In some embodiments, the anti-MUC16 antibody moiety comprises a heavy chain variable domain comprising HC-CDR1, HC-CDR2 and HC-CDR3 set forth in SEQ ID NOS: 35, 36, and 37, respectively, and a light chain variable domain comprising LC-CDR1, LC-CDR2 and LC-CDR3 set forth in SEQ ID NOS: 32, 33, and 34, respectively. In some embodiments, the anti-MUC16 antibody moiety comprises a heavy chain variable domain comprising SEQ ID NO: 22 or 23, and a light chain variable domain comprising SEQ ID NO: 20 or 21. In some embodiments, the anti-MUC16 antibody moiety comprises a heavy chain variable domain set forth in SEQ ID NO: 22 or 23, and a light chain variable domain set forth in SEQ ID NO: 20 or 21. 
     In some embodiments, the anti-MUC16 antibody moiety comprises a heavy chain variable domain comprising a HC-FW1 set forth in SEQ ID NO: 167, a HC-FW2 set forth in SEQ ID NO: 168, a HC-FW3 set forth in SEQ ID NO: 169, a HC-FW4 set forth in SEQ ID NO: 170, a LC-FW1 set forth in SEQ ID NO: 147, a LC-FW2 set forth in SEQ ID NO: 148, a LC-FW3 set forth in SEQ ID NO: 149, and/or a LC-FW4 set forth in SEQ ID NO: 150. 
     In some embodiments, the anti-MUC16 antibody moiety comprises a heavy chain variable domain comprising a HC-FW1 set forth in SEQ ID NO: 171, a HC-FW2 set forth in SEQ ID NO: 172, a HC-FW3 set forth in SEQ ID NO: 173, a HC-FW4 set forth in SEQ ID NO: 174, a LC-FW1 set forth in SEQ ID NO: 151, a LC-FW2 set forth in SEQ ID NO: 152, a LC-FW3 set forth in SEQ ID NO: 153, and/or a LC-FW4 set forth in SEQ ID NO: 154. 
     In some embodiments, the anti-MUC16 antibody moiety comprises a heavy chain variable domain comprising HC-CDR1, HC-CDR2, and HC-CDR3 set forth in SEQ ID NOS: 35, 36, and 37, respectively, and a HC-FW1, HC-FW2, HC-FW3, and a HC-FW4 set forth in SEQ ID NOS: 167, 168, 169, and 170, respectively; and a light chain variable domain comprising LC-CDR1, LC-CDR2 and LC-CDR3 set forth in SEQ ID NOS: 32, 33, and 34, respectively, and a LC-FW1, LC-FW2, LC-FW3, and a LC-FW4 set forth in SEQ ID NOS: 147, 148, 149, and 150, respectively. 
     In some embodiments, the anti-MUC16 antibody moiety comprises a heavy chain variable domain comprising HC-CDR1, HC-CDR2, and HC-CDR3 set forth in SEQ ID NOS: 35, 36, and 37, respectively, and a HC-FW1, HC-FW2, HC-FW3, and a HC-FW4 set forth in SEQ ID NOS: 171, 172, 173, and 174, respectively; and a light chain variable domain comprising LC-CDR1, LC-CDR2 and LC-CDR3 set forth in SEQ ID NOS: 32, 33, and 34, respectively, and a LC-FW1, LC-FW2, LC-FW3, and a LC-FW4 set forth in SEQ ID NOS: 151, 152, 153, and 154, respectively. 
     In some embodiments, the antibody heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 22 or 23, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions or having at least about 95% (for example at least about any of 96%, 97%, 98%, or 99%) sequence identity to SEQ ID NO: 22 or 23. In some embodiments, the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 20 or 21, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions or having at least about 95% (for example at least about any of 96%, 97%, 98%, or 99%) sequence identity to SEQ ID NO: 20 or 21. 
     Exemplary antibody sequences of the humanized 4H11 and 18C6 antibody agents provided herein are shown in the Tables below. The exemplary CDR sequences in Table 1 are predicted using the IgBLAST algorithm. See, for example, Ye J. et al.,  Nucleic Acids Research  41:W34-W40 (2013), the disclosure of which is incorporated herein by reference in its entirety. Those skilled in the art will recognize that many algorithms are known for prediction of CDR positions in antibody heavy chain and light chain variable regions, and antibody agents comprising CDRs from antibodies described herein, but based on prediction algorithms other than IgBLAST, are within the scope of the present technology. 
     The exemplary antibody heavy chain and light chain variable region sequences are delimited according to the INTERNATIONAL IMMUNOGENETICS INFORMATION SYSTEM® (IMGT). See, for example, Lefranc, M.-P. et al., Nucleic Acids Res., 43:D413-422 (2015), the disclosure of which is incorporated herein by reference in its entirety. Those skilled in the art will recognize that antibody agents comprising V H  or V L  sequences from antibodies described herein, but based on algorithms other than IMGT, are within the scope of the present technology. 
     
       
         
           
               
             
               
                 TABLE 1 
               
               
                   
               
               
                 Exemplary anti-MUC16 antibody CDR sequences. 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
            
               
                 Antibody 
                   
                   
                   
               
               
                 ID 
                 HC-CDR1 
                 HC-CDR2 
                 HC-CDR3 
               
               
                   
               
               
                 4H11 
                 GFTFSSYA 
                 ISSAGGYI 
                 ARQGFGNYGDYYAMDY 
               
               
                   
                 (SEQ ID NO: 17) 
                 (SEQ ID NO: 18) 
                 (SEQ ID NO: 19) 
               
               
                   
               
               
                 18C6 
                 GFSLSTVGMG 
                 IWWDDEDK 
                 TRIGTAQATDALDY 
               
               
                   
                 (SEQ ID NO: 35) 
                 (SEQ ID NO: 36) 
                 (SEQ ID NO: 37) 
               
               
                   
               
               
                 Antibody 
                   
                   
                   
               
               
                 ID 
                 LC-CDR1 
                 LC-CDR2 
                 LC-CDR3 
               
               
                   
               
               
                 4H11 
                 QSLLNSRTRKNQ 
                 WAS 
                 QQSYNLLT 
               
               
                   
                 (SEQ ID NO: 14) 
                 (SEQ ID NO: 15) 
                 (SEQ ID NO: 16) 
               
               
                   
               
               
                 18C6 
                 KSLLHSNGNTY 
                 YMS 
                 MQSLEYPLT 
               
               
                   
                 (SEQ ID NO: 32) 
                 (SEQ ID NO: 33) 
                 (SEQ ID NO: 34) 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 2 
               
             
            
               
                   
               
               
                 Exemplary anti-MUC16 antibody VH and VL domain sequences. 
               
            
           
           
               
               
               
            
               
                 Clone 
                   
                   
               
               
                 ID 
                 Description 
                 Sequence 
               
               
                   
               
               
                 4H11 
                 VH 
                 EVKLQESGGGFVKPGGSLRVSCAASGFTFSSYAMSWVRLAPEMRL 
               
               
                   
                 Domain 
                 EWVATISSAGGYIFYSDSVQGRFTISRDNAKNSLHLQMGSLRSGDT 
               
               
                   
                 (H1) 
                 AMYYCARQGFGNYGDYYAMDYWGQGTTVTVSS (SEQ ID NO: 4) 
               
               
                   
               
               
                 4H11 
                 VH 
                 EVQLVESGGGLVKPGGSLRVSCAASGFTFSSYAMSWVRLAPGKGL 
               
               
                   
                 Domain 
                 EWVATISSAGGYIFYSDSVQGRFTISRDNAKNSLYLQMNSLRAEDT 
               
               
                   
                 (H2) 
                 AMYYCARQGFGNYGDYYAMDYWGQGTLVTVSS (SEQ ID NO: 5) 
               
               
                   
               
               
                 4H11 
                 VL 
                 DIELTQSPSSLAVSAGERVTMNCKSSQSLLNSRTRKNQLAWYQQKP 
               
               
                   
                 Domain 
                 GQSPELLIYWASTRQSGVPDRFSGSGSGTDFTLTISSVQAEDVAVYY 
               
               
                   
                 (L1) 
                 CQQSYNLLTFGPGTKLEIKR (SEQ ID NO: 2) 
               
               
                   
               
               
                 4H11 
                 VL 
                 DIVLTQSPDSLAVSLGERVTMNCKSSQSLLNSRTRKNQLAWYQQK 
               
               
                   
                 Domain 
                 PGQSPELLIYWASTRQSGVPDRFSGSGSGTDFTLTISSVQAEDVAVY 
               
               
                   
                 (L2) 
                 YCQQSYNLLTFGQGTKLEIKR (SEQ ID NO: 3) 
               
               
                   
               
               
                 18C6 
                 VH 
                 QVTLKESGPGILQPTQTLTLTCTFSGFSLSTVGMGVGWSRQPSGKG 
               
               
                   
                 Domain 
                 LEWLAHIWWDDEDKYYNPALKSRLTITKDTSKNQVFLKITNVDTA 
               
               
                   
                 (H1) 
                 DTATYYCTRIGTAQATDALDYWGQGTLVTVSS (SEQ ID NO: 22) 
               
               
                   
               
               
                 18C6 
                 VH 
                 QVTLKESGPTLVKPTQTLTLTCTFSGFSLSTVGMGVGWSRQPSGKG 
               
               
                   
                 Domain 
                 LEWLAHIWWDDEDKYYNPALKSRLTITKDTSKNQVVLTITNVDPV 
               
               
                   
                 (H2) 
                 DTATYYCTRIGTAQATDALDYWGQGTLVTVSS 
               
               
                   
                   
                 (SEQ ID NO: 23) 
               
               
                   
               
               
                 18C6 
                 VL 
                 DIVMTQSAPSVPVTPGESVSISCRSSKSLLHSNGNTYLYWFLQKPGQ 
               
               
                   
                 Domain 
                 SPQRLIYYMSNLASGVPDRFSGRGSGTDFTLKISRVEAEDVGVYYC 
               
               
                   
                 (L1) 
                 MQSLEYPLTFGGGTKLEIKR (SEQ ID NO: 20) 
               
               
                   
               
               
                 18C6 
                 VL 
                 DIVMTQSALSLPVTPGEPVSISCRSSKSLLHSNGNTYLYWFLQKPGQ 
               
               
                   
                 Domain 
                 SPQRLIYYMSNLASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYC 
               
               
                   
                 (L2) 
                 MQSLEYPLTFGGGTKLEIKR (SEQ ID NO: 21) 
               
               
                   
               
            
           
         
       
     
     In some embodiments, the anti-MUC16 antibody moiety comprises an antibody heavy chain constant region and an antibody light chain constant region. 
     In some embodiments, the anti-MUC16 antibody moiety comprises an IgG1 heavy chain constant region. In some embodiments, the anti-MUC16 antibody moiety comprises an IgG2 heavy chain constant region. In some embodiments, the anti-MUC16 antibody moiety comprises an IgG3 heavy chain constant region. 
     In some embodiments, the anti-MUC16 antibody moiety comprises an IgG1 heavy chain constant region. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 8, 9, 26, 27, or 47. 
     In some embodiments, the anti-MUC16 antibody moiety comprises an IgG4 heavy chain constant region. In some embodiments, the IgG4 heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 48. 
     In some embodiments, the anti-MUC16 antibody moiety comprises a lambda light chain constant region. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 6, 7, 24, 25, or 49. 
     In some embodiments, the anti-MUC16 antibody moiety comprises a kappa light chain constant region. 
     Full-Length Anti-MUC16 Antibody 
     The anti-MUC16 antibody agent in some embodiments is a full-length anti-MUC16 antibody. In some embodiments, the full-length anti-MUC16 antibody is an IgA, IgD, IgE, IgG, or IgM. In some embodiments, the full-length anti-MUC16 antibody comprises IgG constant domains, such as constant domains of any of IgG1, IgG2, IgG3, and IgG4 including variants thereof. In some embodiments, the full-length anti-MUC16 antibody comprises a lambda light chain constant region. In some embodiments, the full-length anti-MUC16 antibody comprises a kappa light chain constant region. In some embodiments, the full-length anti-MUC16 antibody is a full-length human anti-MUC16 antibody. In some embodiments, the full-length anti-MUC16 antibody comprises an Fc sequence of a mouse immunoglobulin. In some embodiments, the full-length anti-MUC16 antibody comprises an Fc sequence that has been altered or otherwise changed so that it has enhanced antibody dependent cellular cytotoxicity (ADCC) or complement dependent cytotoxicity (CDC) effector function. 
     Thus, for example, in some embodiments, there is provided a full-length anti-MUC16 antibody comprising IgG1 or IgG4 constant domains, wherein the anti-MUC16 antibody specifically binds to MUC16 on a tumor cell. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG1 is human IgG4. In some embodiments, the anti-MUC16 heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 8, 9, 26, or 27. In some embodiments, the anti-MUC16 light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 6, 7, 24, or 25. In some embodiments, the anti-MUC16 heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 8, 9, 26, or 27 and the anti-MUC16 light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 6, 7, 24, or 25. In some embodiments, binding of the anti-MUC16 antibody to an MUC16-expressing cell (e.g., an MUC16-expressing cancer cell) inhibits tumor growth or metastasis of a tumor or induces regression of a tumor. In some embodiments, binding of the anti-MUC16 antibody to an MUC16-expressing cell (e.g., an MUC16-expressing cancer cell) inhibits Matrigel invasion in vitro of the MUC16-expressing cells. 
     In some embodiments, there is provided a full-length anti-MUC16 antibody comprising IgG1 or IgG4 constant domains, wherein the anti-MUC16 antibody comprises a) a heavy chain variable domain comprising SEQ ID NO: 4 or 5; and b) a light chain variable domain comprising SEQ ID NO: 2 or 3. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the anti-MUC16 heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 8 or 9. In some embodiments, the anti-MUC16 light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 6 or 7. In some embodiments, the anti-MUC16 antibody comprises a heavy chain comprising SEQ ID NO: 12 or 13 and a light chain comprising SEQ ID NO: 10 or 11. 
     In some embodiments, there is provided a full-length anti-MUC16 antibody comprising IgG1 or IgG4 constant domains, wherein the anti-MUC16 antibody comprises a) a heavy chain variable domain comprising SEQ ID NO: 22 or 23; and b) a light chain variable domain comprising SEQ ID NO: 20 or 21. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the anti-MUC16 heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 26 or 27. In some embodiments, the anti-MUC16 light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 24 or 25. In some embodiments, the anti-MUC16 antibody comprises a heavy chain comprising SEQ ID NO: 30 or 31 and a light chain comprising SEQ ID NO: 28 or 29. 
     Chimeric Anti-MUC16 Constructs 
     In some embodiments, the anti-MUC16 antibody agent is an anti-MUC16 chimeric antigen receptor (CAR) or variant thereof that specifically binds to MUC16. In some embodiments, the anti-MUC16 antibody agent is an anti-MUC16 CAR. CARs are well known in the art, and the anti-MUC16 antibody agent can be a CAR according to any CAR known in the art, such as described in Sadelain et al.,  Nature  545: 423-431 (2017), the disclosure of which is explicitly incorporated herein for use in the present technology. 
     The term “chimeric antigen receptor (CAR)” as used herein refers to an artificially constructed hybrid single-chain protein or single-chain polypeptide containing a single-chain variable fragment (scFv) as a part of the extracellular antigen-binding domain, linked directly or indirectly to a transmembrane domain (e.g., an immune cell co-stimulatory signaling molecule transmembrane domain), which is in turn linked directly or indirectly to an intracellular immune cell (e.g., T cell or NK cell) signaling domain. The intracellular signaling domain (ISD) comprises a primary signaling sequence, or primary immune cell signaling sequence, from an antigen-dependent, TCR-associated T cell activation molecule, e.g., a portion of the intracellular domain of CD3ζ, TCRζ, FcRγ, FcRβ, CD3γ, CD3δ, CD3ε, CD5, CD22, CD79a, CD79b, or CD66d). The ISD can further comprise a co-stimulatory signaling sequence; e.g., a portion of the intracellular domain of an antigen-independent, co-stimulatory molecule such as CD27, CD28, 4-1BB (CD137), OX40, CD30, CD40, PD-1, ICOS, lymphocyte function-associated antigen-1 (LFA-1), CD2, CD7, LIGHT, NKG2C, B7-H3, a ligand that specifically binds with CD83, or the like. Characteristics of CARs include their ability to redirect immune cell (e.g., T cell or NK cell) specificity and reactivity toward a selected target in either MHC-restricted (in cases of TCR-mimic antibodies) or non-MHC-restricted (in cases of antibodies against cell surface proteins) manners, exploiting the antigen-binding properties of monoclonal antibodies. The non-MHC-restricted antigen recognition gives immune cells (e.g., T cells or NK cells) expressing CARs the ability to recognize antigen independent of antigen processing, thus bypassing a major mechanism of tumor escape. 
     In some embodiments, the anti-MUC16 CAR comprises an anti-MUC16 antibody moiety according to any of the anti-MUC16 antibody moieties described herein. For example, in some embodiments, there is provided an anti-MUC16 CAR comprising an anti-MUC16 antibody moiety. In some embodiments, the anti-MUC16 antibody moiety of an anti-MUC16 CAR comprises a) a heavy chain variable domain comprising SEQ ID NO: 4 or 5; and b) a light chain variable domain comprising SEQ ID NO: 2 or 3. In some embodiments, the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 4 or 5, or a variant thereof having at least about 95% (for example at least about any of 96%, 97%, 98%, or 99%) sequence identity, and the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 2 or 3, or a variant thereof having at least about 95% sequence identity. In some embodiments, the anti-MUC16 CAR comprises a sequence selected from among SEQ ID NOS: 80-83 or 97-99. 
     In some embodiments, the anti-MUC16 antibody moiety of an anti-MUC16 CAR comprises a) a heavy chain variable domain comprising SEQ ID NO: 22 or 23; and b) a light chain variable domain comprising SEQ ID NO: 20 or 21. In some embodiments, the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 22 or 23, or a variant thereof having at least about 95% (for example at least about any of 96%, 97%, 98%, or 99%) sequence identity, and the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 20 or 21, or a variant thereof having at least about 95% sequence identity. In some embodiments, the anti-MUC16 CAR comprises a sequence selected from among SEQ ID NOS: 84-87 or 100-103. 
     In some embodiments, the anti-MUC16 antibody agent is an anti-MUC16 chimeric receptor comprising T cell receptor (TCR) transmembrane domains. For example, in some embodiments, the anti-MUC16 antibody agent is an antibody-T cell receptor (abTCR) as described in PCT Patent Application Publication No. WO2017070608, the disclosure of which is explicitly incorporated herein for use in the present technology and for possible inclusion in one or more claims herein. In some embodiments, the anti-MUC16 abTCR comprises an anti-MUC16 antibody moiety according to any of the anti-MUC16 antibody moieties described herein. For example, in some embodiments, there is provided an anti-MUC16 abTCR comprising an anti-MUC16 antibody moiety. 
     In some embodiments, the anti-MUC16 antibody moiety of an anti-MUC16 abTCR comprises a) a heavy chain variable domain comprising SEQ ID NO: 4 or 5; and b) a light chain variable domain comprising SEQ ID NO: 2 or 3. In some embodiments, the heavy chain variable domain of an anti-MUC16 abTCR comprises the amino acid sequence of SEQ ID NO: 4 or 5, or a variant thereof having at least about 95% (for example at least about any of 96%, 97%, 98%, or 99%) sequence identity, and the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 2 or 3, or a variant thereof having at least about 95% sequence identity. 
     In some embodiments, the anti-MUC16 antibody moiety of an anti-MUC16 abTCR comprises a) a heavy chain variable domain comprising SEQ ID NO: 22 or 23; and b) a light chain variable domain comprising SEQ ID NO: 20 or 21. In some embodiments, the heavy chain variable domain of an anti-MUC16 abTCR comprises the amino acid sequence of SEQ ID NO: 22 or 23, or a variant thereof having at least about 95% (for example at least about any of 96%, 97%, 98%, or 99%) sequence identity, and the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 20 or 21, or a variant thereof having at least about 95% sequence identity. 
     In some embodiments, the anti-MUC16 antibody agent is a chimeric co-stimulatory receptor comprising an anti-MUC16 antibody moiety that specifically binds to MUC16 and a co-stimulatory signaling domain. In some embodiments, the anti-MUC16 chimeric co-stimulatory receptor is capable of stimulating an immune cell on the surface of which it is functionally expressed upon binding MUC16. In some embodiments, the anti-MUC16 chimeric co-stimulatory receptor lacks a functional primary immune cell signaling sequence. In some embodiments, the anti-MUC16 chimeric co-stimulatory receptor lacks any primary immune cell signaling sequence. In some embodiments, the anti-MUC16 chimeric co-stimulatory receptor comprises a single polypeptide chain comprising the anti-MUC16 antibody moiety, a transmembrane domain, and the co-stimulatory signaling domain. In some embodiments, the anti-MUC16 chimeric co-stimulatory receptor comprises a first polypeptide chain and a second polypeptide chain, wherein the first and second polypeptide chains together form the anti-MUC16 antibody moiety, a transmembrane module, and co-stimulatory signaling module comprising the co-stimulatory signaling domain. In some embodiments, the first and second polypeptide chains are separate polypeptide chains, and the anti-MUC16 chimeric co-stimulatory receptor is a multimer, such as a dimer. In some embodiments, the first and second polypeptide chains are covalently linked, such as by a peptide linkage, or by another chemical linkage, such as a disulfide linkage. In some embodiments, the first polypeptide chain and the second polypeptide chain are linked by at least one disulfide bond. In some embodiments, the anti-MUC16 antibody moiety is a Fab, a Fab′, a (Fab′)2, an Fv, or a single chain Fv (scFv). In some embodiments, the anti-MUC16 scFv comprise a sequence selected from any one of SEQ ID NOS: 53-68. 
     Examples of co-stimulatory immune cell signaling domains for use in the anti-MUC16 chimeric co-stimulatory receptors of the present technology include the cytoplasmic sequences of co-receptors of the T cell receptor (TCR), which can act in concert with a chimeric receptor (e.g., a CAR or abTCR) to initiate signal transduction following chimeric receptor engagement, as well as any derivative or variant of these sequences and any synthetic sequence that has the same functional capability. 
     It is known that signals generated through the TCR alone are insufficient for full activation of the T cell and that a secondary or co-stimulatory signal is also required. Thus, T cell activation can be said to be mediated by two distinct classes of intracellular signaling sequence: those that initiate antigen-dependent primary activation through the TCR (referred to herein as “primary immune cell signaling sequences”) and those that act in an antigen-independent manner to provide a secondary or co-stimulatory signal (referred to herein as “co-stimulatory immune cell signaling sequences”). 
     Primary immune cell signaling sequences that act in a stimulatory manner may contain signaling motifs which are known as immunoreceptor tyrosine-based activation motifs or ITAMs. Examples of ITAM-containing primary immune cell signaling sequences include those derived from TCRζ, FcRγ, FcRβ, CD3γ, CD3δ, CD3ε, CD5, CD22, CD79a, CD79b, and CD66d. A “functional” primary immune cell signaling sequence is a sequence that is capable of transducing an immune cell activation signal when operably coupled to an appropriate receptor. “Non-functional” primary immune cell signaling sequences, which may comprise fragments or variants of primary immune cell signaling sequences, are unable to transduce an immune cell activation signal. The anti-MUC16 chimeric co-stimulatory receptors described herein lack a functional primary immune cell signaling sequence, such as a functional signaling sequence comprising an ITAM. In some embodiments, the anti-MUC16 chimeric co-stimulatory receptors lack any primary immune cell signaling sequence. 
     The co-stimulatory immune cell signaling sequence can be a portion of the intracellular domain of a co-stimulatory molecule including, for example, CD27, CD28, 4-1BB (CD137), OX40, CD30, CD40, PD-1, ICOS, lymphocyte function-associated antigen-1 (LFA-1), CD2, CD7, LIGHT, NKG2C, B7-H3, a ligand that specifically binds with CD83, and the like. 
     In some embodiments, the anti-MUC16 antibody moiety of an anti-MUC16 chimeric co-stimulatory receptor comprises a) a heavy chain variable domain comprising SEQ ID NO: 4 or 5; and b) a light chain variable domain comprising SEQ ID NO: 2 or 3. In some embodiments, the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 4 or 5, or a variant thereof having at least about 95% (for example at least about any of 96%, 97%, 98%, or 99%) sequence identity, and the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 2 or 3, or a variant thereof having at least about 95% sequence identity. 
     In some embodiments, the anti-MUC16 antibody moiety of an anti-MUC16 chimeric co-stimulatory receptor comprises a) a heavy chain variable domain comprising SEQ ID NO: 22 or 23; and b) a light chain variable domain comprising SEQ ID NO: 20 or 21. In some embodiments, the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 22 or 23, or a variant thereof having at least about 95% (for example at least about any of 96%, 97%, 98%, or 99%) sequence identity, and the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 20 or 21, or a variant thereof having at least about 95% sequence identity. 
     In some embodiments, the anti-MUC16 chimeric co-stimulatory receptor is expressed in an immune cell. In some embodiments, the anti-MUC16 chimeric co-stimulatory receptor is expressed in an immune cell that expresses another chimeric receptor. In some embodiments, the other chimeric receptor is a CAR or an abTCR. In some embodiments, the other chimeric receptor binds to MUC16. In some embodiments, the other chimeric receptor does not bind to MUC16. In some embodiments, the other chimeric receptor binds to an antigen associated with a cancer characterized by high expression of MUC16 and/or high aerobic glycolysis. In some embodiments, the other chimeric receptor binds to an antigen associated with any of the cancers described herein (such as kidney cancer, cervical cancer, prostate cancer, breast cancer, colon cancer, brain cancer, or pancreatic cancer). In some embodiments, the other chimeric receptor binds to an antigen associated with kidney cancer. In some embodiments, the kidney cancer is renal cell carcinoma (RCC). In some embodiments, the RCC is metastatic RCC. In some embodiments, the immune cell is a T cell. In some embodiments, expression of the anti-MUC16 chimeric co-stimulatory receptor in the immune cell is inducible. In some embodiments, the expression of the anti-MUC16 chimeric co-stimulatory receptor in the immune cell is inducible upon signaling through the other chimeric receptor. 
     Binding Affinity 
     Binding affinity can be indicated by K d , K off , K on , or K a . The term “K off ”, as used herein, is intended to refer to the off-rate constant for dissociation of an antibody agent from the antibody agent/antigen complex, as determined from a kinetic selection set up. The term “K on ”, as used herein, is intended to refer to the on-rate constant for association of an antibody agent to the antigen to form the antibody agent/antigen complex. The term equilibrium dissociation constant “K a ”, as used herein, refers to the dissociation constant of a particular antibody agent-antigen interaction, and describes the concentration of antigen required to occupy one half of all of the antibody-binding domains present in a solution of antibody agent molecules at equilibrium, and is equal to K off /K on . The measurement of K a  presupposes that all binding agents are in solution. In the case where the antibody agent is tethered to a cell wall, e.g., in a yeast expression system, the corresponding equilibrium rate constant is expressed as EC50, which gives a good approximation of K a . The affinity constant, K a , is the inverse of the dissociation constant, K d . 
     The dissociation constant (K a ) is used as an indicator showing affinity of antibody moieties to antigens. For example, easy analysis is possible by the Scatchard method using antibody agents marked with a variety of marker agents, as well as by using Biacore (made by Amersham Biosciences), analysis of biomolecular interactions by surface plasmon resonance, according to the user&#39;s manual and attached kit. The K a  value that can be derived using these methods is expressed in units of M (Mols). An antibody agent that specifically binds to a target may have a K a  of, for example, ≤10 −7  M, ≤10 −8  M, ≤10 −9  M, ≤10 −10  M, ≤10 −11  M, ≤10 −12  M, or ≤10 −13  M. 
     Binding specificity of the antibody agent can be determined experimentally by methods known in the art. Such methods comprise, but are not limited to, Western blots, ELISA-, RIA-, ECL-, IRMA-, EIA-, BIAcore-tests and peptide scans. In some embodiments, the binding affinity of the anti-MUC16 antibody agent is measured by testing the binding affinity of the anti-MUC16 antibody agent to cells expressing MUC16 on the surface (e.g., HepG2 cells). 
     In some embodiments, the anti-MUC16 antibody agent specifically binds to a target MUC16 (e.g., nMUC16) with a K d  of about 10 −7 M to about 10 −13  M (such as about 10 −7  M to about 10 −13  M, about 10 −9 M to about 10 −13  M, or about 10 −10 M to about 10 −12 M). Thus in some embodiments, the K d  of the binding between the anti-nMUC16 antibody agent and nMUC16, the K d  of the binding between the anti-sMUC16 antibody agent and sMUC16, or the K d  of the binding between the anti-MUC16 antibody agent and MUC16 (any format), is about 10 −7 M to about 10 −13 M, about 1×10 −7 M to about 5×10 −13 M, about 10 −7 M to about 10 −12 M, about 10 −7 M to about 10 −11 M, about 10 −7 M to about 10 −10  M, about 10 −7 M to about 10 −9 M, about 10 −8 M to about 10 −13 M, about 1×10 −8 M to about 5×10 −13 M, about 10 −8 M to about 10 −12 M, about 10 −8 M to about 10 −11 M, about 10 −8 M to about 10 −10  M, about 10 −8 M to about 10 −9 M, about 5×10 −9 M to about 1×10 −13  M, about 5×10 −9 M to about 1×10 −12  M, about 5×10 −9 M to about 1×10 −11 M, about 5×10 −9 M to about 1×10 −10  M, about 10 −9 M to about 10 −13 M, about 10 −9 M to about 10 −12 M, about 10 −9 M to about 10 −11 M, about 10 −9 M to about 10 −10  M, about 5×10 −10  M to about 1×10 −13 M, about 5×10 −10  M to about 1×10 −12 M, about 5×10 −10  M to about 1×10 −11 M, about 10 −10  M to about 10 −13 M, about 1×10 −10  M to about 5×10 −13 M, about 1×10 −10  M to about 1×10 −12  M, about 1×10 −10  M to about 5×10 −12  M, about 1×10 −10  M to about 1×10 −11 M, about 10 −11 M to about 10 −13 M, about 1×10 −11 M to about 5×10 −13 M, about 10 −11  M to about 10 −12 M, or about 10 −12 M to about 10 −13 M. In some embodiments, the K d  of the binding between the anti-nMUC16 antibody agent and an nMUC16 is about 10 −7  M to about 10 −13 M. 
     In some embodiments, the K d  of the binding between the anti-MUC16 antibody agent and a non-target is more than the K d  of the binding between the anti-MUC16 antibody agent and the target, and is herein referred to in some embodiments as the binding affinity of the anti-MUC16 antibody agent to the target (e.g., cell surface-bound MUC16) is higher than that to a non-target. In some embodiments, the non-target is an antigen that is not MUC16. In some embodiments, the K d  of the binding between the anti-MUC16 antibody agent (against nMUC16) and a non-MUC16 target can be at least about 10 times, such as about 10-100 times, about 100-1000 times, about 10 3 -10 4  times, about 10 4 -10 5  times, about 10 5 -10 6  times, about 10 6 -10 7  times, about 10 7 -10 8  times, about 10 8 -10 9  times, about 10 9 -10 10  times, about 10 10 -10 11  times, or about 10 11 -10 12  times of the K d  of the binding between the anti-MUC16 antibody agent and a target MUC16. 
     In some embodiments, the anti-MUC16 antibody agent binds to a non-target with a K d  of about 10 −1 M to about 10 −6  M (such as about 10 −1 M to about 10 −6  M, about 10 −1 M to about 10 −5  M, or about 10 −2  M to about 10 −4  M). In some embodiments, the non-target is an antigen that is not MUC16. Thus in some embodiments, the K d  of the binding between the anti-MUC16 antibody agent and a non-MUC16 target is about 10 −1 M to about 10 M, about 1×10 −1  M to about 5×10 −6  M, about 10 −1 M to about 10 −5  M, about 1×10 −1  M to about 5×10 −5  M, about 10 −1  M to about 10 −4  M, about 1×10 −1  M to about 5×10 −4  M, about 10 −1 M to about 10 −3  M, about 1×10 −1 M to about 5×10 −3  M, about 10 −1 M to about 10 −2  M, about 10 −2  M to about 10 −6  M, about 1×10 −2 M to about 5×10 −6  M, about 10 −2 M to about 10 −5 M, about 1×10 −2 M to about 5×10 −5 M, about 10 −2  M to about 10 −4 M, about 1×10 −2  M to about 5×10 −4  M, about 10 −2  M to about 10 −3 M, about 10 −3 M to about 10 −6  M, about 1×10 −3 M to about 5×10 −6  M, about 10 −3 M to about 10 −5 M, about 1×10 −3 M to about 5×10 −5  M, about 10 −3 M to about 10 −4 M, about 10 −4 M to about 10 −6  M, about 1×10 −4 M to about 5×10 −6  M, about 10 −4 M to about 10 −5 M, or about 10 −5 M to about 10 −6  M. 
     In some embodiments, when referring to that the anti-MUC16 antibody agent specifically recognizes a target MUC16 (e.g., cell surface-bound MUC16) at a high binding affinity, and binds to a non-target at a low binding affinity, the anti-MUC16 antibody agent will bind to the target MUC16 (e.g., cell surface-bound MUC16) with a K d  of about 10 −7 M to about 10 −13 M (such as about 10 −7 M to about 10 −13 M, about 10 −9  M to about 10 −13  M, or about 10 −10  M to about 10 −12  M), and will bind to the non-target with a K d  of about 10 −1 M to about 10 −6 M (such as about 10 −1 M to about 10 −6 M, about 10 −1 M to about 10 −5 M, or about 10 −2  M to about 10 −4  M). 
     In some embodiments, when referring to that the anti-MUC16 antibody agent specifically recognizes a cell surface-bound MUC16, the binding affinity of the anti-MUC16 antibody agent is compared to a control anti-MUC16 antibody agent. In some embodiments, the K d  of the binding between the control anti-MUC16 antibody agent and a cell surface-bound MUC16 can be at least about 2 times, such as about 2 times, about 3 times, about 4 times, about 5 times, about 6 times, about 7 times, about 8 times, about 9 times, about 10 times, about 10-100 times, about 100-1000 times, about 10 3 -10 4  times, about 10 4 -10 5  times, about 10 5 -10 6  times, about 10 6 -10 7  times, about 10 7 -10 8  times, about 10 8 -10 9  times, about 10 9 -10 10  times, about 10 10 -10 11  times, or about 10 11 -10 12  times of the K d  of the binding between the anti-nMUC16 antibody agent described herein and a cell surface-bound MUC16. 
     Functional Activities of Anti-MUC16 Antibody Agents 
     In certain embodiments, an anti-MUC16 antibody agent or an antigen-binding fragment thereof described herein inhibits Matrigel invasion in vitro of cells recombinantly expressing a MUC16 polypeptide. In some embodiments the MUC16 comprises SEQ ID NO: 44 or 180 (MUC16 c114). In certain embodiments, the cells recombinantly expressing glycosylated MUC16 c114 are SKOV3 cells. In certain embodiments, the MUC16 polypeptide is glycosylated. In certain embodiments, the glycosylated form of MUC16 polypeptide is N-glycosylated at amino acid residue Asn30 (corresponding to Asn1806 of mature MUC16 (SEQ ID NO: 1)). In certain embodiments, MUC16 polypeptide is N-glycosylated at amino acid residues Asn24 and Asn30 (corresponding to Asn1800 and Asn1806, respectively, of mature MUC16 (SEQ ID NO: 1)). In certain embodiments, the MUC16 polypeptide is N-glycosylated at amino acid residues Asn1, Asn24, and Asn30 of SEQ ID NO: 44 or 180 (also referred to as Asn1777, Asn1800, and Asn1806, respectively, in Yin and Lloyd (2001)  J Biol Chem  276: 27371-27375). In certain embodiments, the glycosylation comprises N-linked chitobiose. In certain embodiments, the glycosylation consists of an N-linked chitobiose. In certain embodiments, Matrigel invasion is inhibited by at least 1.25, 1.5, 1.75, 2, 3, 4, 5, 6, 7, 8, 9, or 10-fold as compared to Matrigel invasion in vitro of the cells wherein the cells are treated with a control antibody (e.g., an antibody that does not target MUC16). In certain embodiments, Matrigel invasion is inhibited by about 1.25, 1.5, 1.75, 2, 3, 4, 5, 6, 7, 8, 9, or 10-fold as compared to Matrigel invasion in vitro of the cells wherein the cells are treated with a control antibody (e.g., an antibody that does not target MUC16). 
     Assays to determine the MUC16 anti-MUC16 antibody agent or antigen-binding fragment-mediated inhibition of Matrigel invasion are known to a person skilled in the art. For example, BD BioCoat™ Matrigel™ Invasion Inserts or Chambers (catalog #354480 in 24 well plate) and Control Inserts (catalog #354578 in 24 well plate) can be purchased from BD Biosciences, MA. Matrigel Invasion assay can be performed as per manufacturer&#39;s protocol. Briefly, the Matrigel chambers in 24 well plates (stored at −20° C.) and control inserts (stored at 4° C.) are allowed to come to room temperature. Both inserts are rehydrated with 0.5 mL of serum free medium in the insert as well as in the outside well of the 24 well plate, for 2 hours at 37° C. 5% CO 2  humidified incubator. Cultured SKOV3 cells are trypsinized and washed with culture medium. A million cells are separated into another centrifuge tube and washed 3 times with serum free medium. These cells are later adjusted to give 5,000 cells in 0.5 mL serum free medium. The medium in the rehydrated inserts are removed and the insert was transferred into a new 24 well plate containing 0.75 mL of 10% Fetal Bovine Serum (FBS) containing culture medium in the well which serves as a chemo attractant. Immediately, 0.5 mL of the cells (5,000 cells) in serum free medium is added to the insert. Proper care is taken to see that there is no air bubble is trapped in the insert and the outside well. The 24 well plate is incubated at 37° C. 5% C02 humidified incubator for 48 hrs. After incubation, the non-invading cells are removed from the upper surface of the membrane by “scrubbing” by inserting a cotton tipped swab into Matrigel or control insert and gently applied pressure while moving the tip of the swab over the membrane surface. The scrubbing is repeated with a second swab moistened with medium. Then the inserts are stained in a new 24 well plate containing 0.5 mL of 0.5% crystal violet stain in distilled water for 30 minutes. Following staining the inserts are rinsed in 3 beakers of distilled water to remove excess stain. The inserts are air dried for in a new 24 well plate. The invaded cells are hand counted under an inverted microscope at 200× magnification. Several fields of triplicate membranes were counted and recorded in the figure. 
     In certain embodiments, an anti-MUC16 antibody agent or an antigen-binding fragment thereof described herein is capable of inhibiting or reducing metastasis, inhibiting tumor growth or inducing tumor regression in mouse model studies. For example, tumor cell lines can be introduced into athymic nude mice, and the athymic mice can be administered an anti-MUC16 antibody agent or an antigen-binding fragment thereof described herein one or more times, and tumor progression of the injected tumor cells can be monitored over a period of weeks and/or months. In some cases, administration of an anti-MUC16 antibody agent or an antigen-binding fragment thereof to the athymic nude mice can occur prior to introduction of the tumor cell lines. In a certain embodiment, SKOV3 cells expressing MUC16 c114 are utilized for the mouse xenograft models described herein. 
     In some embodiments, an anti-MUC16 antibody agent or an antigen-binding fragment thereof described herein inhibits tumor growth or induce tumor regression in a mouse model by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% as assessed by methods described herein or known to one of skill in the art, as compared to mock-treated mice. In some embodiments, an anti-MUC16 antibody agent or an antigen-binding fragment thereof described herein inhibits tumor growth or induce tumor regression in a mouse model by at least about 25% or 35%), optionally to about 75%, as assessed by methods described herein or known to one of skill in the art, as compared to mock-treated mice. In some embodiments, an anti-MUC16 antibody agent or an antigen-binding fragment thereof described herein inhibit tumor growth or induce tumor regression in a mouse model by at least about 1 fold, 1.2 fold, 1.3 fold, 1.4 fold, 1.5 fold, 2 fold, 2.5 fold, 3 fold, 3.5 fold, 4 fold, 4.5 fold, 5 fold, 6 fold, 7 fold, 8 fold, 9 fold, 10 fold, 15 fold, 20 fold, 30 fold, 40 fold, 50 fold, 60 fold, 70 fold, 80 fold, 90 fold, or 100 fold as assessed by methods described herein or known to one of skill in the art, as compared to mock-treated mice. Mock-treated mice can, for example, be treated with phosphate buffered saline or a control (e.g., anti-IgG antibody). 
     Determining tumor growth inhibition or tumor regression can be assessed, for example, by monitoring tumor size over a period of time, such as by physical measurement of palpable tumors, or other visual detection methods. For example, tumor cell lines can be generated to recombinantly express a visualization agent, such as green fluorescent protein (GFP) or luciferase, then in vivo visualization of GFP can be carried out by microscopy, and in vivo visualization of luciferase can be carried out by administering luciferase substrate to the xenograft mice and detecting luminescent due to the luciferase enzyme processing the luciferase substrate. The degree or level of detection of GFP or luciferase correlates to the size of the tumor in the xenograft mice. 
     In certain embodiments, an anti-MUC16 antibody agent or an antigen-binding fragment thereof described herein can increase survival of animals in tumor xenograft models as compared to mock-treated mice. In some embodiments, an anti-MUC16 antibody agent or an antigen-binding fragment thereof described herein increases survival of mice in tumor xenograft models by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% as assessed by methods described herein or known to one of skill in the art, as compared to mock-treated mice. In some embodiments, an anti-MUC16 antibody agent or an antigen-binding fragment thereof described herein increases survival of mice in tumor xenograft models by at least about 25% or 35%, optionally to about 75%), as assessed by methods described herein or known to one of skill in the art, as compared to mock-treated mice in tumor xenograft models. In some embodiments, an anti-MUC16 antibody agent or an antigen-binding fragment thereof described herein increases survival of mice in tumor xenograft models by at least about 1 fold, 1.2 fold, 1.3 fold, 1.4 fold, 1.5 fold, 2 fold, 2.5 fold, 3 fold, 3.5 fold, 4 fold, 4.5 fold, 5 fold, 6 fold, 7 fold, 8 fold, 9 fold, 10 fold, 15 fold, 20 fold, 30 fold, 40 fold, 50 fold, 60 fold, 70 fold, 80 fold, 90 fold, or 100 fold as assessed by methods described herein or known to one of skill in the art, as compared to mock-treated mice in tumor xenograft models. Survival can, for example, be determined by plotting a survival curve of number of surviving mice against time (e.g., days or weeks) after tumor cell line injection. Mock-treated mice can, for example, be treated with phosphate buffered saline or a control (e.g., anti-IgG antibody). 
     In certain embodiments, an anti-MUC16 antibody agent or an antigen-binding fragment thereof described herein is internalized into a cell expressing a MUC16 polypeptide upon contacting the cell with the anti-MUC16 antibody agent or an antigen-binding fragment thereof. “Internalized” or “internalization,” when in reference to a molecule that is internalized by a cell, refers to passage of the molecule that is in contact with the extracellular surface of a cell membrane across the cell membrane to the intracellular surface of the cell membrane and/or into the cell cytoplasm. In certain embodiments, the cells recombinantly expressing glycosylated MUC16 c114 are SKOV3 cells. In certain embodiments, the glycosylated form of MUC16 c114 is N-glycosylated, e.g., at Asn1, Asn24, and Asn30 of SEQ ID NO: 44 or 180 (also referred to as Asn1777, Asn1800, and Asn1806, respectively, in Yin and Lloyd (2001)  J Biol Chem  276: 27371-27375). In certain embodiments, the glycosylation comprises N-linked chitobiose. In certain embodiments, the glycosylation consists of an N-linked chitobiose. 
     Assays to determine internalization of an anti-MUC16 antibody agent or an antigen-binding fragment thereof described herein to a cell, such as, for example, using radiolabeled antibodies, are known to a person skilled in the art. For example, internalization of  89 Zr-labeled antibody can be investigated on SKOV3 cells expressing MUC16 c114. Briefly, approximately 1×10 5  cells are seeded in a 12-well plate and incubated overnight at 37° C. 5% CO 2  incubator. A volume of radiolabeled protein is added to each well and the plates are incubated at 37° C. and 4° C. for 1, 5, 12, and 24 hours. Following each incubation period, the medium is collected and the cells are rinsed with 1 mL of phosphate buffered saline (PBS). Surface-bound activity is collected by washing the cells in 1 mL of 100 mM acetic acid with 100 mM glycine (1:1, pH 3.5) at 4° C. The adherent cells are then lysed with 1 mL of 1 M NaOH. Each wash is collected and counted for activity. The ratio of activity of the final wash to the total activity of all the washes is used to determine the % internalized. In certain embodiments, the assay is performed at 37° C. In certain embodiments, the anti-MUC16 antibody agent or an antigen-binding fragment thereof is internalized in at least 1, 2, 3, 5, 6, 7, 8, 9, or 10 percent of cells incubated with the anti-MUC16 antibody agent or an antigen-binding fragment thereof. In certain embodiments, the anti-MUC16 antibody agent or an antigen-binding fragment thereof is internalized in about 1, 2, 3, 5, 6, 7, 8, 9, or 10 percent of cells incubated with the anti-MUC16 antibody agent or an antigen-binding fragment thereof. In certain embodiments, the anti-MUC16 antibody agent or an antigen-binding fragment thereof is internalized within 1, 2, 3, 4, 8, 12, 16, 20, or 24 hours of contacting the cells with the anti-MUC16 antibody agent or an antigen-binding fragment thereof. 
     Nucleic Acids 
     Nucleic acid molecules encoding the anti-MUC16 antibody agents or an antigen-binding fragment thereof (such as anti-MUC16 antibodies, e.g., full-length anti-MUC16 antibodies) are also contemplated. In some embodiments, there is provided a nucleic acid (or a set of nucleic acids) encoding a full-length anti-MUC16 antibody, including any of the full-length anti-MUC16 antibodies described herein, or an antigen-binding fragment thereof. In some embodiments, the nucleic acid (or a set of nucleic acids) encoding the anti-MUC16 antibody agent described herein may further comprises a nucleic acid sequence encoding a peptide tag (such as protein purification tag, e.g., His-tag, HA tag). 
     Also contemplated here are isolated host cells comprising an anti-MUC16 antibody agent, an isolated nucleic acid encoding the polypeptide components of the anti-MUC16 antibody agent, or a vector comprising a nucleic acid encoding the polypeptide components of the anti-MUC16 antibody agent described herein. 
     The present application also includes variants to these nucleic acid sequences. For example, the variants include nucleotide sequences that hybridize to the nucleic acid sequences encoding the anti-MUC16 antibody agents (such as anti-MUC16 antibodies, e.g., full-length anti-MUC16 antibodies), antigen-binding fragments thereof, or anti-MUC16 antibody moieties of the present application under at least moderately stringent hybridization conditions. 
     The present technology also provides vectors in which a nucleic acid of the present technology is inserted. 
     In brief summary, the expression of an anti-MUC16 antibody agent (e.g., full-length anti-MUC16 antibody) or an antigen-binding fragment thereof by a natural or synthetic nucleic acid encoding the anti-MUC16 antibody agent can be achieved by inserting the nucleic acid into an appropriate expression vector, such that the nucleic acid is operably linked to 5′ and 3′ regulatory elements, including for example a promoter (e.g., a lymphocyte-specific promoter) and a 3′ untranslated region (UTR). The vectors can be suitable for replication and integration in eukaryotic host cells. Typical cloning and expression vectors contain transcription and translation terminators, initiation sequences, and promoters useful for regulation of the expression of the desired nucleic acid sequence. 
     The nucleic acids of the present technology may also be used for nucleic acid immunization and gene therapy, using standard gene delivery protocols. Methods for gene delivery are known in the art. See, e.g., U.S. Pat. Nos. 5,399,346, 5,580,859, 5,589,466, incorporated by reference herein in their entireties. In some embodiments, the present technology provides a gene therapy vector. 
     The nucleic acid can be cloned into a number of types of vectors. For example, the nucleic acid can be cloned into a vector including, but not limited to a plasmid, a phagemid, a phage derivative, an animal virus, and a cosmid. Vectors of particular interest include expression vectors, replication vectors, probe generation vectors, and sequencing vectors. 
     Further, the expression vector may be provided to a cell in the form of a viral vector. Viral vector technology is well known in the art and is described, for example, in Green and Sambrook (2013, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory, New York), and in other virology and molecular biology manuals. Viruses which are useful as vectors include, but are not limited to, retroviruses, adenoviruses, adeno-associated viruses, herpes viruses, and lentiviruses. In general, a suitable vector contains an origin of replication functional in at least one organism, a promoter sequence, convenient restriction endonuclease sites, and one or more selectable markers (see, e.g., WO 01/96584; WO 01/29058; and U.S. Pat. No. 6,326,193). 
     A number of viral based systems have been developed for gene transfer into mammalian cells. For example, retroviruses provide a convenient platform for gene delivery systems. A selected gene can be inserted into a vector and packaged in retroviral particles using techniques known in the art. The recombinant virus can then be isolated and delivered to cells of the subject either in vivo or ex vivo. A number of retroviral systems are known in the art. In some embodiments, adenovirus vectors are used. A number of adenovirus vectors are known in the art. In some embodiments, lentivirus vectors are used. Vectors derived from retroviruses such as the lentivirus are suitable tools to achieve long-term gene transfer since they allow long-term, stable integration of a transgene and its propagation in daughter cells. Lentiviral vectors have the added advantage over vectors derived from onco-retroviruses such as murine leukemia viruses in that they can transduce non-proliferating cells, such as hepatocytes. They also have the added advantage of low immunogenicity. 
     Additional promoter elements, e.g., enhancers, regulate the frequency of transcriptional initiation. Typically, these are located in the region 30-110 bp upstream of the start site, although a number of promoters have recently been shown to contain functional elements downstream of the start site as well. The spacing between promoter elements frequently is flexible, so that promoter function is preserved when elements are inverted or moved relative to one another. In the thymidine kinase (tk) promoter, the spacing between promoter elements can be increased to 50 bp apart before activity begins to decline. 
     One example of a suitable promoter is the immediate early cytomegalovirus (CMV) promoter sequence. This promoter sequence is a strong constitutive promoter sequence capable of driving high levels of expression of any polynucleotide sequence operatively linked thereto. Another example of a suitable promoter is Elongation Growth Factor-1α (EF-1α). However, other constitutive promoter sequences may also be used, including, but not limited to the simian virus 40 (SV40) early promoter, mouse mammary tumor virus (MMTV), human immunodeficiency virus (HIV) long terminal repeat (LTR) promoter, MoMuLV promoter, an avian leukemia virus promoter, an Epstein-Barr virus immediate early promoter, a Rous sarcoma virus promoter, as well as human gene promoters such as, but not limited to, the actin promoter, the myosin promoter, the hemoglobin promoter, and the creatine kinase promoter. Further, the present technology should not be limited to the use of constitutive promoters. Inducible promoters are also contemplated as part of the present technology. The use of an inducible promoter provides a molecular switch capable of turning on expression of the polynucleotide sequence which it is operatively linked when such expression is desired, or turning off the expression when expression is not desired. Examples of inducible promoters include, but are not limited to a metallothionine promoter, a glucocorticoid promoter, a progesterone promoter, and a tetracycline promoter. 
     In some embodiments, the expression of the anti-MUC16 antibody agent is inducible. In some embodiments, a nucleic acid sequence encoding the anti-MUC16 antibody agent is operably linked to an inducible promoter, including any inducible promoter described herein. 
     Inducible Promoters 
     The use of an inducible promoter provides a molecular switch capable of turning on expression of the polynucleotide sequence which it is operatively linked when such expression is desired, or turning off the expression when expression is not desired. Exemplary inducible promoter systems for use in eukaryotic cells include, but are not limited to, hormone-regulated elements (e.g., see Mader, S. and White, J. H.  Proc. Natl. Acad. Sci. USA  90:5603-5607 (1993)), synthetic ligand-regulated elements (see, e.g., Spencer, D. M. et al 1993)  Science  262: 1019-1024) and ionizing radiation-regulated elements (e.g., see Manome, Y. et al.,  Biochemistry  32: 10607-10613 (1993); Datta, R. et al.,  Proc. Natl. Acad. Sci. USA  89: 1014-10153 (1992)). Further exemplary inducible promoter systems for use in in vitro or in vivo mammalian systems are reviewed in Gingrich et al.,  Annual Rev. Neurosci  21:377-405 (1998). In some embodiments, the inducible promoter system for use to express the anti-MUC16 antibody agent is the Tet system. In some embodiments, the inducible promoter system for use to express the anti-MUC16 antibody agent is the lac repressor system from  E. coli.    
     An exemplary inducible promoter system for use in the present technology is the Tet system. Such systems are based on the Tet system described by Gossen et al., (1993). In an exemplary embodiment, a polynucleotide of interest is under the control of a promoter that comprises one or more Tet operator (TetO) sites. In the inactive state, Tet repressor (TetR) will bind to the TetO sites and repress transcription from the promoter. In the active state, e.g., in the presence of an inducing agent such as tetracycline (Tc), anhydrotetracycline, doxycycline (Dox), or an active analog thereof, the inducing agent causes release of TetR from TetO, thereby allowing transcription to take place. Doxycycline is a member of the tetracycline family of antibiotics having the chemical name of 1-dimethylamino-2,4a,5,7,12-pentahydroxy-11-methyl-4,6-dioxo-1,4a,11,11a,12,12a-hexahydrotetracene-3-carboxamide. 
     In one embodiment, a TetR is codon-optimized for expression in mammalian cells, e.g., murine or human cells. Most amino acids are encoded by more than one codon due to the degeneracy of the genetic code, allowing for substantial variations in the nucleotide sequence of a given nucleic acid without any alteration in the amino acid sequence encoded by the nucleic acid. However, many organisms display differences in codon usage, also known as “codon bias” (i.e., bias for use of a particular codon(s) for a given amino acid). Codon bias often correlates with the presence of a predominant species of tRNA for a particular codon, which in turn increases efficiency of mRNA translation. Accordingly, a coding sequence derived from a particular organism (e.g., a prokaryote) may be tailored for improved expression in a different organism (e.g., a eukaryote) through codon optimization. 
     Other specific variations of the Tet system include the following “Tet-Off” and “Tet-On” systems. In the Tet-Off system, transcription is inactive in the presence of Tc or Dox. In that system, a tetracycline-controlled transactivator protein (tTA), which is composed of TetR fused to the strong transactivating domain of VP16 from Herpes simplex virus, regulates expression of a target nucleic acid that is under transcriptional control of a tetracycline-responsive promoter element (TRE). The TRE is made up of TetO sequence concatamers fused to a promoter (commonly the minimal promoter sequence derived from the human cytomegalovirus (hCMV) immediate-early promoter). In the absence of Tc or Dox, tTA binds to the TRE and activates transcription of the target gene. In the presence of Tc or Dox, tTA cannot bind to the TRE, and expression from the target gene remains inactive. 
     Conversely, in the Tet-On system, transcription is active in the presence of Tc or Dox. The Tet-On system is based on a reverse tetracycline-controlled transactivator, rtTA. Like tTA, rtTA is a fusion protein comprised of the TetR repressor and the VP16 transactivation domain. However, a four amino acid change in the TetR DNA binding moiety alters rtTA&#39;s binding characteristics such that it can only recognize the tetO sequences in the TRE of the target transgene in the presence of Dox. Thus, in the Tet-On system, transcription of the TRE-regulated target gene is stimulated by rtTA only in the presence of Dox. 
     Another inducible promoter system is the lac repressor system from  E. coli  (See Brown et al., Cell 49:603-612 (1987)). The lac repressor system functions by regulating transcription of a polynucleotide of interest operably linked to a promoter comprising the lac operator (lacO). The lac repressor (lacR) binds to LacO, thus preventing transcription of the polynucleotide of interest. Expression of the polynucleotide of interest is induced by a suitable inducing agent, e.g., isopropyl-β-D-thiogalactopyranoside (IPTG). 
     In order to assess the expression of a polypeptide or portions thereof, the expression vector to be introduced into a cell can also contain either a selectable marker gene or a reporter gene or both to facilitate identification and selection of expressing cells from the population of cells sought to be transfected or infected through viral vectors. In other aspects, the selectable marker may be carried on a separate piece of DNA and used in a co-transfection procedure. Both selectable markers and reporter genes may be flanked with appropriate regulatory sequences to enable expression in the host cells. Useful selectable markers include, for example, antibiotic-resistance genes, such as neo and the like. 
     Reporter genes are used for identifying potentially transfected cells and for evaluating the functionality of regulatory sequences. In general, a reporter gene is a gene that is not present in or expressed by the recipient organism or tissue and that encodes a polypeptide whose expression is manifested by some easily detectable property, e.g., enzymatic activity. Expression of the reporter gene is assayed at a suitable time after the DNA has been introduced into the recipient cells. Suitable reporter genes may include genes encoding luciferase, β-galactosidase, chloramphenicol acetyl transferase, secreted alkaline phosphatase, or the green fluorescent protein gene (e.g., Ui-Tel et al., 2000  FEBS Letters  479: 79-82). Suitable expression systems are well known and may be prepared using known techniques or obtained commercially. In general, the construct with the minimal 5′ flanking region showing the highest level of expression of reporter gene is identified as the promoter. Such promoter regions may be linked to a reporter gene and used to evaluate agents for the ability to modulate promoter-driven transcription. 
     In some embodiments, there is provided nucleic acid encoding a full-length anti-MUC16 antibody according to any of the full-length anti-MUC16 antibodies described herein. In some embodiments, the nucleic acid comprises one or more nucleic acid sequences encoding the heavy and light chains of the full-length anti-MUC16 antibody. In some embodiments, each of the one or more nucleic acid sequences are contained in separate vectors. In some embodiments, at least some of the nucleic acid sequences are contained in the same vector. In some embodiments, all of the nucleic acid sequences are contained in the same vector. Vectors may be selected, for example, from the group consisting of mammalian expression vectors and viral vectors (such as those derived from retroviruses, adenoviruses, adeno-associated viruses, herpes viruses, and lentiviruses). 
     Methods of introducing and expressing genes into a cell are known in the art. In the context of an expression vector, the vector can be readily introduced into a host cell, e.g., mammalian, bacterial, yeast, or insect cell by any method in the art. For example, the expression vector can be transferred into a host cell by physical, chemical, or biological means. 
     Physical methods for introducing a polynucleotide into a host cell include calcium phosphate precipitation, lipofection, particle bombardment, microinjection, electroporation, and the like. Methods for producing cells comprising vectors and/or exogenous nucleic acids are well-known in the art. See, for example, Green and Sambrook (2013, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory, New York). In some embodiments, the introduction of a polynucleotide into a host cell is carried out by calcium phosphate transfection. 
     Biological methods for introducing a polynucleotide of interest into a host cell include the use of DNA and RNA vectors. Viral vectors, and especially retroviral vectors, have become the most widely used method of inserting genes into mammalian, e.g., human cells. Other viral vectors can be derived from lentivirus, poxviruses, herpes simplex virus 1, adenoviruses and adeno-associated viruses, and the like. See, for example, U.S. Pat. Nos. 5,350,674 and 5,585,362. 
     Chemical means for introducing a polynucleotide into a host cell include colloidal dispersion systems, such as macromolecule complexes, nanocapsules, microspheres, beads, and lipid-based systems including oil-in-water emulsions, micelles, mixed micelles, and liposomes. An exemplary colloidal system for use as a delivery vehicle in vitro and in vivo is a liposome (e.g., an artificial membrane vesicle). 
     In the case where a non-viral delivery system is utilized, an exemplary delivery vehicle is a liposome. The use of lipid formulations is contemplated for the introduction of the nucleic acids into a host cell (in vitro, ex vivo or in vivo). In another aspect, the nucleic acid may be associated with a lipid. The nucleic acid associated with a lipid may be encapsulated in the aqueous interior of a liposome, interspersed within the lipid bilayer of a liposome, attached to a liposome via a linking molecule that is associated with both the liposome and the oligonucleotide, entrapped in a liposome, complexed with a liposome, dispersed in a solution containing a lipid, mixed with a lipid, combined with a lipid, contained as a suspension in a lipid, contained or complexed with a micelle, or otherwise associated with a lipid. Lipid, lipid/DNA or lipid/expression vector associated compositions are not limited to any particular structure in solution. For example, they may be present in a bilayer structure, as micelles, or with a “collapsed” structure. They may also simply be interspersed in a solution, possibly forming aggregates that are not uniform in size or shape. Lipids are fatty substances which may be naturally occurring or synthetic lipids. For example, lipids include the fatty droplets that naturally occur in the cytoplasm as well as the class of compounds which contain long-chain aliphatic hydrocarbons and their derivatives, such as fatty acids, alcohols, amines, amino alcohols, and aldehydes. 
     Regardless of the method used to introduce exogenous nucleic acids into a host cell or otherwise expose a cell to the inhibitor of the present technology, in order to confirm the presence of the recombinant DNA sequence in the host cell, a variety of assays may be performed. Such assays include, for example, “molecular biological” assays well known to those of skill in the art, such as Southern and Northern blotting, RT-PCR and PCR; “biochemical” assays, such as detecting the presence or absence of a particular peptide, e.g., by immunological means (ELISAs and Western blots) or by assays described herein to identify agents falling within the scope of the present technology. 
     Preparation of Anti-MUC16 Antibody Agents and Anti-MUC16 Antibody Moieties 
     In some embodiments, the anti-MUC16 antibody agent is a monoclonal antibody or derived from a monoclonal antibody. In some embodiments, the anti-MUC16 antibody agent comprises V H  and V L  domains, or variants thereof, from the monoclonal antibody. In some embodiments, the anti-MUC16 antibody agent further comprises C H 1 and C L  domains, or variants thereof, from the monoclonal antibody. Monoclonal antibodies can be prepared, e.g., using known methods in the art, including hybridoma methods, phage display methods, or using recombinant DNA methods. Additionally, exemplary phage display methods are described herein and in the Examples below. 
     In a hybridoma method, a hamster, mouse, or other appropriate host animal is typically immunized with an immunizing agent to elicit lymphocytes that produce or are capable of producing antibodies that will specifically bind to the immunizing agent. Alternatively, the lymphocytes can be immunized in vitro. The immunizing agent can include a polypeptide or a fusion protein of the protein of interest. Generally, peripheral blood lymphocytes (“PBLs”) are used if cells of human origin are desired, or spleen cells or lymph node cells are used if non-human mammalian sources are desired. The lymphocytes are then fused with an immortalized cell line using a suitable fusing agent, such as polyethylene glycol, to form a hybridoma cell. Immortalized cell lines are usually transformed mammalian cells, particularly myeloma cells of rodent, bovine, and human origin. Usually, rat or mouse myeloma cell lines are employed. The hybridoma cells can be cultured in a suitable culture medium that preferably contains one or more substances that inhibit the growth or survival of the unfused, immortalized cells. For example, if the parental cells lack the enzyme hypoxanthine guanine phosphoribosyl transferase (HGPRT or HPRT), the culture medium for the hybridomas typically will include hypoxanthine, aminopterin, and thymidine (“HAT medium”), which prevents the growth of HGPRT-deficient cells. 
     In some embodiments, the immortalized cell lines fuse efficiently, support stable high-level expression of antibody by the selected antibody-producing cells, and are sensitive to a medium such as HAT medium. In some embodiments, the immortalized cell lines are murine myeloma lines, which can be obtained, for instance, from the Salk Institute Cell Distribution Center, San Diego, Calif. and the American Type Culture Collection, Manassas, Va. Human myeloma and mouse-human heteromyeloma cell lines also have been described for the production of human monoclonal antibodies. 
     The culture medium in which the hybridoma cells are cultured can then be assayed for the presence of monoclonal antibodies directed against the polypeptide. The binding specificity of monoclonal antibodies produced by the hybridoma cells can be determined by immunoprecipitation or by an in vitro binding assay, such as radioimmunoassay (MA) or enzyme-linked immunosorbent assay (ELISA). Such techniques and assays are known in the art. The binding affinity of the monoclonal antibody can, for example, be determined by the Scatchard analysis of Munson and Pollard,  Anal. Biochem.,  107:220 (1980). 
     After the desired hybridoma cells are identified, the clones can be sub cloned by limiting dilution procedures and grown by standard methods. Goding, supra. Suitable culture media for this purpose include, for example, Dulbecco&#39;s Modified Eagle&#39;s Medium and RPMI-1640 medium. Alternatively, the hybridoma cells can be grown in vivo as ascites in a mammal. 
     The monoclonal antibodies secreted by the sub clones can be isolated or purified from the culture medium or ascites fluid by conventional immunoglobulin purification procedures such as, for example, protein A-Sepharose, hydroxylapatite chromatography, gel electrophoresis, dialysis, or affinity chromatography. 
     In some embodiments, according to any of the anti-MUC16 antibody agents described herein, the anti-MUC16 antibody agent comprises sequences from a clone selected from an antibody library (such as a phage library presenting scFv or Fab fragments). The clone may be identified by screening combinatorial libraries for antibody fragments with the desired activity or activities. For example, a variety of methods are known in the art for generating phage display libraries and screening such libraries for antibodies possessing the desired binding characteristics. Such methods are reviewed, e.g., in Hoogenboom et al.,  Methods in Molecular Biology  178:1-37 (O&#39;Brien et al., ed., Human Press, Totowa, N.J., 2001) and further described, e.g., in McCafferty et al.,  Nature  348:552-554; Clackson et al.,  Nature  352: 624-628 (1991); Marks et al.,  J. Mol. Biol.  222: 581-597 (1992); Marks and Bradbury,  Methods in Molecular Biology  248:161-175 (Lo, ed., Human Press, Totowa, N.J., 2003); Sidhu et al.,  J. Mol. Biol.  338(2): 299-310 (2004); Lee et al.,  J. Mol. Biol.  340(5): 1073-1093 (2004); Fellouse,  Proc. Natl. Acad. Sci. USA  101(34): 12467-12472 (2004); and Lee et al.,  J Immunol. Methods  284(1-2): 119-132(2004). 
     In certain phage display methods, repertoires of V H  and V L  genes are separately cloned by polymerase chain reaction (PCR) and recombined randomly in phage libraries, which can then be screened for antigen-binding phage as described in Winter et al.,  Ann. Rev. Immunol.,  12: 433-455 (1994). Phage typically display antibody fragments, either as scFv fragments or as Fab fragments. Libraries from immunized sources provide high-affinity antibodies to the immunogen without the requirement of constructing hybridomas. Alternatively, the naive repertoire can be cloned (e.g., from human) to provide a single source of antibodies to a wide range of non-self and also self-antigens without any immunization as described by Griffiths et al.,  EMBO J,  12: 725-734 (1993). Finally, naive libraries can also be made synthetically by cloning unrearranged V-gene segments from stem cells, and using PCR primers containing random sequence to encode the highly variable CDR3 regions and to accomplish rearrangement in vitro, as described by Hoogenboom and Winter,  J. Mol. Biol.,  227: 381-388 (1992). Patent publications describing human antibody phage libraries include, for example: U.S. Pat. No. 5,750,373, and US Patent Publication Nos. 2005/0079574, 2005/0119455, 2005/0266000, 2007/0117126, 2007/0160598, 2007/0237764, 2007/0292936, and 2009/0002360. 
     The anti-MUC16 antibody agents can be prepared using phage display to screen libraries for anti-MUC16 antibody moieties specific to the target MUC16 (e.g., nMUC16). The library can be a human scFv phage display library having a diversity of at least one ×10 9  (such as at least about any of 1×10 9 , 2.5×10 9 , 5×10 9 , 7.5×10 9 , 1×10 10 , 2.5×10 10 , 5×10 10 , 7.5×10 10 , or 1×10 11 ) unique human antibody fragments. In some embodiments, the library is a naïve human library constructed from DNA extracted from human PMBCs and spleens from healthy donors, encompassing all human heavy and light chain subfamilies. In some embodiments, the library is a naïve human library constructed from DNA extracted from PBMCs isolated from patients with various diseases, such as patients with autoimmune diseases, cancer patients, and patients with infectious diseases. In some embodiments, the library is a semi-synthetic human library, wherein heavy chain CDR3 is completely randomized, with all amino acids (with the exception of cysteine) equally likely to be present at any given position (see, e.g., Hoet, R. M. et al.,  Nat. Biotechnol.  23(3):344-348, 2005). In some embodiments, the heavy chain CDR3 of the semi-synthetic human library has a length from about 5 to about 24 (such as about any of 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24) amino acids. In some embodiments, the library is a fully-synthetic phage display library. In some embodiments, the library is a non-human phage display library. 
     Phage clones that bind to the target MUC16 (e.g., nMUC16) with high affinity can be selected by iterative binding of phage to the target MUC16, which is bound to a solid support (such as, for example, beads for solution panning or mammalian cells for cell panning), followed by removal of non-bound phage and by elution of specifically bound phage. The bound phage clones are then eluted and used to infect an appropriate host cell, such as  E. coli  XL1-Blue, for expression and purification. In an example of cell panning, HEK293 cells overexpressing MUC16 on cell surface are mixed with the phage library, after which the cells are collected and the bound clones are eluted and used to infect an appropriate host cell for expression and purification (all see Examples). The panning can be performed for multiple (such as about any of 2, 3, 4, 5, 6 or more) rounds with solution panning, cell panning, or a combination of both, to enrich for phage clones binding specifically to the target MUC16. Enriched phage clones can be tested for specific binding to the target MUC16 by any methods known in the art, including for example ELISA and FACS. 
     Monoclonal antibodies can also be made by recombinant DNA methods, such as those described in U.S. Pat. No. 4,816,567. DNA encoding the monoclonal antibodies of the present technology can be readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that are capable of binding specifically to genes encoding the heavy and light chains of murine antibodies). Hybridoma cells as described above or MUC16-specific phage clones of the present technology can serve as a source of such DNA. Once isolated, the DNA can be placed into expression vectors, which are then transfected into host cells such as simian COS cells, Chinese hamster ovary (CHO) cells, or myeloma cells that do not otherwise produce immunoglobulin protein, to obtain the synthesis of monoclonal antibodies in the recombinant host cells. The DNA also can be modified, for example, by substituting the coding sequence for human heavy- and light-chain constant domains and/or framework regions in place of the homologous non-human sequences (U.S. Pat. No. 4,816,567; Morrison et al., supra) or by covalently joining to the immunoglobulin coding sequence all or part of the coding sequence for a non-immunoglobulin polypeptide. Such a non-immunoglobulin polypeptide can be substituted for the constant domains of an antibody agent of the present technology, or can be substituted for the variable domains of one antigen-combining site of an antibody agent of the present technology to create a chimeric bivalent antibody agent. 
     The antibodies can be monovalent antibodies. Methods for preparing monovalent antibodies are known in the art. For example, one method involves recombinant expression of immunoglobulin light chain and modified heavy chain. The heavy chain is truncated generally at any point in the Fc region so as to prevent heavy-chain crosslinking. Alternatively, the relevant cysteine residues are substituted with another amino acid residue or are deleted so as to prevent crosslinking. 
     In vitro methods are also suitable for preparing monovalent antibodies. Digestion of antibodies to produce fragments thereof, particularly Fab fragments, can be accomplished using any method known in the art. 
     Antibody variable domains with the desired binding specificities (antibody-antigen combining sites) can be fused to immunoglobulin constant-domain sequences. The fusion preferably is with an immunoglobulin heavy-chain constant domain, comprising at least part of the hinge, CH2, and CH3 regions. In some embodiments, the first heavy-chain constant region (CH1) containing the site necessary for light-chain binding is present in at least one of the fusions. DNAs encoding the immunoglobulin heavy-chain fusions and, if desired, the immunoglobulin light chain, are inserted into separate expression vectors, and are co-transfected into a suitable host organism. 
     Human and Humanized Antibodies 
     The anti-MUC16 antibody agents (e.g., full-length anti-MUC 16 antibodies) or an antigen-binding fragment thereof can be humanized antibody agents or human antibody agents. Humanized forms of non-human (e.g., murine) antibody moieties are chimeric immunoglobulins, immunoglobulin chains, or fragments thereof (such as Fv, Fab, Fab′, F(ab′)2, scFv, or other antigen-binding subsequences of antibodies) that typically contain minimal sequence derived from non-human immunoglobulin. Humanized antibody moieties include human immunoglobulins, immunoglobulin chains, or fragments thereof (recipient antibody) in which residues from a CDR of the recipient are replaced by residues from a CDR of a non-human species (donor antibody) such as mouse, rat, or rabbit having the desired specificity, affinity, and capacity. In some instances, Fv framework residues of the human immunoglobulin are replaced by corresponding non-human residues. Humanized antibody moieties can also comprise residues that are found neither in the recipient antibody nor in the imported CDR or framework sequences. In general, the humanized antibody can comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin, and all or substantially all of the FR regions are those of a human immunoglobulin consensus sequence. 
     Generally, a humanized antibody agent has one or more amino acid residues introduced into it from a source that is non-human. These non-human amino acid residues are often referred to as “import” residues, which are typically taken from an “import” variable domain. According to some embodiments, humanization can be essentially performed following the method of Winter and co-workers (Jones et al.,  Nature,  321: 522-525 (1986); Riechmann et al.,  Nature,  332: 323-327 (1988); Verhoeyen et al.,  Science,  239: 1534-1536 (1988)), by substituting rodent CDRs or CDR sequences for the corresponding sequences of a human antibody. Accordingly, such “humanized” antibody moieties are antibody moieties (U.S. Pat. No. 4,816,567), wherein substantially less than an intact human variable domain has been substituted by the corresponding sequence from a non-human species. In practice, humanized antibody moieties are typically human antibody moieties in which some CDR residues and possibly some FR residues are substituted by residues from analogous sites in rodent antibodies. 
     As an alternative to humanization, human antibody moieties can be generated. For example, it is now possible to produce transgenic animals (e.g., mice) that are capable, upon immunization, of producing a full repertoire of human antibodies in the absence of endogenous immunoglobulin production. For example, it has been described that the homozygous deletion of the antibody heavy-chain joining region (JH) gene in chimeric and germ-line mutant mice results in complete inhibition of endogenous antibody production. Transfer of the human germ-line immunoglobulin gene array into such germ-line mutant mice will result in the production of human antibodies upon antigen challenge. See, e.g., Jakobovits et al.,  PNAS USA,  90:2551 (1993); Jakobovits et al.,  Nature,  362:255-258 (1993); Bruggemann et al.,  Year in Immunol.,  7:33 (1993); U.S. Pat. Nos. 5,545,806, 5,569,825, 5,591,669; 5,545,807; and WO 97/17852. Alternatively, human antibodies can be made by introducing human immunoglobulin loci into transgenic animals, e.g., mice in which the endogenous immunoglobulin genes have been partially or completely inactivated. Upon challenge, human antibody production is observed that closely resembles that seen in humans in all respects, including gene rearrangement, assembly, and antibody repertoire. This approach is described, for example, in U.S. Pat. Nos. 5,545,807; 5,545,806; 5,569,825; 5,625,126; 5,633,425; and 5,661,016, and Marks et al.,  Bio/Technology,  10: 779-783 (1992); Lonberg et al.,  Nature,  368: 856-859 (1994); Morrison,  Nature,  368: 812-813 (1994); Fishwild et al.,  Nature Biotechnology,  14: 845-851 (1996); Neuberger,  Nature Biotechnology,  14: 826 (1996); Lonberg and Huszar,  Intern. Rev. Immunol.,  13: 65-93 (1995). 
     Human antibody agents may also be generated by in vitro activated B cells (see U.S. Pat. Nos. 5,567,610 and 5,229,275) or by using various techniques known in the art, including phage display libraries. Hoogenboom and Winter,  J. Mol. Biol.,  227:381 (1991); Marks et al.,  J. Mol. Biol.,  222:581 (1991). The techniques of Cole et al. and Boerner et al. are also available for the preparation of human monoclonal antibodies. Cole et al.,  Monoclonal Antibodies and Cancer Therapy , Alan R. Liss, p. 77 (1985) and Boerner et al.,  J. Immunol.,  147(1): 86-95 (1991). 
     Anti-MUC16 Antibody Agent Variants 
     In some embodiments, amino acid sequence variants of the anti-MUC16 antibody agents (e.g., full-length anti-MUC16 antibody) or an antigen-binding fragment thereof provided herein are contemplated. For example, it may be desirable to improve the binding affinity and/or other biological properties of the antibody agent. Amino acid sequence variants of an antibody agent may be prepared by introducing appropriate modifications into the nucleotide sequence encoding the antibody agent, or by peptide synthesis. Such modifications include, for example, deletions from, and/or insertions into and/or substitutions of residues within the amino acid sequences of the antibody agent. Any combination of deletion, insertion, and substitution can be made to arrive at the final construct, provided that the final construct possesses the desired characteristics, e.g., antigen-binding. 
     In some embodiments, anti-MUC16 antibody agent variants having one or more amino acid substitutions are provided. Sites of interest for substitutional mutagenesis include the HVRs and FRs. Amino acid substitutions may be introduced into an antibody agent of interest and the products screened for a desired activity, e.g., retained/improved antigen binding, decreased immunogenicity, or improved ADCC or CDC. 
     Conservative substitutions are shown in Table 3 below. 
     
       
         
           
               
             
               
                 TABLE 3 
               
             
            
               
                   
               
               
                 CONSERVATIVE SUBSTITITIONS 
               
            
           
           
               
               
               
               
            
               
                   
                 Original 
                 Exemplary 
                 Preferred 
               
               
                   
                 Residue 
                 Substitutions 
                 Substitutions 
               
               
                   
                   
               
               
                   
                 Ala (A) 
                 Val; Leu; Ile 
                 Val 
               
               
                   
                 Arg (R) 
                 Lys; Gln; Asn 
                 Lys 
               
               
                   
                 Asn (N) 
                 Gln; His; Asp, Lys; Arg 
                 Gln 
               
               
                   
                 Asp (D) 
                 Glu; Asn 
                 Glu 
               
               
                   
                 Cys (C) 
                 Ser; Ala 
                 Ser 
               
               
                   
                 Gln (Q) 
                 Asn; Glu 
                 Asn 
               
               
                   
                 Glu (E) 
                 Asp; Gln 
                 Asp 
               
               
                   
                 Gly (G) 
                 Ala 
                 Ala 
               
               
                   
                 His (H) 
                 Asn; Gln; Lys; Arg 
                 Arg 
               
               
                   
                 Ile (I) 
                 Leu; Val; Met; Ala; Phe; Norleucine 
                 Leu 
               
               
                   
                 Leu (L) 
                 Norleucine; Ile; Val; Met; Ala; Phe 
                 Ile 
               
               
                   
                 Lys (K) 
                 Arg; Gln; Asn 
                 Arg 
               
               
                   
                 Met (M) 
                 Leu; Phe; Ile 
                 Leu 
               
               
                   
                 Phe (F) 
                 Trp; Leu; Val; Ile; Ala; Tyr 
                 Tyr 
               
               
                   
                 Pro (P) 
                 Ala 
                 Ala 
               
               
                   
                 Ser (S) 
                 Thr 
                 Thr 
               
               
                   
                 Thr (T) 
                 Val; Ser 
                 Ser 
               
               
                   
                 Trp (W) 
                 Tyr; Phe 
                 Tyr 
               
               
                   
                 Tyr (Y) 
                 Trp; Phe; Thr; Ser 
                 Phe 
               
               
                   
                 Val (V) 
                 Ile; Leu; Met; Phe; Ala; Norleucine 
                 Leu 
               
               
                   
                   
               
            
           
         
       
     
     Amino acids may be grouped into different classes according to common side-chain properties: hydrophobic: Norleucine, Met, Ala, Val, Leu, Ile; neutral hydrophilic: Cys, Ser, Thr, Asn, Gln; acidic: Asp, Glu; basic: His, Lys, Arg; residues that influence chain orientation: Gly, Pro; and aromatic: Trp, Tyr, Phe. Non-conservative substitutions involve exchanging a member of one of these classes for another class. 
     An exemplary substitutional variant is an affinity matured antibody agent, which may be conveniently generated, e.g., using phage display-based affinity maturation techniques. Briefly, one or more CDR residues are mutated and the variant antibody moieties displayed on phage and screened for a particular biological activity (e.g., binding affinity). Alterations (e.g., substitutions) may be made in HVRs, e.g., to improve antibody affinity. Such alterations may be made in HVR “hotspots,” i.e., residues encoded by codons that undergo mutation at high frequency during the somatic maturation process (see, e.g., Chowdhury,  Methods Mol. Biol.  207:179-196 (2008)), and/or specificity determining residues (SDRs), with the resulting variant V H  or V L  being tested for binding affinity. Affinity maturation by constructing and reselecting from secondary libraries has been described, e.g., in Hoogenboom et al., in  Methods in Molecular Biology  178:1-37 (O&#39;Brien et al., ed., Human Press, Totowa, N.J., (2001).) 
     In some embodiments of affinity maturation, diversity is introduced into the variable genes chosen for maturation by any of a variety of methods (e.g., error-prone PCR, chain shuffling, or oligonucleotide-directed mutagenesis). A secondary library is then created. The library is then screened to identify any antibody agent variants with the desired affinity. Another method to introduce diversity involves HVR-directed approaches, in which several HVR residues (e.g., 4-6 residues at a time) are randomized. HVR residues involved in antigen binding may be specifically identified, e.g., using alanine scanning mutagenesis or modeling. CDR-H3 and CDR-L3 in particular are often targeted. 
     In some embodiments, substitutions, insertions, or deletions may occur within one or more HVRs so long as such alterations do not substantially reduce the ability of the antibody agent to bind antigen. For example, conservative alterations (e.g., conservative substitutions as provided herein) that do not substantially reduce binding affinity may be made in HVRs. Such alterations may be outside of HVR “hotspots” or SDRs. In some embodiments of the variant V H  and V L  sequences provided above, each HVR either is unaltered, or contains no more than one, two or three amino acid substitutions. 
     A useful method for identification of residues or regions of an antibody agent that may be targeted for mutagenesis is called “alanine scanning mutagenesis” as described by Cunningham and Wells (1989)  Science,  244:1081-1085. In this method, a residue or group of target residues (e.g., charged residues such as Arg, Asp, His, Lys, and Glu) are identified and replaced by a neutral or negatively charged amino acid (e.g., alanine or polyalanine) to determine whether the interaction of the antibody agent with antigen is affected. Further substitutions may be introduced at the amino acid locations demonstrating functional sensitivity to the initial substitutions. Alternatively, or additionally, a crystal structure of an antigen-antibody agent complex can be determined to identify contact points between the antibody agent and antigen. Such contact residues and neighboring residues may be targeted or eliminated as candidates for substitution. Variants may be screened to determine whether they contain the desired properties. 
     Amino acid sequence insertions include amino- and/or carboxyl-terminal fusions ranging in length from one residue to polypeptides containing a hundred or more residues, as well as intrasequence insertions of single or multiple amino acid residues. Examples of terminal insertions include an antibody agent with an N-terminal methionyl residue. Other insertional variants of the antibody agent molecule include the fusion to the N- or C-terminus of the antibody agent to an enzyme (e.g. for ADEPT) or a polypeptide which increases the serum half-life of the antibody agent. 
     Fc Region Variants 
     In some embodiments, one or more amino acid modifications may be introduced into the Fc region of an antibody agent (e.g., a full-length anti-MUC16 antibody or anti-MUC16 Fc fusion protein) provided herein, thereby generating an Fc region variant. In some embodiments, the Fc region variant has enhanced ADCC effector function, often related to binding to Fc receptors (FcRs). In some embodiments, the Fc region variant has decreased ADCC effector function. There are many examples of changes or mutations to Fc sequences that can alter effector function. For example, WO 00/42072 and Shields et al.,  J Biol. Chem.  9(2): 6591-6604 (2001) describe antibody variants with improved or diminished binding to FcRs. The contents of those publications are specifically incorporated herein by reference. 
     Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) is a mechanism of action of therapeutic antibodies against tumor cells. ADCC is a cell-mediated immune defense whereby an effector cell of the immune system actively lyses a target cell (e.g., a cancer cell), whose membrane-surface antigens have been bound by specific antibodies (e.g., an anti-MUC16 antibody). The typical ADCC involves activation of NK cells by antibodies. An NK cell expresses CD16 which is an Fc receptor. This receptor recognizes, and binds to, the Fc portion of an antibody bound to the surface of a target cell. The most common Fc receptor on the surface of an NK cell is called CD16 or FcγRIII. Binding of the Fc receptor to the Fc region of an antibody results in NK cell activation, release of cytolytic granules and consequent target cell apoptosis. The contribution of ADCC to tumor cell killing can be measured with a specific test that uses NK-92 cells that have been transfected with a high-affinity FcR. Results are compared to wild-type NK-92 cells that do not express the FcR. 
     In some embodiments, the present technology contemplates an anti-MUC16 antibody agent variant (such as a full-length anti-MUC16 antibody variant) comprising an Fc region that possesses some but not all effector functions, which makes it a desirable candidate for applications in which the half-life of the anti-MUC16 antibody agent in vivo is important yet certain effector functions (such as CDC and ADCC) are unnecessary or deleterious. In vitro and/or in vivo cytotoxicity assays can be conducted to confirm the reduction/depletion of CDC and/or ADCC activities. For example, Fc receptor (FcR) binding assays can be conducted to ensure that the antibody agent lacks FcγR binding (hence likely lacking ADCC activity), but retains FcRn binding ability. The primary cells for mediating ADCC, NK cells, express FcγRIII only, whereas monocytes express FcγRI, FcγRII and FcγRIII FcR expression on hematopoietic cells is summarized in Table 3 on page 464 of Ravetch and Kinet,  Annu. Rev. Immunol.  9:457-492 (1991). Non-limiting examples of in vitro assays to assess ADCC activity of a molecule of interest is described in U.S. Pat. No. 5,500,362 (see, e.g. Hellstrom, I. et al.,  Proc. Nat&#39;l Acad. Sci. USA  83:7059-7063 (1986)) and Hellstrom, I et al.,  Proc. Nat&#39;l Acad. Sci. USA  82:1499-1502 (1985); U.S. Pat. No. 5,821,337 (see Bruggemann, M. et al.,  J. Exp. Med.  166:1351-1361 (1987)). Alternatively, non-radioactive assay methods may be employed (see, for example, ACTI™ non-radioactive cytotoxicity assay for flow cytometry (CellTechnology, Inc. Mountain View, Calif.; and CytoTox 96™ non-radioactive cytotoxicity assay (Promega, Madison, Wis.). Useful effector cells for such assays include peripheral blood mononuclear cells (PBMC) and Natural Killer (NK) cells. Alternatively, or additionally, ADCC activity of the molecule of interest may be assessed in vivo, e.g., in an animal model such as that disclosed in Clynes et al.,  Proc. Nat&#39;l Acad. Sci. USA  95:652-656 (1998). C1q binding assays may also be carried out to confirm that the antibody agent is unable to bind C1q and hence lacks CDC activity. See, e.g., C1q and C3c binding ELISA in WO 2006/029879 and WO 2005/100402. To assess complement activation, a CDC assay may be performed (see, for example, Gazzano-Santoro et al.,  J. Immunol. Methods  202:163 (1996); Cragg, M. S. et al.,  Blood  101:1045-1052 (2003); and Cragg, M. S. and M. J. Glennie, Blood 103:2738-2743 (2004)). FcRn binding and in vivo clearance/half-life determinations can also be performed using methods known in the art (see, e.g., Petkova, S. B. et al.,  Int&#39;l. Immunol.  18(12):1759-1769 (2006)). 
     Antibodies with reduced effector function include those with substitution of one or more of Fc region residues 238, 265, 269, 270, 297, 327 and 329 (U.S. Pat. No. 6,737,056). Such Fc mutants include Fc mutants with substitutions at two or more of amino acid positions 265, 269, 270, 297 and 327, including the so-called “DANA” Fc mutant with substitution of residues 265 and 297 to alanine (U.S. Pat. No. 7,332,581). 
     Certain antibody agent variants with improved or diminished binding to FcRs are described. (See, e.g., U.S. Pat. No. 6,737,056; WO 2004/056312, and Shields et al.,  J. Biol. Chem.  9(2): 6591-6604 (2001).) 
     In some embodiments, there is provided an anti-MUC16 antibody agent (such as a full-length anti-MUC16 antibody) variant comprising a variant Fc region comprising one or more amino acid substitutions which improve ADCC. In some embodiments, the variant Fc region comprises one or more amino acid substitutions which improve ADCC, wherein the substitutions are at positions 298, 333, and/or 334 of the variant Fc region (EU numbering of residues). In some embodiments, the anti-MUC16 antibody agent (e.g., full-length anti-MUC16 antibody) variant comprises the following amino acid substitution in its variant Fc region: S298A, E333A, and K334A. 
     In some embodiments, alterations are made in the Fc region that result in altered (i.e., either improved or diminished) C1q binding and/or Complement Dependent Cytotoxicity (CDC), e.g., as described in U.S. Pat. No. 6,194,551, WO 99/51642, and Idusogie et al.,  J. Immunol.  164: 4178-4184 (2000). 
     In some embodiments, there is provided an anti-MUC16 antibody agent (such as a full-length anti-MUC16 antibody) variant comprising a variant Fc region comprising one or more amino acid substitutions which increase half-life and/or improve binding to the neonatal Fc receptor (FcRn). Antibodies with increased half-lives and improved binding to FcRn are described in US2005/0014934A1 (Hinton et al.). Those antibodies comprise an Fc region with one or more substitutions therein which improve binding of the Fc region to FcRn. Such Fc variants include those with substitutions at one or more of Fc region residues: 238, 256, 265, 272, 286, 303, 305, 307, 311, 312, 317, 340, 356, 360, 362, 376, 378, 380, 382, 413, 424 or 434, e.g., substitution of Fc region residue 434 (U.S. Pat. No. 7,371,826). 
     See also Duncan &amp; Winter,  Nature  322:738-40 (1988); U.S. Pat. Nos. 5,648,260; 5,624,821; and WO 94/29351 concerning other examples of Fc region variants. 
     Anti-MUC16 antibody agents (such as full-length anti-MUC16 antibodies) comprising any of the Fc variants described herein, or combinations thereof, are contemplated. 
     Glycosylation Variants 
     In some embodiments, an anti-MUC16 antibody agent (such as a full-length anti-MUC16 antibody) or an antigen-binding fragment thereof provided herein is altered to increase or decrease the extent to which the anti-MUC16 antibody agent is glycosylated. Addition or deletion of glycosylation sites to an anti-MUC16 antibody agent may be conveniently accomplished by altering the amino acid sequence of the anti-MUC16 antibody agent or polypeptide portion thereof such that one or more glycosylation sites is created or removed. 
     Where the anti-MUC16 antibody agent or an antigen-binding fragment thereof comprises an Fc region, the carbohydrate attached thereto may be altered. Native antibodies produced by mammalian cells typically comprise a branched, biantennary oligosaccharide that is generally attached by an N-linkage to Asn297 of the CH2 domain of the Fc region. See, e.g., Wright et al.,  TIBTECH  15:26-32 (1997). The oligosaccharide may include various carbohydrates, e.g., mannose, N-acetyl glucosamine (GlcNAc), galactose, and sialic acid, as well as a fucose attached to a GlcNAc in the “stem” of the biantennary oligosaccharide structure. In some embodiments, modifications of the oligosaccharide in an anti-MUC16 antibody agent of the present technology may be made in order to create anti-MUC16 antibody agent variants with certain improved properties. 
     The N-glycans attached to the CH2 domain of Fc is heterogeneous. Antibodies or Fc fusion proteins generated in CHO cells are fucosylated by fucosyltransferase activity. See Shoji-Hosaka et al.,  J. Biochem.  140:777-83 (2006). Normally, a small percentage of naturally occurring afucosylated IgGs may be detected in human serum. N-glycosylation of the Fc is important for binding to FcγR; and afucosylation of the N-glycan increases Fc&#39;s binding capacity to FcγRIIIa. Increased FcγRIIIa binding can enhance ADCC, which can be advantageous in certain antibody agent therapeutic applications in which cytotoxicity is desirable. 
     In some embodiments, an enhanced effector function can be detrimental when Fc-mediated cytotoxicity is undesirable. In some embodiments, the Fc fragment or CH2 domain is not glycosylated. In some embodiments, the N-glycosylation site in the CH2 domain is mutated to prevent from glycosylation. 
     In some embodiments, anti-MUC16 antibody agent (such as a full-length anti-MUC16 antibody) variants are provided comprising an Fc region wherein a carbohydrate structure attached to the Fc region has reduced fucose or lacks fucose, which may improve ADCC function. Specifically, anti-MUC16 antibody agents are contemplated herein that have reduced fucose relative to the amount of fucose on the same anti-MUC16 antibody agent produced in a wild-type CHO cell. That is, they are characterized by having a lower amount of fucose than they would otherwise have if produced by native CHO cells (e.g., a CHO cell that produce a native glycosylation pattern, such as, a CHO cell containing a native FUT8 gene). In some embodiments, the anti-MUC16 antibody agent is one wherein less than about 50%, 40%, 30%, 20%, 10%, or 5% of the N-linked glycans thereon comprise fucose. For example, the amount of fucose in such an anti-MUC16 antibody agent may be from 1% to 80%, from 1% to 65%, from 5% to 65% or from 20% to 40%. In some embodiments, the anti-MUC16 antibody agent is one wherein none of the N-linked glycans thereon comprise fucose, i.e., wherein the anti-MUC16 antibody agent is completely without fucose, or has no fucose or is afucosylated. The amount of fucose is determined by calculating the average amount of fucose within the sugar chain at Asn297, relative to the sum of all glycostructures attached to Asn 297 (e.g., complex, hybrid and high mannose structures) as measured by MALDI-TOF mass spectrometry, as described in WO 2008/077546, for example. Asn297 refers to the asparagine residue located at about position 297 in the Fc region (EU numbering of Fc region residues); however, Asn297 may also be located about ±3 amino acids upstream or downstream of position 297, i.e., between positions 294 and 300, due to minor sequence variations in antibodies. Such fucosylation variants may have improved ADCC function. See, e.g., US Patent Publication Nos. US 2003/0157108 (Presta, L.); US 2004/0093621 (Kyowa Hakko Kogyo Co., Ltd). Examples of publications related to “defucosylated” or “fucose-deficient” antibody agent variants include: US 2003/0157108; WO 2000/61739; WO 2001/29246; US 2003/0115614; US 2002/0164328; US 2004/0093621; US 2004/0132140; US 2004/0110704; US 2004/0110282; US 2004/0109865; WO 2003/085119; WO 2003/084570; WO 2005/035586; WO 2005/035778; WO2005/053742; WO2002/031140; Okazaki et al.,  J. Mol. Biol.  336:1239-1249 (2004); Yamane-Ohnuki et al.,  Biotech. Bioeng.  87: 614 (2004). Examples of cell lines capable of producing defucosylated antibodies include Lec13 CHO cells deficient in protein fucosylation (Ripka et al.,  Arch. Biochem. Biophys.  249:533-545 (1986); US Pat Appl No US 2003/0157108 A1, Presta, L; and WO 2004/056312 A1, Adams et al., especially at Example 11), and knockout cell lines, such asα-1,6-fucosyltransferase gene, FUT8, knockout CHO cells (see, e.g., Yamane-Ohnuki et al.,  Biotech. Bioeng.  87: 614 (2004); Kanda, Y. et al.,  Biotechnol. Bioeng.,  94(4):680-688 (2006); and WO2003/085107). 
     Anti-MUC16 antibody agent (such as a full-length anti-MUC16 antibody) variants are further provided with bisected oligosaccharides, e.g., in which a biantennary oligosaccharide attached to the Fc region of the anti-MUC16 antibody agent is bisected by GlcNAc. Such anti-MUC16 antibody agent (such as a full-length anti-MUC16 antibody) variants may have reduced fucosylation and/or improved ADCC function. Examples of such antibody agent variants are described, e.g., in WO 2003/011878 (Jean-Mairet et al.); U.S. Pat. No. 6,602,684 (Umana et al.); US 2005/0123546 (Umana et al.), and Ferrara et al.,  Biotechnology and Bioengineering,  93(5): 851-861 (2006). Anti-MUC16 antibody agent (such as full-length anti-MUC16 antibody) variants with at least one galactose residue in the oligosaccharide attached to the Fc region are also provided. Such anti-MUC16 antibody agent variants may have improved CDC function. Such antibody agent variants are described, e.g., in WO 1997/30087 (Patel et al.); WO 1998/58964 (Raju, S.); and WO 1999/22764 (Raju, S.). 
     In some embodiments, the anti-MUC16 antibody agent (such as a full-length anti-MUC16 antibody) variants comprising an Fc region are capable of binding to an FcγRIII. In some embodiments, the anti-MUC16 antibody agent (such as a full-length anti-MUC16 antibody) variants comprising an Fc region have ADCC activity in the presence of human effector cells (e.g., T cell) or have increased ADCC activity in the presence of human effector cells compared to the otherwise same anti-MUC16 antibody agent (such as a full-length anti-MUC16 antibody) comprising a human wild-type IgG1Fc region. 
     Cysteine Engineered Variants 
     In some embodiments, it may be desirable to create cysteine engineered anti-MUC16 antibody agents (such as a full-length anti-MUC16 antibody) or an antigen-binding fragment thereof in which one or more amino acid residues are substituted with cysteine residues. In some embodiments, the substituted residues occur at accessible sites of the anti-MUC16 antibody agent or an antigen-binding fragment thereof. By substituting those residues with cysteine, reactive thiol groups are thereby positioned at accessible sites of the anti-MUC16 antibody agent and may be used to conjugate the anti-MUC16 antibody agent to other moieties, such as drug moieties or linker-drug moieties, to create an anti-MUC16 immunoconjugate, as described further herein. Cysteine engineered anti-MUC16 antibody agents (such as anti-MUC16 antibodies, e.g., full-length anti-MUC16 antibodies) may be generated as described, e.g., in U.S. Pat. No. 7,521,541. 
     Derivatives 
     In some embodiments, an anti-MUC16 antibody agent (such as a full-length anti-MUC16 antibody) or an antigen-binding fragment thereof provided herein may be further modified to contain additional non-proteinaceous moieties that are known in the art and readily available. The moieties suitable for derivatization of the anti-MUC16 antibody agent include but are not limited to water soluble polymers. Non-limiting examples of water soluble polymers include, but are not limited to, polyethylene glycol (PEG), copolymers of ethylene glycol/propylene glycol, carboxymethylcellulose, dextran, polyvinyl alcohol, polyvinyl pyrrolidone, poly-1,3-dioxolane, poly-1,3,6-trioxane, ethylene/maleic anhydride copolymer, polyaminoacids (either homopolymers or random copolymers), and dextran or poly(n-vinyl pyrrolidone)polyethylene glycol, propropylene glycol homopolymers, prolypropylene oxide/ethylene oxide co-polymers, polyoxyethylated polyols (e.g., glycerol), polyvinyl alcohol, and mixtures thereof. Polyethylene glycol propionaldehyde may have advantages in manufacturing due to its stability in water. The polymer may be of any molecular weight, and may be branched or unbranched. The number of polymers attached to the anti-MUC16 antibody agent may vary, and if more than one polymer are attached, they can be the same or different molecules. In general, the number and/or type of polymers used for derivatization can be determined based on considerations including, but not limited to, the particular properties or functions of the anti-MUC16 antibody agent to be improved, whether the anti-MUC16 antibody agent derivative will be used in a therapy under defined conditions, etc. 
     In some embodiments, conjugates of an anti-MUC16 antibody agent (such as a full-length anti-MUC16 antibody) or an antigen-binding fragment thereof and nonproteinaceous moiety that may be selectively heated by exposure to radiation are provided. In some embodiments, the nonproteinaceous moiety is a carbon nanotube (Kam et al.,  Proc. Natl. Acad. Sci. USA  102: 11600-11605 (2005)). The radiation may be of any wavelength, and includes, but is not limited to, wavelengths that do not harm ordinary cells, but which heat the nonproteinaceous moiety to a temperature at which cells proximal to the anti-MUC16 antibody agent-nonproteinaceous moiety are killed. 
     Antibody Conjugates 
     In certain embodiments, provided herein are anti-MUC16 antibody agent or antigen-binding fragments thereof conjugates, wherein said anti-MUC16 antibody agent or antigen-binding fragments thereof is conjugated to one or more agents, e.g., an imaging agent or a cytotoxic agent. Also provided herein are bispecific antibody conjugates, wherein said bispecific antibody is conjugated to one or more agent, e.g., an imaging agent or a cytotoxic agent. Also provided herein are antibody heavy chain conjugates, wherein said antibody heavy chain is conjugated to one or more agent, e.g., an imaging agent or a cytotoxic agent. Also provided herein are antibody light chain conjugates, wherein said antibody light chain is conjugated to one or more agent, e.g., an imaging agent or a cytotoxic agent. Also provided herein are fusion protein conjugates, wherein said fusion protein is conjugated to an agent, e.g., an imaging agent or a cytotoxic agent. In certain embodiments, the agent is conjugated covalently or non-covalently. 
     In certain embodiments, the imaging agent is a detectable label, such as, a chromogenic, enzymatic, radioisotopic, isotopic, fluorescent, toxic, chemiluminescent, nuclear magnetic resonance contrast agent or another label. 
     The detectable group can be any material having a detectable physical or chemical property. Such detectable labels have been well-developed in the field of immunoassays and imaging. In general, almost any label useful in such methods can be applied to the present technology. Thus, a label is any composition detectable by spectroscopic, photochemical, biochemical, immunochemical, electrical, optical or chemical means. Labels useful in the practice of the present technology include magnetic beads (e.g., Dynabeads™), fluorescent dyes (e.g., fluorescein isothiocyanate, Texas red, rhodamine, and the like), radiolabels (e.g.,  3 H,  14 C,  35 S,  125 I,  121 I,  131 I,  112 In,  99 mTc), other imaging agents such as microbubbles (for ultrasound imaging),  18 F,  11 C,  15 O,  89 Zr,  89 Zr-DFO (for Positron emission tomography),  99m TC,  111 In (for Single photon emission tomography), enzymes (e.g., horse radish peroxidase, alkaline phosphatase and others commonly used in an ELISA), and calorimetric labels such as colloidal gold or colored glass or plastic (e.g., polystyrene, polypropylene, latex, and the like) beads. Patents that describe the use of such labels include U.S. Pat. Nos. 3,817,837; 3,850,752; 3,939,350; 3,996,345; 4,277,437; 4,275,149; and 4,366,241, each incorporated herein by reference in their entirety and for all purposes. See also Handbook of Fluorescent Probes and Research Chemicals (6 th  Ed., Molecular Probes, Inc., Eugene Oreg.). 
     The label can be coupled directly or indirectly to the desired component of an assay according to methods well known in the art. As indicated above, a wide variety of labels can be used, with the choice of label depending on factors such as required sensitivity, ease of conjugation with the compound, stability requirements, available instrumentation, and disposal provisions. 
     Non-limiting examples of suitable chromogenic labels include diaminobenzidine and 4-hydroxyazo-benzene-2-carboxylic acid. 
     Non-limiting examples of suitable enzyme labels include malate dehydrogenase, staphylococcal nuclease, delta-5-steroid isomerase, yeast-alcohol dehydrogenase, alpha-glycerol phosphate dehydrogenase, triose phosphate isomerase, peroxidase, alkaline phosphatase, asparaginase, glucose oxidase, beta-galactosidase, ribonuclease, urease, catalase, glucose-6-phosphate dehydrogenase, glucoamylase, and acetylcholine esterase. 
     Suitable radioisotopes are well known to those skilled in the art and include beta-emitters, gamma-emitters, positron-emitters, and x-ray emitters. Non-limiting examples of suitable radioisotopic labels include  3 H,  18 F,  111 In,  125 I,  131 I,  32 P,  33 P,  35 S,  11 C,  14 C,  51 Cr,  57 To,  58 CO,  59 Fe,  75 Se,  152 Eu,  90 Y,  67 Cu,  217 Ci,  211 At,  212 Pb,  47 Sc,  223 Ra,  223 Ra,  89 Zr,  177 Lu, and  109 Pd. In certain embodiments,  111 In is a preferred isotope for in vivo imaging as it avoids the problem of dehalogenation of  125 In or  131 I-labeled anti-MUC16 antibody agents or antigen-binding fragments thereof in the liver. In addition,  111 In has a more favorable gamma emission energy for imaging (Perkins et al,  Eur. J. Nucl. Med.  70:296-301 (1985); Carasquillo et al.,  J. Nucl. Med.  25:281-287 (1987)). For example,  111 In coupled to monoclonal antibodies with 1-(P-isothiocyanatobenzyl)-DPTA has shown little uptake in non-tumorous tissues, particularly the liver, and therefore enhances specificity of tumor localization (Esteban et al.,  J. Nucl. Med.  28:861-870 (1987)). 
     Non-limiting examples of suitable non-radioactive isotopic labels include 157Gd,  55 Mn,  162 Dy,  52 Tr, and  56 Fe. 
     Non-limiting examples of suitable fluorescent labels include a  152 Eu label, a fluorescein label, an isothiocyanate label, a rhodamine label, a phycoerythrin label, a phycocyanin label, an allophycocyanin label, a Green Fluorescent Protein (GFP) label, an o-phthaldehyde label, and a fluorescamine label. 
     Non-limiting examples of chemiluminescent labels include a luminol label, an isoluminol label, an aromatic acridinium ester label, an imidazole label, an acridinium salt label, an oxalate ester label, a luciferin label, a luciferase label, and an aequorin label. 
     Non-limiting examples of nuclear magnetic resonance contrasting agents include heavy metal nuclei such as Gd, Mn, and iron. 
     Techniques known to one of ordinary skill in the art for conjugating the above-described labels to said anti-MUC16 antibody agents or antigen-binding fragments thereof, bispecific antibodies, antibody heavy chains, antibody light chains, and fusion proteins are described in, for example, Kennedy et at.,  Clin. CMm. Acta  70: 1-31 (1976), and Schurs et al,  Clin. CMm. Acta  81: 1-40 (1977). Coupling techniques mentioned in the latter are the glutaraldehyde method, the periodate method, the dimaleimide method, the m-maleimidobenzyl-N-hydroxy-succinimide ester method, all of which methods are incorporated by reference herein. 
     Nonlimiting examples of cytotoxic agents include a cytostatic or cytocidal agent, a radioactive metal ion, e.g., alpha-emitters, and toxins, e.g.,  pseudomonas  exotoxin, abrin, cholera toxin, ricin A, and diphtheria toxin. 
     In certain embodiments, the agent is a diagnostic agent. A diagnostic agent is an agent useful in diagnosing or detecting a disease by locating the cells containing the antigen. Useful diagnostic agents include, but are not limited to, radioisotopes, dyes (such as with the biotin-streptavidin complex), contrast agents, fluorescent compounds or molecules and enhancing agents (e.g., paramagnetic ions) for magnetic resonance imaging (MM). U.S. Pat. No. 6,331,175 describes MM technique and the preparation of antibodies conjugated to a MRI enhancing agent and is incorporated in its entirety by reference. Preferably, the diagnostic agents are selected from the group consisting of radioisotopes, enhancing agents for use in magnetic resonance imaging, and fluorescent compounds. In order to load an anti-MUC16 antibody agent or antigen-binding fragment thereof with radioactive metals or paramagnetic ions, it may be necessary to react it with a reagent having a long tail to which are attached a multiplicity of chelating groups for binding the ions. Such a tail can be a polymer such as a polylysine, polysaccharide, or other derivatized or derivatizable chain having pendant groups to which can be bound chelating groups such as, for example, ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTP A), porphyrins, polyamines, crown ethers, bis-thiosemicarbazones, polyoximes, and like groups known to be useful for this purpose. Chelates are coupled to the antibodies using standard chemistries. The chelate is normally linked to the antibody by a group which enables formation of a bond to the molecule with minimal loss of immunoreactivity and minimal aggregation and/or internal cross-linking other, more unusual, methods and reagents for conjugating chelates to antibodies are disclosed in U.S. Pat. No. 4,824,659 to Hawthorne, entitled “Antibody Conjugates,” issued Apr. 25, 1989, the disclosure of which is incorporated herein in its entirety by reference. Particularly useful metal-chelate combinations include 2-benzyl-DTPA and its monomethyl and cyclohexyl analogs, used with diagnostic isotopes for radio-imaging. The same chelates, when complexed with non-radioactive metals, such as manganese, iron and gadolinium are useful for MRI, when used along with an anti-MUC16 antibody agent or antigen-binding fragment thereof provided herein. 
     Macrocyclic chelates such as NOTA, DOTA, and TETA are of use with a variety of metals and radiometals, most particularly with radionuclides of gallium, yttrium and copper, respectively. Such metal-chelate complexes can be made very stable by tailoring the ring size to the metal of interest. Other ring-type chelates such as macrocyclic polyethers, which are of interest for stably binding nuclides, such as  223 Ra for RAIT are encompassed herein. 
     Pharmaceutical Compositions 
     Also provided herein are compositions (such as pharmaceutical compositions, also referred to herein as formulations) comprising an anti-MUC16 antibody agent (such as a full-length anti-MUC16 antibody) or an antigen-binding fragment thereof, nucleic acid encoding the antibody agent, vector comprising the nucleic acid encoding the antibody agent, or host cell comprising the nucleic acid or vector. In some embodiments, there is provided a pharmaceutical composition comprising an anti-MUC16 antibody agent and optionally a pharmaceutically acceptable carrier. 
     Suitable formulations of the anti-MUC16 antibody agents (such as anti-MUC16 antibodies, e.g., full-length anti-MUC16 antibodies) or an antigen-binding fragment thereof are obtained by mixing an anti-MUC16 antibody agent having the desired degree of purity with optional pharmaceutically acceptable carriers, excipients or stabilizers ( Remington&#39;s Pharmaceutical Sciences  16th edition, Osol, A. Ed. (1980)), in the form of lyophilized formulations or aqueous solutions. Acceptable carriers, excipients, or stabilizers are nontoxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propylparaben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as olyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g. Zn-protein complexes); and/or non-ionic surfactants such as TWEEN™, PLURONICS™ or polyethylene glycol (PEG). Exemplary formulations are described in WO98/56418, expressly incorporated herein by reference. Lyophilized formulations adapted for subcutaneous administration are described in WO97/04801. Such lyophilized formulations may be reconstituted with a suitable diluent to a high protein concentration and the reconstituted formulation may be administered subcutaneously to the individual to be treated herein. Lipofectins or liposomes can be used to deliver the anti-MUC16 antibody agents of this present technology into cells. 
     The formulation herein may also contain one or more active compounds in addition to the anti-MUC16 antibody agent (such as a full-length anti-MUC16 antibody) or an antigen-binding fragment thereof as necessary for the particular indication being treated, preferably those with complementary activities that do not adversely affect each other. For example, it may be desirable to further provide an anti-neoplastic agent, a growth inhibitory agent, a cytotoxic agent, or a chemotherapeutic agent in addition to the anti-MUC16 antibody agent or an antigen-binding fragment thereof. Such molecules are suitably present in combination in amounts that are effective for the purpose intended. The effective amount of such other agents depends on the amount of anti-MUC16 antibody agent present in the formulation, the type of disease or disorder or treatment, and other factors discussed above. These are generally used in the same dosages and with administration routes as described herein or about from 1 to 99% of the heretofore employed dosages. 
     The anti-MUC16 antibody agents (such as anti-MUC16 antibodies, e.g., full-length anti-MUC16 antibodies) or an antigen-binding fragment thereof may also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly-(methylmethacylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules) or in macroemulsions. Sustained-release preparations may be prepared. 
     Sustained-release preparations of the anti-MUC16 antibody agents (such as anti-MUC16 antibodies, e.g., full-length anti-MUC16 antibodies) or an antigen-binding fragment thereof can be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the antibody agent (or fragment thereof), which matrices are in the form of shaped articles, e.g., films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)), polylactides (U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid and ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPOT™ (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D (−)-3-hydroxybutyric acid. While polymers such as ethylene-vinyl acetate and lactic acid-glycolic acid enable release of molecules for over 100 days, certain hydro gels release proteins for shorter time periods. When encapsulated antibody agents remain in the body for a long time, they can denature or aggregate as a result of exposure to moisture at 37° C., resulting in a loss of biological activity and possible changes in immunogenicity. Rational strategies can be devised for stabilization of anti-MUC16 antibody agents depending on the mechanism involved. For example, if the aggregation mechanism is discovered to be intermolecular S—S bond formation through thio-disulfide interchange, stabilization can be achieved by modifying sulfhydryl residues, lyophilizing from acidic solutions, controlling moisture content, using appropriate additives, and developing specific polymer matrix compositions. 
     In some embodiments, the anti-MUC16 antibody agent (such as a full-length anti-MUC16 antibody) or an antigen-binding fragment thereof is formulated in a buffer comprising a citrate, NaCl, acetate, succinate, glycine, polysorbate 80 (Tween 80), or any combination of the foregoing. In some embodiments, the anti-MUC16 antibody agent or an antigen-binding fragment thereof is formulated in a buffer comprising about 100 mM to about 150 mM glycine. In some embodiments, the anti-MUC16 antibody agent or an antigen-binding fragment thereof is formulated in a buffer comprising about 50 mM to about 100 mM NaCl. In some embodiments, the anti-MUC16 antibody agent or an antigen-binding fragment thereof is formulated in a buffer comprising about 10 mM to about 50 mM acetate. In some embodiments, the anti-MUC16 antibody agent or an antigen-binding fragment thereof is formulated in a buffer comprising about 10 mM to about 50 mM succinate. In some embodiments, the anti-MUC16 antibody agent or an antigen-binding fragment thereof is formulated in a buffer comprising about 0.005% to about 0.02% polysorbate 80. In some embodiments, the anti-MUC16 antibody agent or an antigen-binding fragment thereof is formulated in a buffer having a pH between about 5.1 and 5.6. In some embodiments, the anti-MUC16 antibody agent or an antigen-binding fragment thereof is formulated in a buffer comprising 10 mM citrate, 100 mM NaCl, 100 mM glycine, and 0.01% polysorbate 80, wherein the formulation is at pH 5.5. 
     The formulations to be used for in vivo administration must be sterile. This is readily accomplished by, e.g., filtration through sterile filtration membranes. 
     Methods of Treatment Using Anti-Muc16 Antibody Agents 
     In certain embodiments, provided herein are methods for treating a cancer in a subject, in particular, a MUC16-positive cancer in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of anti-MUC16 antibody agent or an antigen-binding fragment thereof. In some embodiments, the anti-MUC16 antibody agent or antigen-binding fragment thereof is administered at a therapeutically effective dose, such as a dose described herein. In some embodiments, the anti-MUC16 antibody agent or antigen-binding fragment thereof is administered according to a method as described herein. In some embodiments, the anti-MUC16 antibody agent or antigen-binding fragment thereof is administered in combination with one or more additional pharmaceutically active agents. 
     For use of an anti-MUC16 antibody agent or antigen-binding fragment thereof in a subject of a particular species, an anti-MUC16 antibody agent or antigen-binding fragment thereof is used that binds to MUC16 of that particular species. For example, to treat a human, an anti-MUC16 antibody agent or antigen-binding fragment thereof is used that binds to human MUC16. In some embodiments, the anti-MUC16 antibody agent or antigen-binding fragment thereof is an immunoglobulin. 
     In addition, for use of an anti-MUC16 antibody agent or antigen-binding fragment thereof in a subject of a particular species, the anti-MUC16 antibody agent, preferably, the constant region of an anti-MUC16 antibody agent or antigen-binding fragment thereof, is derived from that particular species. For example, to treat a human, an anti-MUC16 antibody agent or antigen-binding fragment thereof can comprise an anti-MUC16 antibody agent or antigen-binding fragment thereof that is an immunoglobulin, wherein the immunoglobulin comprises a human constant region. In some embodiments, the subject is a human. 
     In some embodiments, the MUC16-positive cancer is ovarian cancer, lung cancer, pancreatic cancer, breast cancer, fallopian tube cancer, uterine (e.g., endometrial) cancer, primary peritoneum cancer or cancer of any other tissue that expresses the MUC16 receptor. 
     In some embodiments, treatment can be to achieve beneficial or desired clinical results including, but not limited to, alleviation of a symptom, diminishment of extent of a disease, stabilizing (i.e., not worsening) of state of a disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. In a specific embodiment, “treatment” can also be to prolong survival as compared to expected survival if not receiving treatment. In some embodiments, the administration of an anti-MUC16 antibody agent or an antigen-binding fragment thereof described herein, or a pharmaceutical composition described herein to a subject with cancer (e.g., ovarian cancer, lung cancer, pancreatic cancer, breast cancer, fallopian tube cancer, uterine (e.g., endometrial) cancer, or primary peritoneum cancer, or cancer of any other tissue that expresses the MUC16 receptor) achieves at least one, two, three, four or more of the following effects: (i) the reduction or amelioration of the severity of one or more symptoms of cancer; (ii) the reduction in the duration of one or more symptoms associated with cancer; (iii) the prevention in the recurrence of a symptom associated with cancer; (iv) the reduction in hospitalization of a subject; (v) a reduction in hospitalization length; (vi) the increase in the survival of a subject; (vii) the enhancement or improvement of the therapeutic effect of another therapy; (viii) the inhibition of the development or onset of one or more symptoms associated with cancer; (ix) the reduction in the number of symptoms associated with cancer; (x) improvement in quality of life as assessed by methods well known in the art; (x) inhibition of the recurrence of a tumor; (xi) the regression of tumors and/or one or more symptoms associated therewith; (xii) the inhibition of the progression of tumors and/or one or more symptoms associated therewith; (xiii) a reduction in the growth of a tumor; (xiv) a decrease in tumor size (e.g., volume or diameter); (xv) a reduction in the formation of a newly formed tumor; (xvi) prevention, eradication, removal, or control of primary, regional and/or metastatic tumors; (xvii) a decrease in the number or size of metastases; (xviii) a reduction in mortality; (xix) an increase in relapse free survival; (xx) the size of the tumor is maintained and does not increase or increases by less than the increase of a tumor after administration of a standard therapy as measured by conventional methods available to one of skill in the art, such as magnetic resonance imaging (MRI), dynamic contrast-enhanced MRI (DCE-MRI), X-ray, and computed tomography (CT) scan, or a positron emission tomography (PET) scan; and/or (xxi) an increase in the length of remission in patients. Treatment can be to achieve one or more of the foregoing. 
     A subject treated in accordance with the methods provided herein can be any mammal, such as a rodent, a cat, a canine, a horse, a cow, a pig, a monkey, a primate, or a human, etc. In some embodiments, the subject is a human. In some embodiments, the subject is a canine. As used herein, the terms “subject” and “patient” are used interchangeably. 
     In certain embodiments, a subject treated in accordance with the methods provided herein has been diagnosed with a MUC16-positive cancer, including but not limited to, ovary, lung, pancreas, breast, uterine, fallopian tube, or primary peritoneum cancer, or cancer of any other tissue that expresses the MUC16. 
     Diagnostic Uses 
     In certain embodiments, anti-MUC16 antibody agents or antigen-binding fragments thereof described herein can be used for diagnostic purposes to detect, diagnose, or monitor a condition described herein (e.g., a condition involving MUC16-positive cancer cells). In certain embodiments, anti-MUC16 antibody agents or antigen-binding fragments thereof for use in diagnostic purposes are labeled. 
     In certain embodiments, provided herein are methods for the detection of a condition described herein comprising (a) assaying the expression of MUC16 or a fragment thereof in cells or a tissue sample of a subject using one or more anti-MUC16 antibody agents or antigen-binding fragments thereof described herein; and (b) comparing the level of MUC16 or the fragment thereof expression with a control level, for example, levels in normal tissue samples (e.g., from a subject not having a condition described herein, or from the same patient before onset of the condition), whereby an increase or decrease in the assayed level of MUC16 or the fragment thereof expression compared to the control level of MUC16 or the fragment thereof expression is indicative of a condition described herein. 
     Antibodies described herein can be used to assay the levels of MUC16 or a fragment thereof in a biological sample using classical immunohistological methods as described herein or as known to those of skill in the art (e.g., see Jalkanen et al.,  J. Cell. Biol.  101: 976-985 (1985); and Jalkanen et al.,  J. Cell. Biol.  105:3087-3096 (1987)). Other antibody-based methods useful for detecting protein gene expression include immunoassays, such as the enzyme linked immunosorbent assay (ELISA) and the radioimmunoassay (MA). Suitable antibody assay labels are known in the art and include enzyme labels, such as, glucose oxidase; radioisotopes, such as iodine ( 125 I,  121 I), carbon ( 14 C), sulfur ( 35 S), tritium ( 3 H), indium ( 121 In), and technetium ( 99 Tc); luminescent labels, such as luminol; and fluorescent labels, such as fluorescein and rhodamine, and biotin. In some embodiments, the assay labels are conjugated to the anti-MUC16 antibody agents or antigen-binding fragment thereof provided herein for direct detection. In some embodiments, the assay labels are conjugated to a secondary antibody that binds to an anti-MUC16 antibody agents or antigen-binding fragment thereof provided herein. The secondary antibody type is selected according to the class of the primary antibody (e.g., IgG or IgM), the source host, and the kind of label which is preferred. In some embodiments, the secondary antibody is a class or isotype specific antibody (e.g., IgG, IgM, IgA, IgE or IgG). In some embodiments, the secondary antibody is a subclass specific antibody (e.g., IgG1, IgG2, IgG2, IgG4, IgA1, or IgA2). In some embodiments, the secondary antibody binds to one or more classes or subclasses of antibodies. In some embodiments, the secondary antibody binds to the heavy chain of the primary antibody. In some embodiments, the secondary antibody binds to the light chain of the primary antibody. In some embodiments, the secondary antibody binds to a kappa light chain of the primary antibody. In some embodiments, the secondary antibody binds to a lambda light chain of the primary antibody. In some embodiments, the secondary antibody is an anti-Fc or an anti-F(ab) or anti-(Fab′)2 fragment antibody. In some embodiments, the secondary antibody is a rabbit, mouse, goat, donkey or chicken antibody. 
     In certain embodiments, monitoring of a condition described herein (e.g., a MUC16-positive cancer), is carried out by repeating the method for diagnosing for a period of time after initial diagnosis. 
     Presence of the labeled molecule can be detected in the subject (i.e., in vivo) using methods known in the art for in vivo scanning. Skilled artisans will be able to determine the appropriate method for detecting a particular label. Methods and devices that may be used in the diagnostic methods of the present technology include, but are not limited to, computed tomography (CT), whole body scan such as position emission tomography (PET), magnetic resonance imaging (MRI), and sonography. 
     Also disclosed herein is a method for detecting cancer in a subject in vivo comprising (a) administering to the subject an effective amount of any of the anti-MUC16 constructs disclosed herein, wherein the anti-MUC16 construct is configured to localize to a cancer cell expressing MUC16 and is labeled with a radioisotope; and (b) detecting the presence of a tumor in the subject by detecting radioactive levels emitted by the anti-MUC16 construct that are higher than a reference value, optionally wherein the radioisotope is  89 Zr-desferrioxamine B (DFO). In some embodiments, the subject is diagnosed with or is suspected of having cancer. Additionally or alternatively, in some embodiments, the radioactive levels emitted by the anti-MUC16 construct are detected using positron emission tomography or single photon emission computed tomography. In any of the preceding embodiments, the method further comprises administering to the subject an effective amount of an immunoconjugate comprising an anti-MUC16 construct of the present technology conjugated to a radionuclide. The radionuclide may be an alpha particle-emitting isotope, a beta particle-emitting isotope, an Auger-emitter, or any combination thereof. 
     Delivery of Anti-Muc16 Antibody Agents 
     An anti-MUC16 antibody agent or antigen-binding fragment thereof as described herein, or composition containing, or cells expressing the antibodies, or antigen-binding fragments thereof, described herein may be delivered to a subject by a variety of routes. These include, but are not limited to, parenteral, intranasal, intratracheal, oral, intradermal, topical, intramuscular, intraperitoneal, transdermal, intravenous, intratumoral, conjunctival and subcutaneous routes. Pulmonary administration can also be employed, e.g., by use of an inhaler or nebulizer, and formulation with an aerosolizing agent for use as a spray. In one embodiment, an anti-MUC16 antibody agent or antigen-binding fragment thereof, or a composition described herein is administered parenterally to a subject. In some embodiments, said parenteral administration is intravenous, intramuscular, or subcutaneous. 
     The amount of an anti-MUC16 antibody agent or antigen-binding fragment thereof, or composition which will be effective in the treatment and/or prevention of a condition will depend on the nature of the disease, and can be determined by standard clinical techniques. 
     The precise dose to be employed in a composition will also depend on the route of administration, and the type of cancer, and should be decided according to the judgment of the practitioner and each subject&#39;s circumstances. For example, effective doses may also vary depending upon means of administration, target site, physiological state of the patient (including age, body weight and health), whether the patient is human or animal, other medications administered, or whether treatment is prophylactic or therapeutic. Treatment dosages are optimally titrated to optimize safety and efficacy. 
     In certain embodiments, an in vitro assay is employed to help identify optimal dosage ranges. Effective doses may be extrapolated from dose response curves derived from in vitro or animal model test systems. 
     For an anti-MUC16 antibody agent or an antigen-binding fragment thereof, the dosage may range from about 0.0001 to 100 mg/kg, and more usually 0.01 to 15 mg/kg, of the patient body weight. For example, dosages can be 1 mg/kg body weight, 10 mg/kg body weight, or within the range of 1-10 mg/kg or in other words, 70 mg or 700 mg or within the range of 70-700 mg, respectively, for a 70 kg patient. Generally, human antibodies have a longer half-life within the human body than antibodies from other species due to the immune response to the foreign polypeptides. Thus, lower dosages of human antibodies and less frequent administration is often possible. 
     In certain embodiments, such as in the administration of engineered cells expressing the antibodies or antigen-binding fragments thereof, or CARs, a subject is administered to the subject at a range of about one million to about 100 billion cells, such as, e.g., 1 million to about 50 billion cells (e.g., about 5 million cells, about 25 million cells, about 500 million cells, about 1 billion cells, about 5 billion cells, about 20 billion cells, about 30 billion cells, about 40 billion cells, or a range defined by any two of the foregoing values), such as about 10 million to about 100 billion cells (e.g., about 20 million cells, about 30 million cells, about 40 million cells, about 60 million cells, about 70 million cells, about 80 million cells, about 90 million cells, about 10 billion cells, about 25 billion cells, about 50 billion cells, about 75 billion cells, about 90 billion cells, or a range defined by any two of the foregoing values), and in some cases about 100 million cells to about 50 billion cells (e.g., about 120 million cells, about 250 million cells, about 350 million cells, about 450 million cells, about 650 million cells, about 800 million cells, about 900 million cells, about 3 billion cells, about 30 billion cells, about 45 billion cells) or any value in between these ranges. In some embodiments, the dose of total cells and/or dose of individual sub-populations of cells is within a range of between at or about 10 4  and at or about 10 9  cells/kilograms (kg) body weight, such as between 10 5  and 10 6  cells/kg body weight, for example, at or about 1×10 5  cells/kg, 1.5×10 5  cells/kg, 2×10 5  cells/kg, or 1×10 6  cells/kg, 2×10 6  cells/kg, 5×10 6  cells/kg, or 10×10 6  cells/kg body weight. For example, in some embodiments, the cells are administered at, or within a certain range of error of, between at or about 10 4  and at or about 10 9  T cells/kilograms (kg) body weight, such as between 10 5  and 10 7  T cells/kg body weight. 
     An anti-MUC16 antibody agent or antigen-binding fragment thereof can be administered on multiple occasions. Intervals between single dosages can be 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 6 months, 1 year, or 2 years. 
     Combination Therapies 
     In some embodiments, the methods provided herein for treating cancer (e.g., ovarian cancer, pancreatic cancer, lung cancer, breast cancer, fallopian tube cancer, uterine (e.g., endometrial) cancer, or primary peritoneum cancer) in a subject, comprising administering to a subject in need thereof a pharmaceutical composition comprising an anti-MUC16 antibody agent or an antigen-binding fragment thereof described herein, further comprise administering to the subject one or more additional therapeutic agents. In some embodiments, the additional therapeutic agent is for treating the cancer in the subject (e.g., ovarian cancer, pancreatic cancer, lung cancer, breast cancer, fallopian tube cancer, uterine (e.g., endometrial) cancer, and primary peritoneum cancer). In some embodiments, the additional therapeutic agent is for treating any side effects of treatment with an anti-MUC16 antibody agent or an antigen-binding fragment thereof described herein. 
     In some embodiments, the additional agent is an agent used to treat ovarian cancer. In some embodiments, the additional agent is an agent used to treat pancreatic cancer. In some embodiments, the additional agent is an agent used to treat lung cancer. In some embodiments, the additional agent is an agent used to treat breast cancer. In some embodiments, the additional agent is an agent used to treat fallopian tube cancer. In some embodiments, the additional agent is an agent used to treat uterine (e.g., endometrial) cancer. In some embodiments, the additional agent is an agent used to treat primary peritoneum cancer. 
     An anti-MUC16 antibody agent or antigen-binding fragment thereof described herein can be administered with an additional therapeutic agent concurrently or sequentially (before and/or after). The antibody or antigen binding fragment thereof and the additional therapeutic agent can be administered in the same or different compositions, and by the same or different routes of administration. A first therapy (which is an anti-MUC16 antibody agent or an antigen-binding fragment thereof described herein, or the additional therapeutic agent) can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of the second therapy (the anti-MUC16 antibody agent or an antigen-binding fragment thereof described herein, or the additional therapeutic agent) to a subject with cancer (e.g., ovarian cancer, pancreatic cancer, lung cancer, breast cancer, fallopian tube cancer, uterine (e.g., endometrial) cancer, and primary peritoneum cancer). In certain embodiments, an additional therapeutic agent administered to a subject in combination with an anti-MUC16 antibody agent or an antigen-binding fragment thereof described herein is administered in the same composition (pharmaceutical composition). In other embodiments, an additional therapeutic agent administered in combination with an anti-MUC16 antibody agent or an antigen-binding fragment thereof described herein is administered to a subject in a different composition than the anti-MUC16 antibody agent or an antigen-binding fragment thereof described herein (e.g., two or more pharmaceutical compositions are used). 
     Articles of Manufacture and Kits 
     In some embodiments of the present technology, there is provided an article of manufacture containing materials useful for the treatment of a cancer characterized by high MUC16 expression and/or high aerobic glycolysis (e.g., kidney cancer, cervical cancer, or prostate cancer), or for delivering an anti-MUC16 antibody agent (such as a full-length anti-MUC16 antibody) to a cell expressing MUC16 on its surface. The article of manufacture can comprise a container and a label or package insert on or associated with the container. Suitable containers include, for example, bottles, vials, syringes, etc. The containers may be formed from a variety of materials such as glass or plastic. Generally, the container holds a composition which is effective for treating a disease or disorder described herein, and may have a sterile access port (for example the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). At least one active agent in the composition is an anti-MUC16 antibody agent of the present technology. The label or package insert indicates that the composition is used for treating the particular condition. The label or package insert will further comprise instructions for administering the anti-MUC16 antibody agent composition to the patient. Articles of manufacture and kits comprising combinatorial therapies described herein are also contemplated. 
     Package insert refers to instructions customarily included in commercial packages of therapeutic products that contain information about the indications, usage, dosage, administration, contraindications and/or warnings concerning the use of such therapeutic products. In some embodiments, the package insert indicates that the composition is used for treating cancer (such as HCC, melanoma, lung squamous cell carcinoma, ovarian carcinoma, yolk sac tumor, choriocarcinoma, neuroblastoma, hepatoblastoma, Wilms&#39; tumor, testicular nonseminomatous germ cell tumor, gastric carcinoma, or liposarcoma). 
     Additionally, the article of manufacture may further comprise a second container comprising a pharmaceutically acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer&#39;s solution and dextrose solution. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes. 
     Kits are also provided that are useful for various purposes, e.g., for treatment of a cancer characterized by high MUC16 expression and/or high aerobic glycolysis (e.g., kidney cancer, cervical cancer, or prostate cancer), or for delivering an anti-MUC16 antibody agent (such as a full-length anti-MUC16 antibody) to a cell expressing MUC16 on its surface, optionally in combination with the articles of manufacture. Kits of the present technology include one or more containers comprising an anti-MUC16 antibody agent composition (or unit dosage form and/or article of manufacture), and in some embodiments, further comprise another agent (such as the agents described herein) and/or instructions for use in accordance with any of the methods described herein. The kit may further comprise a description of selection of individuals suitable for treatment. Instructions supplied in the kits of the present technology are typically written instructions on a label or package insert (e.g., a paper sheet included in the kit), but machine-readable instructions (e.g., instructions carried on a magnetic or optical storage disk) are also acceptable. 
     For example, in some embodiments, the kit comprises a composition comprising an anti-MUC16 antibody agent (such as a full-length anti-MUC16 antibody). In some embodiments, the kit comprises a) a composition comprising an anti-MUC16 antibody agent, and b) an effective amount of at least one other agent, wherein the other agent enhances the effect (e.g., treatment effect, detecting effect) of the anti-MUC16 antibody agent. In some embodiments, the kit comprises a) a composition comprising an anti-MUC16 antibody agent, and b) instructions for administering the anti-MUC16 antibody agent composition to an individual for treatment of a cancer characterized by high MUC16 expression and/or high aerobic glycolysis (e.g., kidney cancer, cervical cancer, or prostate cancer). In some embodiments, the kit comprises a) a composition comprising an anti-MUC16 antibody agent, b) an effective amount of at least one other agent, wherein the other agent enhances the effect (e.g., treatment effect, detecting effect) of the anti-MUC16 antibody agent, and c) instructions for administering the anti-MUC16 antibody agent composition and the other agent(s) to an individual for treatment of a cancer characterized by high MUC16 expression and/or high aerobic glycolysis (e.g., kidney cancer, cervical cancer, or prostate cancer). The anti-MUC16 antibody agent and the other agent(s) can be present in separate containers or in a single container. For example, the kit may comprise one distinct composition or two or more compositions wherein one composition comprises an anti-MUC16 antibody agent and another composition comprises another agent. 
     In some embodiments, the kit comprises a nucleic acid (or set of nucleic acids) encoding an anti-MUC16 antibody agent (such as a full-length anti-MUC16 antibody). In some embodiments, the kit comprises a) a nucleic acid (or set of nucleic acids) encoding an anti-MUC16 antibody agent, and b) a host cell for expressing the nucleic acid (or set of nucleic acids). In some embodiments, the kit comprises a) a nucleic acid (or set of nucleic acids) encoding an anti-MUC16 antibody agent, and b) instructions for i) expressing the anti-MUC16 antibody agent in a host cell, ii) preparing a composition comprising the anti-MUC16 antibody agent, and iii) administering the composition comprising the anti-MUC16 antibody agent to an individual for the treatment of a cancer characterized by high MUC16 expression and/or high aerobic glycolysis (e.g., kidney cancer, cervical cancer, or prostate cancer). In some embodiments, the kit comprises a) a nucleic acid (or set of nucleic acids) encoding an anti-MUC16 antibody agent, b) a host cell for expressing the nucleic acid (or set of nucleic acids), and c) instructions for i) expressing the anti-MUC16 antibody agent in the host cell, ii) preparing a composition comprising the anti-MUC16 antibody agent, and iii) administering the composition comprising the anti-MUC16 antibody agent to an individual for the treatment of a cancer characterized by high MUC16 expression and/or high aerobic glycolysis (e.g., kidney cancer, cervical cancer, or prostate cancer). 
     Also disclosed herein are kits comprising an anti-MUC16 construct of the present technology, a murine anti-MUC16 antibody or antigen binding fragment thereof, and instructions for use, wherein the murine anti-MUC16 antibody or antigen binding fragment includes (a) a variable heavy (VH) chain comprising a heavy chain complementarity determining region 1 (HC-CDR1), HC-CDR2, and HC-CDR3 of SEQ ID NOS: 17, 18, and 19, respectively, and a variable light (VL) chain comprising a light chain complementarity determining region 1 (LC-CDR1), LC-CDR2, and LC-CDR3 of SEQ ID NOS: 14, 15, and 16, respectively; or (b) a variable heavy (VH) chain comprising a heavy chain complementarity determining region 1 (HC-CDR1), HC-CDR2, and HC-CDR3 of SEQ ID NOS: 35, 36, and 37, respectively, and a variable light (VL) chain comprising a light chain complementarity determining region 1 (LC-CDR1), LC-CDR2, and LC-CDR3 of SEQ ID NOS: 32, 33, and 34, respectively. The murine anti-MUC16 antibody or antigen binding fragment (e.g., those described in U.S. Pat. No. 9,169,328) may be used to identify a patient that is responsive to treatment with the anti-MUC16 construct. In some embodiments, the murine anti-MUC16 antibody or antigen binding fragment is used to detect MUC16-expressing tumors in a sample obtained from the patient via western blotting, immunohistochemistry, high-performance liquid chromatography (HPLC), liquid chromatography-mass spectrometry (LC/MS), enzyme-linked immunosorbent assay (ELISA), immunoprecipitation, or immunoelectrophoresis. 
     The kits of the present technology are in suitable packaging. Suitable packaging includes, but is not limited to, vials, bottles, jars, flexible packaging (e.g., sealed Mylar or plastic bags), and the like. Kits may optionally provide additional components such as buffers and interpretative information. The present application thus also provides articles of manufacture, which include vials (such as sealed vials), bottles, jars, flexible packaging, and the like. 
     The instructions relating to the use of the anti-MUC16 antibody agent compositions generally include information as to dosage, dosing schedule, and route of administration for the intended treatment. The containers may be unit doses, bulk packages (e.g., multi-dose packages) or sub-unit doses. For example, kits may be provided that contain sufficient dosages of an anti-MUC16 antibody agent (such as a full-length anti-MUC16 antibody) as disclosed herein to provide effective treatment of an individual for an extended period, such as any of a week, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or more. Kits may also include multiple unit doses of the anti-MUC16 antibody agent and pharmaceutical compositions and instructions for use and packaged in quantities sufficient for storage and use in pharmacies, for example, hospital pharmacies and compounding pharmacies. 
     Those skilled in the art will recognize that several embodiments are possible within the scope and spirit of the present technology. The present technology will now be described in greater detail by reference to the following non-limiting examples. The following examples further illustrate the present technology but, of course, should not be construed as in any way limiting its scope. 
     EXAMPLES 
     The present technology is further illustrated by the following Examples, which should not be construed as limiting in any way. The following Examples demonstrate the preparation, characterization, and use of illustrative anti-MUC16 antibodies of the present technology. The following Examples demonstrate the production of human and bispecific antibodies of the present technology, and characterization of their binding specificities and in vivo biological activities. 
     Example 1: In Vitro Characterization of Antibodies Binding to the Carboxy-Terminus of MUC16 
     Murine monoclonal antibodies were previously developed against the peptide sequence in the ectodomain (juxtamembrane) portion of the MUC16 carboxy-terminus (called herein “peptide-2”). This example described the testing of six of these murine monoclonal antibodies which showed differential binding to MUC16. The goal of the study was to identify the best antibody candidate for humanization and potential translation in the clinic. The study was divided into three phases. In the first phase, the six antibodies were evaluated based on the results of a comparative in vitro screening process. The objective of this phase of the study was to select two lead candidates for in vivo analyses based on the following 3 parameters: 1) amenability of the antibodies to bioconjugation; 2) outcome of radiolabeling the antibodies, including radiochemical yields and molar activities; and 3) performance of the radioimmunoconjugates in cell-based assays including determination of the immunoreactive fraction, saturation binding, and cellular internalization. 
     In the second phase of the study, the in vivo tumor-targeting and radiopharmacologic profiles of the two lead candidates identified from the in vitro screening process were evaluated (see Example 2). 
     Finally, in the third phase of the study, humanization of the lead MUC16 carboxy-terminus binding antibody identified from the preceding phase was performed. The humanized variant was then evaluated for its in vivo tumor-targeting and radiopharmacologic profile (see Example 3). 
     Three of the antibodies, 9C9, 4H11 and 4A5, that were chosen in in the study had previously demonstrated robust and high affinity binding to the MUC16 carboxy-terminus using various methods of analyses, including enzyme linked immunosorbent assay (ELISA) with supernatants from cultures of their respective hybridomas, Western blotting with purified recombinant pFUSE MUC16c114 containing the 58 amino acid residues of the ectodomain MUC16 carboxy-terminus fused to the human Fc antibody domain, flow cytometry analyses and saturation binding assays with MUC16-expressing OVCAR3 cells. Two other antibodies, 4C7 and 29G9, showed binding to MUC16 via ELISA and western blot analyses. The last antibody, 4A2, showed positivity by ELISA alone. 
     The ideal characteristics of  89 Zr, including its physical (decay) half-life (t 1/2 2=72.4 h), which matches well with the biological half-life and in vivo pharmacokinetics of tumor-targeting by antibodies, combined with its ability to residualize within cells after internalization, made it an isotope of choice for radiolabeling the various MUC16 carboxy-terminus-binding antibodies and evaluating their in vitro and in vivo radiopharmacologic profiles.  89 Zr was produced at Memorial Sloan Kettering Cancer Center on a TR19/9 cyclotron (Ebco Industries Inc.) via the  89 Y(p,n) 89 Zr reaction and purified to yield  89 Zr with a specific activity of 196-496 MBq/mg. Activity measurements were made using a CRC-15R Dose Calibrator (Capintec). For the quantification of activities, samples were counted on an Automatic Wizard gamma counter (Perkin Elmer). The radiolabeling of ligands was monitored using instant thin-layer chromatography paper (Agilent Technologies) and analyzed on a Bioscan AR-2000 radio-ITLC plate reader using Winscan Radio-TLC software (Bioscan Inc.). 
     To radiolabel the antibodies with  89 Zr, the isothiocyanate-functionalized variant of desferrioxamine (p-SCN-Bn-DFO) was conjugated to produce DFO-immunoconjugates of all six antibodies using identical reaction conditions. The objective was to facilitate bioconjugation of the bifunctional chelator with epsilon-amine(s) on lysine residues, which are randomly distributed in the structure of the antibody. Briefly, the antibodies were suspended in citrate buffer (25 mM sodium citrate, 150 mM sodium chloride) at an average concentration of 2-3 mg/mL. The antibodies were buffer-exchanged using disposable Sephadex G-25 PD10 desalting columns (17085101; GE Healthcare, Life Sciences) pre-equilibrated with chelexed PBS and concentrated using centrifugal filter units with a 50,000 molecular weight cutoff (Amicon Ultra 4 Centrifugal Filtration Units, Millipore) to obtain a final concentration of 12-15 mg/mL. The pH of the antibody solution was adjusted to 8.5-9.0 using 0.1 M Na 2 CO 3 . Thereafter, 10 molar equivalents of isothiocynato-desferrioxamine (p-SCN-Bn-DFO) (B-705; Macrocyclics, Inc.) dissolved in DMSO (41640; Sigma Aldrich) at a concentration of 10 mg/mL. The reaction was incubated at 37° C. for 1 h on a thermomixer set at 500 rpm. The DFO-conjugated antibodies were purified using PD10 desalting columns and concentrated using centrifugal filter units as described above. 
       89 Zr was provided by the Radiochemistry and Molecular Imaging Probes core at MSKCC as [ 89 Zr]Zr-oxalate dissolved in 1M oxalic acid. The solution was neutralized with 1M sodium carbonate to reach pH ˜7. Each immunoconjugate dissolved in chelexed PBS pH 7.4 was incubated with neutralized  89 Zr at 37° C. for 1 hour. The progress of the radiolabeling reactions was monitored via radio-instant thin layer chromatography (radio-ITLC) by spotting 0.5 μL of the crude reaction mixture on a silica-gel impregnated glass-microfiber paper strip (iTLC-SG; Varian) and analyzed on an ITLC scanner (AR-2000; Bioscan Inc.) using 50 mM EDTA pH 5.5 as the solvent for the mobile phase. On the ITLC, the  89 Zr-labeled radioimmunoconjugates complexes remained at the origin, while free  89 Zr was taken up by EDTA in the mobile phase and migrated with the solvent front. Crude radiochemical yields were calculated using the radio-ITLC data. The  89 Zr-radioimmunoconjugates were then purified via size exclusion chromatography using PD10 desalting columns, followed by centrifugal filtration to concentrate the final volume to prepare the tracer doses. The radiochemical purity of the purified radioimmunoconjugates was confirmed via radio-ITLC prior to using them for animal experiments. 
     The determine serum stability, 100 μL of each of the radioimmunoconjugates was incubated with 900 μL of human serum (H4522; Sigma Aldrich) and agitated constantly on a thermomixer set at 37° C. Samples were taken from each microcentrifuge tube and analyzed via radio-ITLC at day 0, 1, 3, 5, and 7. All samples were analyzed in triplicates. The serum stability of the radioimmunoconjugates was measured as the percentage of  89 Zr retained at the origin of the radio-ITLC strip and reported as % intact. 
     The immunoreactive fraction of the  89 Zr-DFO-antibodies was determined using a modified cell binding assay following the procedure described by Lindmo et al. (1984)  J Immunol Methods  72:77-89) To this end, SKOV3 c114  cells were suspended in microcentrifuge tubes at concentrations ranging from 5.0×10 5 -5.0×10 6  cells/mL in 500 μL PBS supplemented with 1% BSA (pH 7.4). Aliquots of the various radioimmunoconjugates—50 μL of 1 μCi/mL stock were added to each tube before the final volume of the cells and radioimmunoconjugates per tube was made up to 500 μL. The samples were incubated for 60 min on a thermomixer set to 37° C. and 500 rpm. The treated cells were then pelleted via centrifugation (1400 rpm for 4 min), the supernatant was aspirated out and the pellet was washed three times with ice-cold PBS before removing the supernatant and counting the radioactivity associated with the cell pellets. The activity data were background-corrected and compared with the total number of counts in appropriate control samples. Immunoreactive fractions were determined by linear regression analysis of total/bound radioactivity plotted against the inverse of normalized cell concentration. Additionally, the immunoreactivity of the lead antibody [ 89 Zr]Zr-DFO-4H11 was evaluated in a bead-based binding assay (see  FIG. 5 ). 
     To generate SKOV3 c114  cells, SKOV3 cells purchased from the American Type Cell Culture (ATCC, Manassas, Va.) were transfected with a plasmid, phrGFP-MUC16 c114 , encoding the 114 amino acids from the carboxy-terminus of MUC16. Un-transfected SKOV3 (wild type) cells were also cultured and used as a negative control in the experiments. The cells were cultured in RPMI McCoy&#39;s 5A Medium, modified to contain 1.5 mM L-glutamine, 100 units/mL penicillin G and 100 μg/mL streptomycin and 10% fetal bovine serum and 800 μg/mL of geneticin G418. The cells were maintained at 37° C. in water-jacketed incubators and supplied with 5% CO 2 . The cell lines were sub-cultured by splitting a T-150 flask (1:5) once per week using 0.25% trypsin/0.53 mM EDTA in Hank&#39;s Buffered Salt Solution without calcium and magnesium. MUC16-expressing OVCAR3 cells were obtained from ATCC and cultured using RPMI 1640 medium supplemented with heat inactivated fetal bovine serum (20% v/v, GIBCO, Life Technologies), 2 mM L-glutamine, 10 mM HEPES, 1 mM sodium pyruvate, 4.5 g/L glucose, 1.5 g/L sodium bicarbonate, 0.01 mg/mL bovine insulin (Gemini Bio-Products, 700-112P), 100 units/mL penicillin and 100 μg/mL streptomycin. 
     For saturation binding studies, six concentrations, 0.1, 1, 5, 10, 25, 50 and 100 nM of the  89 Zr-labeled variants of the MUC16 carboxy-terminus binding antibodies were incubated for 1 hour at 37° C. with 500,000 SKOV3 c114  cells suspended in PBS supplemented with 1% BSA. At the same time, a parallel set up was prepared and analyzed for non-specific binding of the antibody to SKOV3 c114  cells. The latter was prepared by adding the  89 Zr-radioimmunoconjugate variant of the MUC16 carboxy-terminus binding antibody and 100 nM of the respective unlabeled antibody to the mixture of SKOV3 c114  cells. All experiments were carried out in triplicates. 
     Internalization of the various radioimmunoconjugates was investigated using SKOV3 c114  cells. Approximately 1×10 5  cells were seeded in a 12-well plate and incubated overnight. A volume of 2 mL of the radioimmunoconjugates (1 μCi per mL of SKOV3 c114  medium) was added to each well. The plates were incubated at 37° C. versus 4° C. for 1, 4, 12 and 24 h. Following each incubation period, the cell supernatant was collected, and the cells were rinsed twice with 1 mL of ice-cold phosphate buffered saline (PBS). Surface-bound activity was collected by washing the cells in 1 mL of 100 mM acetic acid+100 mM glycine (1:1, pH 3.5). The adherent cells were then lysed with 1 mL of 1M sodium hydroxide. Each wash was collected and counted for activity. The percent internalized activity was calculated as the ratio of the activity of the lysate and the total activity from the medium, PBS, acid, and base washes. 
     Despite performing the bioconjugation and radiolabeling of the immunoconjugates under identical conditions, variable radiochemical yields and molar activities of the radioimmunoconjugates ranging from 1.16 MBq/nmol (0.21 mCi/mg) to 31.8 MBq/nmol (5.74 mCi/mg) were obtained (Table 4). One antibody, 4A2, could not be radiolabeled under the same conditions that were used for bioconjugation and radiolabeling of the other five antibodies, and was dropped from further analyses. Antibodies 29G9 and 4A5 yielded low molar activities upon radiolabeling with  89 Zr. Specifically, the extremely low molar activity of [ 89 Zr]Zr-DFO-4A5 compared poorly with a radioiodinated variant of the same antibody, which previously demonstrated an efficient binding affinity (KD=7.3±1.1 nM) to MUC16-expressing OVCAR3 cells (Dharma et al. (2010)  Appl Immunohistochem Mol Morphol.  18:462-472). Plausibly, the lysine residues in 4A5 may not be as solvent accessible and amenable to amine-based conjugation compared to tyrosine residues, which may be more readily accessible for radioiodination of 4A5, thus leading to the differences in radiochemical yields between the two methods used to radiolabel the antibody. The low immunoreactive fraction may be linked to the low molar activity (higher unlabeled fraction), which can block the radiolabeled antibody&#39;s access to the target. In sum, owing to their low radiochemical yields and poor molar activities, 29G9 and 4A5, were also not pursued further in this study. 
     
       
         
           
               
             
               
                 TABLE 4 
               
             
            
               
                   
               
               
                 In vitro characterization of six MUC16 CTD-binding murine monoclonal antibodies 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                   
                 Molar 
                 Immunoreactive 
                 Binding 
                 Cellular 
               
               
                   
                 MUC16 
                 Activity 
                 Fraction 
                 Affinity 
                 Internalization 
               
               
                 Antibody 
                 Reactivity 
                 (MBq/nmol) 
                 (%) 
                 (nM) 
                 (% IDat 24 h) 
               
               
                   
               
               
                 9C9 
                 ++++ 
                 24.13 
                 84.6 ± 4.4% 
                 9.0 ± 1.49 
                 11.9 ± 2.21 
               
               
                   
                   
                 4.35 mCi/mg 
                   
                   
                   
               
               
                 4H11 
                 ++++ 
                 31.8  
                 88.3 ± 5.9% 
                 6.4 ± 1.20 
                 14.1 ± 1.34 
               
               
                   
                   
                 5.74 mCi/mg 
                   
                   
                   
               
               
                 4C7 
                 ++ 
                 17.7  
                 76.3 ± 3.8% 
                 13.3 ± 2.89 
                 − 
               
               
                   
                   
                 3.19 mCi/mg 
                   
                   
                   
               
               
                 29G9 
                 ++ 
                 6.9 
                 62.0 ± 6.6% 
                 − 
                 − 
               
               
                   
                   
                 1.25 mCi/mg 
                   
                   
                   
               
               
                 4A5 
                 ++++ 
                  1.16 
                 67.2 ± 1.2% 
                 − 
                 − 
               
               
                   
                   
                 0.21 mCi/mg 
                   
                   
                   
               
               
                 4A2 
                 + 
                 − 
                 − 
                 − 
                 − 
               
               
                   
               
               
                 ++++ indicates positivity for MUC16-binding in ELISA, Western Blot, Flow Cytometry, Saturation Binding 
               
               
                 ++ indicates positivity for MUC16-binding in ELISA and Western Blot only 
               
               
                 + indicates positivity for MUC16-binding in ELISA only 
               
               
                 − indicates not applicable and was not performed. 
               
               
                 All data presented are expressed as mean ± SD. When applicable, statistical differences were analyzed by an unpaired, two-tailed Student&#39;s t test (with a Welch&#39;s correction when mentioned). Differences at the 95% confidence level (P &lt; 0.05) were considered statistically significant, and are indicated by asterisks 
               
            
           
         
       
     
     Among the three antibodies remaining, 9C9, 4H11 and 4C7, the radioimmunoconjugate of 4C7 yielded the least molar activity and displayed the lowest immunoreactive fraction. These outcomes combined with its relatively high binding affinity (&gt;10 nM) derived from saturation binding assays led to the exclusion of 4C7 from the second phase of the screening workflow. 
     Thus, 9C9 and 4H11 were identified as the two lead MUC16 carboxy-terminus binding antibodies. Their  89 Zr-labeled variants—[ 89 Zr]Zr-DFO-9C9 and [ 89 Zr]Zr-DFO-4H11 displayed favorable in vitro characteristics including high molar activities, ≥80% immunoreactive fractions and binding affinities in the range of 5-11 nM (Table 4 and  FIG. 3B ). The binding affinity values derived from saturation binding assays in the present study were concordant with previously reported values obtained in similar experiments carried out with radioiodinated variants of 9C9 and 4H11 (Dharma et al. (2010)  Appl Immunohistochem Mol Morphol.  18:462-472). 
     Notably, despite their comparable binding affinity for peptide-2 in the MUC16 carboxy-terminal domain, the  89 Zr-radioimmunoconjugates of 9C9 and 4H11 displayed different rates of cell uptake profiles ( FIG. 3C ). The binding of both the radioimmunoconjugates to SKOV3 c114  cells was low and comparable at 4° C. However, at 37° C., [ 89 Zr]Zr-DFO-4H11 exhibited more uptake of radioactivity with 12.47±3.02% of the normalized applied activity being internalized within 4 hours, followed by a slow accumulation reaching 14.09±1.34% at 24 hours ( FIG. 3C ). On the other hand, [ 89 Zr]Zr-DFO-9C9 displayed relatively slow cell uptake indicated by 5.22±1.34% being internalized by 1 hour, followed by a gradual accumulation that reached 11.89±2.21% at 24 hours. Such differences in the rate of cell uptake and maximal cellular internalization values achieved by the two lead antibody candidates may be attributed to more than one factor including the overall charge of the radioimmunoconjugates, which can be influenced by the composition of amino acids in the antibody class or a difference in the geometry of binding to MUC16 peptide-2, which can be deduced from the crystal structure of the binding pocket(s) of the scFv from 9C9 versus 4H11. The radioimmunoconjugates for both the lead antibody candidates showed comparable and high stability upon incubation in serum ( FIG. 3D ). Interestingly, an unrelated study aimed at exploring the use of single chain variable fragment (scFv) of 9C9 and 4H11 to develop CAR T-cells revealed that the sequence of scFvs from both these antibodies were identical (data not shown) suggesting that both the antibodies may have an identical molecular footprint on MUC16 by virtue of binding to the same epitope in the peptide-2 sequence within the juxtamembrane region of the MUC16 ectodomain. This was experimentally validated in the present study by achieving the blockade of [ 89 Zr]Zr-DFO-mu4H11 binding to biotinylated peptide-2 in the presence of an excess of unlabeled 9C9 antibody ( FIG. 3E ). 
     Example 2: In Vivo Characterization of Antibodies Binding to the Carboxy-Terminus of MUC16 
     Having identified 9C9 and 4H11 as the two lead candidates, the second phase of the study was performed with these antibodies. This second phase involved the in vivo characterization of the tumor-targeting ability and overall radiopharmacologic profiles of these antibodies. To this end, the radioimmunoconjugates, [ 89 Zr]Zr-DFO-9C9 and [ 89 Zr]Zr-DFO-4H11, were synthesized with high radiochemical purity and high molar activity, and tested via PET imaging and biodistribution studies in mice bearing subcutaneously xenografted SKOV3 c114  tumors. 
     8-10-week old nu/nu female mice were purchased from Charles River Laboratories. The animals were housed in ventilated cages, were given food and water ad libitum, and allowed to acclimatize for approximately 1 week prior to inoculation with tumor cells. SKOV3 c114  tumors were implanted on the right shoulder of each mouse via subcutaneous injection of 5×10 6  cells in a 150 μL cell suspension of a 1:1 mixture of fresh media/BD Matrigel (356234, BD Biosciences). Experiments were performed approximately 3 weeks following the injection of the SKOV3 c114  cells. To generate a bilateral tumor model, 5×10 6  SKOV3 cells were inoculated on the right shoulder followed two weeks later by the inoculation of 5×10 6  SKOV3 c114  cells on the left shoulder of 8-10-week old female nu/nu mice. 10×10 6  OVCAR3 cells were implanted in the right shoulder of 6-8-week old female nude mice. Seeds for HGSOC patient-derived xenografts were provided by the MSKCC anti-tumor assessment core and passaged and expanded as subcutaneous xenografts. 
     PET imaging experiments were conducted on an Inveon PET/CT scanner (Siemens Healthcare). Mice bearing subcutaneously xenografted SKOV3 c114  tumors on their right shoulders were administered the  89 Zr-labeled radioimmunoconjugate variants of the lead MUC16 carboxy-terminus binding antibodies (150-260 μCi; 5.55-9.62 MBq in 200 μL of chelexed PBS) via intravenous tail vein injection. Animals were anesthetized by inhalation of 2% isoflurane (Baxter Healthcare) and medical air gas mixture and placed on the scanner bed. PET data for each mouse were recorded via static scans at various time points after injection of the radioimmunoconjugates. Images were analyzed using ASIPro VM software (Concorde Microsystems). PET images of the bilateral tumor model were acquired using a mouse hotel in the Inveon PET/CT scanner, and the images were analyzed using AMIDE software. Briefly, the 3-dimensional ordered subset expectation maximization (3D OSEM) reconstructed images were calibrated for the injected dose of the tracer and smoothed using a Gaussian function by applying a full width at half maximum (FWHM) value of 1.5 prior to overlaying the PET and CT images. 
     Biodistribution studies were performed using  89 Zr-labeled variants of the lead MUC16 carboxy-terminus binding antibodies in female nude mice bearing subcutaneous xenografts of SKOV3 c114+  tumors. The mice were administered 21-30 μCi; 0.77-1.11 MBq of each radioimmunoconjugate suspended in 200 μL PBS via lateral tail vein injection. For the blocking arm, animals were co-injected with 50-fold excess of unlabeled antibody. Animals (n=4 per group) were euthanized by CO 2  asphyxiation to analyze biodistribution of the radioimmunoconjugates at various time points following injection in mice. Following euthanasia, vital organs such as the blood, heart, lungs, liver, spleen, stomach, pancreas, large intestine, small intestine, pancreas, reproductive organs inclusive of the ovary, fallopian tubes and uterus, kidneys, bone, muscle, tail, axillary lymph nodes, and the tumor(s) were harvested, weighed, and assayed for radioactivity on a gamma counter calibrated for  89 Zr. Counts were converted into activity using a calibration curve generated from known standards. Count data were background and decay corrected to the time of injection, and the percent injected dose per gram (% ID/g) for each tissue sample was calculated by normalization to the total activity injected per mouse. 
     Serial PET imaging of [ 89 Zr]Zr-DFO-9C9 ( FIG. 4A ) at 24 h intervals post injection (p.i.) of the radioimmunoconjugate delineated the subcutaneous tumor at 24 h, followed by a gradual accretion of activity in the tumor with progression of time up to 96 h p.i. [ 89 Zr]Zr-DFO-9C9 showed high radioactivity concentration in the liver as early as 24 h p.i., with an apparent wash out of signal from this tissue at later time points. Most notably, [ 89 Zr]Zr-DFO-9C9 displayed relatively high radioactivity concentration in the kidneys. This is an unexpected observation for full-length antibody-based radioimmunoconjugates, which have molecular weights that are above the renal filtration cut-off for clearance by the body. Additionally, the kidneys of mice are not known to express MUC16 or an analog of the MUC16 juxtamembrane carboxy-terminus domain to justify the presence of the antibody in this organ. Furthermore, the maximum intensity projection (MIP) images from longitudinal PET studies of mice injected with [ 89 Zr]Zr-DFO-9C9 indicate a gradual washout of activity from the kidneys between 24 h-96 h p.i. of the radioimmunoconjugate. Plausibly, the high radioactivity concentration in the liver and kidneys of mice at early time points may result from a combination of these organs being highly perfused and the slow in vivo pharmacokinetics of the 9C9 antibody. The persistence of activity in systemic circulation evidenced by PET signal in the heart and aortic arches seen in the MIP images at 72 and 96 h p.i. of [ 89 Zr]Zr-DFO-9C9 suggest a very slow in vivo pharmacokinetic profile for this antibody despite the presence of a target sink provided by the tumor. These in vivo observations corroborate the relatively slow in vitro cell uptake profile demonstrated by the 9C9 antibody in the preceding phase of this study. 
     On the other hand, serial PET imaging of [ 89 Zr]Zr-DFO-4H11 ( FIG. 2B ) at 24 h intervals after injection of the radioimmunoconjugate delineated the subcutaneous SKOV3 c114  tumor at 24 h p.i. A head-to-head comparison of the serial PET images of [ 89 Zr]Zr-DFO-9C9 versus [ 89 Zr]Zr-DFO-4H11 suggest that the radioactivity concentration of [ 89 Zr]Zr-DFO-4H11 in the SKOV3 c114  tumor at the earliest time point was higher than that of [ 89 Zr]Zr-DFO-9C9. [ 89 Zr]Zr-DFO-4H11 also showed uptake of radioactivity in the liver at 24 h p.i., however, the activity concentration in this organ decreased at later time points whilst the accretion of activity in the tumor progressively increased up to 96 h p.i. of the radioimmunoconjugate. In addition to the tumor (primary target sink for the antibody), and the liver (site of clearance for exogenous immunoglobulins), the MIP images for mice injected with [ 89 Zr]Zr-DFO-4H11 showed bilaterally symmetrical PET foci in the axillary lymph nodes. Apart from this anomaly, the in vivo radiopharmacologic profile of [ 89 Zr]Zr-DFO-4H11 was more favorable than its counterpart [ 89 Zr]Zr-DFO-9C9. [ 89 Zr]Zr-DFO-4H11 yielded high contrast PET images owing to a relatively rapid uptake in the SKOV3 c114  tumor as early as 24 h, and minimum activity left in the systemic circulation and background organs except the liver at later time points. 
     The observations from PET imaging were corroborated by independent biodistribution studies, wherein the tumor and organs of interest were harvested at 96 h p.i. of the radioimmunoconjugates in subcutaneous SKOV3 c114  xenografts ( FIG. 6C ). To validate the specificity of antibody binding and activity uptake in the tumor, a blockade arm was included in the in vivo biodistribution study of both the radioimmunoconjugates. Subcutaneous SKOV3 c114  xenografts were co-injected with a 50-fold excess (mass) of unlabeled 9C9 or 4H11 antibody to block the specific uptake of [ 89 Zr]Zr-DFO-9C9 and [ 89 Zr]Zr-DFO-4H11 respectively. Whilst target-mediated uptake of the radioimmunoconjugate and its associated activity is expected to decrease, the activity concentration in tissues displaying non-specific uptake is expected to remain unchanged. However, the efficient blockade of target-mediated specific uptake of the radioimmunoconjugate in the tumor may often manifest as slightly increased activity concentrations in well-perfused non-target background organs including the heart, lungs, liver, spleen and kidneys. This may be attributed to a substantial amount of the radioimmunoconjugate persisting in systemic circulation due to blockade of the target-rich sink provided by the tumor. 
     In sum, the biodistribution profiles of [ 89 Zr]Zr-DFO-9C9 and [ 89 Zr]Zr-DFO-4H11 were consistent with the PET imaging profiles for both radioimmunoconjugates. The uptake of activity in most non-target background organs barring a few case-specific exceptions noted in PET imaging studies was comparable and low (≤5% ID/g). Specifically, [ 89 Zr]Zr-DFO-9C9 showed high activity concentration (11.2±2.35% ID/g) in the kidneys, which was significantly higher than the uptake of [ 89 Zr]Zr-DFO-4H11 (4.3±1.00% ID/g; p-value=0.0016) and [ 89 Zr]Zr-DFO-Isotype IgG (4.9±0.57% ID/g; p-value=0.002) in this organ. SKOV3 c114  xenografts co-injected with 50-fold excess of unlabeled 9C9 antibody did not show a blockade in the uptake of activity from [ 89 Zr]Zr-DFO-9C9 in the kidneys (13.3±2.64% ID/g), suggesting that the uptake of activity in this organ may be non-specific. 
     Intriguingly, unlike PET images, comparative biodistribution studies confirmed that the radioactivity concentrations in the liver of SKOV3 c114  xenografts at 96 h p.i. were not significantly different between the two MUC16-targeting radioimmunoconjugates (9.1±2.49% ID/g for [ 89 Zr]Zr-DFO-9C9 versus 6.3±1.41% ID/g for [ 89 Zr]Zr-DFO-4H11; p-value=0.099) or the isotype IgG (6.4±1.02% ID/g; p-value=0.091). Despite the elevated concentration of activity (11.5±2.80% ID/g) in the axillary lymph nodes of SKOV3 c114  xenografts injected with [ 89 Zr]Zr-DFO-4H11 versus [ 89 Zr]Zr-DFO-9C9 (4.2±0.48% ID/g; p-value=0.002) or isotype IgG (3.4±0.40% ID/g; p-value=0.001), the uptake in these tissues was non-specific since it could not be blocked (13.2±2.72% ID/g p-value=0.43) in mice co-injected with a 50-fold excess of the unlabeled 4H11 antibody. Additional histopathologic analysis of H&amp;E stained sections of harvested PET- and biodistribution-positive lymph nodes from SKOV3 c114  xenografts injected with [ 89 Zr]Zr-DFO-4H11 did not reveal presence of neoplastic cells. Finally, the tumoral uptake of [ 89 Zr]Zr-DFO-9C9 (18.7±2.37% ID/g) and [ 89 Zr]Zr-DFO-4H11 (17.4±2.51% ID/g) was comparable and significantly higher than isotype IgG (4.7±0.42% ID/g; p-values=0.00002 and 0.00006 respectively). Furthermore, the tumoral uptake of [ 89 Zr]Zr-DFO-9C9 and [ 89 Zr]Zr-DFO-4H11 could be blocked (6.8±1.81% ID/g and 7.4±2.18% ID/g) when the MUC16-targeted radioimmunoconjugates were co-injected with a 50-fold excess of their respective unlabeled variants ( FIG. 4C ). 
     Taken together, the results from in vitro studies and the in vivo evaluation using PET imaging and biodistribution studies to compare the tumor-to-background organ uptake ratios of radioactivity associated with the two lead antibodies targeting the ectodomain of MUC16 in SKOV3 c114  ( FIG. 4D ) revealed [ 89 Zr]Zr-DFO-4H11 to yield a relatively better in vivo radiopharmacologic profile. These findings lend credibility to the clinical utility of the murine variant of the 4H11 antibody, which previously demonstrated excellent performance in immunohistochemical staining of formalin-fixed paraffin embedded surgical specimens obtained from HGSOC and lobular breast cancer patients. 
     Example 3: Humanized 4H11 Antibody 
     Murine 4H11 was humanized to ensure a minimum compromise to the binding affinity of the humanized variant for MUC16″. The sequence for the humanized heavy chain is provided as SEQ ID NO: 4, and the sequence for the humanized light chain is provided as SEQ ID NO: 2. To validate the retention of in vitro target binding ability and in vivo pharmacologic profile in the preclinical setting, the humanized variant of 4H11 (“hereafter referred to as hu4H11”) was conjugated with DFO ( FIG. 5A ) as previously described for the murine variant. MALDI-ToF analysis of the immunoconjugate revealed ˜1 DFO conjugated per antibody. Prior to radiolabeling, the DFO-immunoconjugate was tested for target binding via flow cytometry using SKOV3 c114  cells versus SKOV3 cells. 
     A shift in the fluorescence peak to the right on the X-axis of the histogram indicated positive binding of DFO-hu4H11 immunoconjugate to SKOV3 c114  cells, whereas the lack of a shift in fluorescence peak compared to unstained cells and cells stained with secondary antibody alone indicated an absence of binding to SKOV3 (wt) cells ( FIG. 5B ). Notably, the SKOV3 (wt) cell line is more representative of ovarian clear cell carcinomas, an OvCa subtype which is not known to rely on the expression of MUC16. Moving on, the radiolabeling of DFO-hu4H11 with  89 Zr consistently afforded high radiochemical yield and purity of the radioimmunoconjugate with a molar activity of 23.6 MBq/nmol (n=9) ( FIGS. 5C-D ). The target-binding fraction of [ 89 Zr]Zr-DFO-hu4H11 was found to be 96±0.53% and the binding of the radioimmunoconjugate to biotinylated MUC16 peptide-2 captured on the streptavidin magnetic beads could be partially blocked in the presence of a huge excess of unlabeled 4H11 antibody in the bead based radioligand binding assay ( FIG. 5E ). 
     Having characterized in vitro target-binding ability, the hu4H11 immunoconjugate was tested further to evaluate its in vivo biodistribution and radiopharmacologic profile. Consistent with the in vivo profile displayed by its murine predecessor longitudinal PET imaging studies, hu4H11 was able to clearly delineate subcutaneously xenografted SKOV3 c114  tumors at early time points after injection of the radioimmunoconjugate ( FIG. 6A ). Although persistence of some activity in systemic circulation was observed at the intermediate time point of 72 h p.i., a vast majority of the injected activity was found in the tumor by 144 h p.i. Results from biodistribution studies concurred with the observations from PET images and showed a gradual accretion of activity in SKOV3 c114  tumors concomitant with a decrease in the background activity in the blood pool ( FIG. 6B ). The tumoral uptake of [ 89 Zr]Zr-DFO-hu4H11 was repressed in the blockade arm wherein mice were co-injected with a 40-fold excess (by mass) of unlabeled hu4H11 antibody and evaluated for in vivo biodistribution at 72 h p.i. (22.4±3.65 versus 14.3±1.50% ID/g; p-value=0.006). Unlike its murine predecessor, [ 89 Zr]Zr-DFO-hu4H11 did not show PET-positive axillary lymph nodes in the SKOV3 c114  xenografts. However, harvesting the bilateral axillary lymph nodes in biodistribution studies revealed activity concentrations ranging between 7.9±1.23% ID/g at 36 h p.i.—10.3±4.04% ID/g at 144 h p.i. Notably, the absence of repressed radioactivity concentration in the axillary lymph nodes at 72 h p.i. of mice in the blockade arm suggested that the uptake in this tissue may be non-specific. As a radiotracer, [ 89 Zr]Zr-DFO-hu4H11 demonstrated excellent tumor-to-background organ ratios ( FIG. 6C ). Such a favorable in vivo profile bodes well for the future development of hu4H11-based drugs including radiopharmaceuticals for immunoPET and targeted radiotherapy. 
     Further examination of the in vivo specificity of [ 89 Zr]Zr-DFO-hu4H11 binding to MUC16 carboxy-terminus expressing cells was performed in a bilateral tumor model wherein SKOV3 c114  cells were implanted on the left shoulder of nu/nu mice versus SKOV3 tumors implanted on the right shoulder. [ 89 Zr]Zr-DFO-hu4H11 demonstrated excellent specificity for binding to the target expressed by SKOV3 c114  cells as shown by the high tumoral uptake of radioactivity in this tumor versus minimum non-specific uptake in SKOV3 tumors ( FIG. 7A ). The latter is commonly attributed to in vivo enhanced permeability and retention of full-length antibody-based imaging agents in poorly vascularized solid tumor tissue. 
     Ex vivo analysis of the bilateral tumors from mice injected with [ 89 Zr]Zr-DFO-hu4H11 revealed focal accumulation of radioactivity in the perivascular spaces of the MUC16 carboxy-terminus-expressing SKOV3 c114  tumor and regions rich in healthy tumor cells ( FIGS. 7B and 7C ; dashed circle). On the other hand, necrotic regions ( FIGS. 7B and 7C ; dashed triangle) of the SKOV3 c114  tumor revealed an absence of radioactivity. Consistent with the PET images of [ 89 Zr]Zr-DFO-hu4H11 in the bilateral tumor model, the target-negative SKOV3 tumors showed minimal accumulation of radioactivity ( FIG. 7B ). Histopathologic analysis via H&amp;E staining of the bilateral tumors revealed SKOV3 c114  tumors bearing an architecture and morphologic features that were remarkably distinct from the typical cellular morphology of a clear cytoplasm, which is characteristic of SKOV3 cells, a cell line representative of ovarian clear cell carcinoma ( FIG. 7D ). Previous reports have shown that expression of the carboxy-terminus domain of MUC16 in NIH/3T3 cells induces transformation and potentiates metastatic properties in this cell line, whereas ectopic expression of the carboxy-terminus domain in SKOV3 cells increased in vitro cell motility and invasiveness and in vivo tumorigenicity. 
     To test the utility of the 4H11-based radiotracer in a model that is not artificially overexpressing the MUC16 peptide-2, we developed a subcutaneous xenograft model using OVCAR3 cells, which is a representative cell line for HGSOC and naturally expresses copious amounts of MUC16. PET images of [ 89 Zr]Zr-DFO-hu4H11 in this model demonstrated high radioactivity concentration in the OVCAR3 tumor at the intermediate time point of 72 h p.i. ( FIG. 8A ). Finally, to explore the feasibility and demonstrate a proof-of-concept for using [ 89 Zr]Zr-DFO-hu4H11 as an immunoPET agent in the clinic, we used a patient-derived xenograft (PDX) model representative of HGSOC. PET images of [ 89 Zr]Zr-DFO-hu4H11 in this model revealed high radioactivity concentrations in the PDX tumors at 72 h p.i. Notably, the PET images from the OVCAR3 as well as PDX model revealed background activity persisting in the blood pool (BP) inclusive of the heart and descending aorta of mice. This is consistent with observations from previous experiments with the humanized 4H11 antibody ( FIGS. 5-7 ) and appears to be a phenomenon that is independent of the target sink volume provided by the tumor(s). The persistence of activity in systemic circulation may indicate a characteristic feature of the pharmacokinetics and biological half-life of an antibody in vivo. 
     The study highlighted the utility of radiopharmacologic screening to identify the best candidate during the development of antibody-based drugs. Despite the evolution of several nuclear and label-free biophysical and biochemical methods of analyses to characterize key features of antibodies including their binding affinity and rates of cellular internalization, these techniques remain limited in their ability to predict or characterize the in vivo behavior of lead antibody candidates. The results derived from in vitro radiometric assays can be used in combination with in vivo radiopharmacologic profiles revealed by non-invasive nuclear imaging and biodistribution studies as a strategy that can better screen and characterize lead antibody candidates. Radiopharmacologic screening offers the unique benefit of visualization, traceability and quantitative evaluation of the in vivo pharmacokinetics of antibodies, all of which can be achieved with high sensitivity despite microdosing. Having this information can contribute to a better understanding and characterization of the accessibility and engagement of an antibody with its cognate target to define its potency as a drug while simultaneously outlining any anomalous interactions it may have with non-target organs that may lead to potential toxicities. 
     Example 4: Surface Plasmon Resonance (SPR) Characterization of Humanized 41111 Antibodies 
     The relative binding affinities of 4H11 humanized antibodies (H1L1, H1L2, H2L1, H2L2) were compared by surface plasmon resonance using a BIACore-X100 instrument with a Biotin CAP Chip (GE Healthcare). The assay format consisted of capturing the biotinylated MUC16 peptide-2 (TLDRSSVLVDGYSPNRNE; SEQ ID NO: 52) onto a streptavidin coated sensor and flowing over the antibody at various concentrations using single cycle kinetics. Ligand capture was performed by flowing 0.5 μg/ml of biotinylated MUC16 peptide-2 at a rate of 5 μl per minute for 65 seconds. The 4H11 humanized antibodies were then flowed over at the various test concentrations (150 nM, 75 nM, 37.5 nM, 18.8 nM, and 9.4 nM). The assay conditions used for measuring the effects of the added antibodies were as follows: association time of 2 minutes, disassociation time of 10 min, and a flow rate of 30 μl per minute. 
     The relative binding affinities of all 4 antibodies were comparable with 1-3 nM K D  (Table 5). The sensorgram for mouse IgG 4H11 showed similar trend as humanized antibodies (not shown). However, stickiness was observed for kinetic off-step, especially at high concentration. 
     
       
         
           
               
             
               
                 TABLE 5 
               
             
            
               
                   
               
               
                 Binding Parameters of 4H11 antibodies 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                 k a   
                 k d   
                 K D   
               
               
                   
                 Antibody 
                 [1/Ms] 
                 [1/s] 
                 (nM) 
               
               
                   
                   
               
               
                   
                 4H11-H1L1 hIgG 
                 9.27 × 10 4   
                 1.46 × 10 −4   
                 1.57 
               
               
                   
                 4H11-H1L2 hIgG 
                 9.04 × 10 4   
                 1.98 × 10 −4   
                 2.19 
               
               
                   
                 4H11-H2L1 hIgG 
                 7.61 × 10 4   
                 1.01 × 10 −4   
                 1.33 
               
               
                   
                 4H11-H2L2 hIgG 
                 7.38 × 10 4   
                 1.75 × 10 −4   
                 2.37 
               
               
                   
                   
               
            
           
         
       
     
     Example 5: Surface Plasmon Resonance (SPR) Characterization of Humanized 18C6 Antibodies 
     The relative binding affinities of 18C6 humanized antibodies (H1L1, H1L2, H2L1, H2L2) were compared by surface plasmon resonance using a BIACore-X100 instrument with a CMS Chip (GE Healthcare). The assay format consisted of capturing the four humanized antibodies H1L1, H1L2, H2L1, H2L2 on a CMS chip coated with anti-mouse IgG or parental mouse 18C6 IgG on a CMS chip coated with anti-human IgG under near saturating conditions and flowing the MUC16 peptide-2 glycopeptide (TLDRSSVLVDGYSPNRNE; SEQ ID NO: 52) over at various concentrations. 
     Ligand capture was performed by flowing the humanized anti-Muc16 antibodies 18C6 H1L1, 18C6 H1L2, 18C6 H2L1, 18C6 H2L2) and the parental 18C6 mouse antibody onto the respective chips under saturating conditions. The MUC16 peptide-2 was then flowed over at the various test concentrations (150 nM, 75 nM, 37.5 nM, 18.8 nM, and 9.4 nM). The assay conditions used for measuring the effects of the glycopeptide were as follows: association time of 2 minutes, disassociation time of 10 min, and a flow rate of 30 μl per minute. 
     The relative binding affinities of all 4 antibodies tested were comparable with each other and similar to parental 18C6 mouse antibody (Table 6). 
     
       
         
           
               
             
               
                 TABLE 6 
               
             
            
               
                   
               
               
                 Binding Parameters of 18C6 antibodies 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                 k a   
                 k d   
                 K D   
               
               
                   
                 Antibody 
                 [1/MS] 
                 [1/s] 
                 (nM) 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 18C6 parental  
                 4.85 × 10 5   
                 6.8 × 10 −3   
                 14.1 
               
               
                   
                 mouse IgG 
                   
                   
                   
               
               
                   
                 18C6 H1L1 
                 2.87 × 10 5   
                 1.9 × 10 −3   
                 6.7 
               
               
                   
                 18C6 H1L2 
                 2.87 × 10 5   
                 2.5 × 10 −3   
                 8.7 
               
               
                   
                 18C6 H2L1 
                 5.49 × 10 5   
                 5.4 × 10 −3   
                 9.9 
               
               
                   
                 18C6 H2L2 
                 4.33 × 10 5   
                 4.0 × 10 −3   
                 9.2 
               
               
                   
                   
               
            
           
         
       
     
     Example 6: Characterization of Humanized 4H11 and 18C6 Antibodies by Fluorescence Activated Cell Sorting Analysis 
     In this example the ability of the antibodies to bind to MUC16-positive cells (OVCAR3) or cells expressing MUC16 peptides (SKOV3 and A2780 transfectants) was assessed. 
     OVCAR3, SKOV3, and A2780 cell lines were obtained through the American Type Culture Collection (ATCC, Manassas, Va.) and sustained in culture according the supplier&#39;s instructions. MUC16 expressing cell lines were created by transfecting MUC16-negative human ovarian cancer cell lines (SKOV3 and A2780) with the sequence elements of the C-terminal MUC16, which are essential for tumor promoting effects, using the Vitality phrGFP vector expression system, which generates green fluorescent protein fusion proteins (Stratagene, LaJolla, Calif.). (A2780-phrGFP-MUC16c344 and SKOV3-phrGFP-MUC16c344). Stable cell lines were selected using geneticin (G418, Invitrogen, Grand Island, N.Y.) in their respective culture media and isolated by expression of Green Fluorescence Protein. Stable transfectants were routinely maintained in G418 in their culture media, respectively. The ΔMUC16c114 transfectants have cell surface expression of MUC16 protein from the putative cleavage site to the carboxy terminus (amino acids 1776 to 1890). The ΔMUC16c344 transfectants have cell surface expression of MUC16 protein from amino acid 1547 to the carboxy terminus (amino acid 1890). 
     Adherent target cells were removed by 0.05% Trypsin and 0.1% EDTA, washed, and counted by a hemocytometer. Cells were distributed into multiple Eppendorf tubes with at least 0.5-1×10 6  cells per tube. Cells were washed with phosphate buffered saline (PBS) containing 1% FCS and 0.025% Sodium Azide (FACS buffer). For internal FACS staining, cells in the Eppendorf tubes were permeabilized with 1:10 diluted FACS Permeabilizing Solution 2 (BD BioSciences, San Jose, Calif.) for 10 minutes at room temperature and then washed twice with ice cold FACS buffer. For surface FACS staining, cells were incubated either without or with 1 mg/tube of 4H11 or 18C6 mouse mAbs or 4H11 or 18C6 humanized antibodies conjugated to Alex Fluor 647 for 30 minutes on ice. All cells were washed 3 times with FACS buffer. Cells labeled with the 4H11 or 18C6 mouse mAbs were further incubated with 1 mg/tube of second antibody Goat anti-mouse IgG2b-PE (phycoerythrin) for 30 minutes on ice and then washed 3 times with FACS buffer. The cells were analyzed by a FACS Calibur machine. Data for mean PE fluorescence and percentage PE positive cells for the 4H11 or 18C6 mouse mAbs assay are shown in  FIGS. 9A and 9B . Data for mean Alexa-647 fluorescence and percentage Alexa-647 positive cells for the 4H11 or 18C6 humanized antibody assay are shown in  FIGS. 9C and 9D . Data is shown for the H1L2 humanized 4H11 antibody and the H1L1 humanized 18C6 antibody. 
     In a separate experiment, full-length humanized 4H11 antibodies (IgG1-Fc) comprising different combinations of humanized heavy and light chain variable regions of the 4H11 antibody were assayed. An anti-human IgG1-Fc-PE antibody was employed for fluorescent staining of MUC16-positive OVCAR3 or SKOV3 transfectant cells expressing MUC16 peptides.  FIGS. 10A and 10B  provide data for mean PE fluorescence and percentage PE positive cells for the 4H11 H1L1, H1L2, H2L1 and H2L2 antibodies assayed. 
     Amino acid sequences for the 4H11 L1, L2, H1, and H2, variable regions are provided herein as SEQ ID NOS: 2, 3, 4, and 5, respectively. Amino acid sequences for the 18C6 L1, L2, H1, and H2, variable regions are provided herein as SEQ ID NOS: 20, 21, 22, and 23, respectively. 
     Example 7: Characterization of Humanized 4H11 and 18C6 Antibodies by Matrigel Invasion Assay 
     Antibody inhibition of basement membrane invasion was determined in Matrigel invasion chambers as previously described by Rao, et al. (2017)  ACS Chem. Biol.  12 (8): 2085-2096, which is incorporated by reference in its entirety. SKOV3 cell lines expressing the C-terminal portions of MUC16 necessary for invasion were generated as described above. The transfected cells as well as wild type MUC16 expressing ovarian cancer cells (OVCAR3, OVCA-433 and CAOV3) were pretreated without or with full-length humanized 4H11 antibodies (IgG1-Fc) comprising different combinations of humanized heavy and light chain variable regions of the 4H11 antibody prior to exposure to the Matrigel invasion chambers. The number of invading cells was counted.  FIG. 11  shows exemplary data for the MUC16-positive OVCAR, VCA-433 and CAOV3 cell lines, and  FIG. 12  shows exemplary data for the MUC16-expressing SKOV3 cell lines and parent SKOV3 cell line. A SKOV3 cell line expressing the mutant MUC16 peptide N123mut c114 was employed as a negative control for invasion. 
     Example 8: Generation of Anti-MUC16 Bispecific Antibodies 
     This example describes the generation of anti-MUC16 bi-specific antibodies (BsAbs) from the humanized 4H11 and 18C6 anti-MUC16 scFvs. A single-chain BsAb comprising anti-MUC16 scFv at the N-terminal end and an anti-human CD3ε scFv of a mouse monoclonal antibody at the C-terminal end is generated. A 4H11 anti-MUC16 BsAb and an 18C6 anti-MUC16 BsAb are generated by cloning DNA fragments encoding the anti-MUC16 scFv and the anti-human CD3ε scFv antibody derived from parental clone L2K into an expression vector using standard DNA technology. A hexahistidine (His) tag (SEQ ID NO: 41) is inserted downstream of the anti-MUC16 BsAb at the C-terminal end for antibody purification and detection. Sequences for exemplary 4H11 anti-MUC16 BsAbs are provided in SEQ ID NOS: 44 or 180, 69-71 and 88-91. Sequences for exemplary 18C6 anti-MUC16 BsAbs are provided in SEQ ID NOS: 72-75 and 92-95. 
     Chinese hamster ovary (CHO) cells are transfected with the anti-MUC16 BsAb expression vector and stable expression is achieved by standard drug selection with methionine sulfoximine (MSX), a glutamine synthetase (GS)-based method (Fan, et al.,  Biotechnology Bioengineering.  109 (4), 1007-1005 (2012)). CHO cell supernatants containing secreted anti-MUC16 BsAb molecules are collected. Anti-MUC16 BsAbs are purified using HisTrap HP column (GE healthcare) by FPLC AKTA system. Briefly, CHO cell culture is clarified and loaded onto the column with low imidazole concentration (20 mM), and then an isocratic high imidazole concentration elution buffer (500 mM) is used to elute the bound anti-MUC16 bi-specific antibody protein. The bands for the BsAbs are observed by SDS-PAGE, indicating that the BsAbs are successfully purified. 
     Example 9: Anti-MUC16 BsAb—MUC16+ Cell Specificity 
     In this example, the specificity of the 4H11 and 18C6 anti-MUC16 BsAbs for binding to cancer cells that express MUC16 is assessed. In one study, two target cell lines are employed, a MUC16 +  OVCAR3 cell line and a MUC16 −  SKOV3 cell line. OVCAR3 and SKOV3 cell lines are obtained through the American Type Culture Collection (ATCC, Manassas, Va.) and sustained in culture according to the ATCC literature. FACS analysis of anti-MUC16 antibody binding to the two target cell lines is performed to confirm that antibody binding is observed only with the MUC16+ OVCAR3 cell line. SKOV3 or OVCAR3 cell lines are incubated with the anti-MUC16 Ab followed by a secondary antibody or with a secondary antibody alone as a control. The MUC16+ OVCAR3 cell line are expected to exhibit an increase in binding over the control cells while SKOV3 exhibit low or no signal. 
     Example 10: Anti-MUC16 BsAb—Directed Cell Cytotoxicity 
     In this example, the ability of the 4H11 and 18C6 anti-MUC16 BsAbs to induce MUC16-specific cell toxicity is assessed. 4H11 anti-MUC16 BsAb and 18C6 anti-MUC16 BsAb are incubated at a concentration of about 0.2 μg/ml with either the MUC16 +  OVCAR3 target cell line or the MUC16 −  SKOV3 target cell line and human activated T cells at an effector: target (E:T) ratio of 5:1 for 16 hours. The cytotoxicity is measured by lactate dehydrogenase (LDH) release assay. The BsAbs are expected to be able to induce cell lysis of OVCAR3 cells, while cell lysis of SKOV3 is expected to be minimal, indicating that the MUC16 +  target specificity is required for the T cell activation. The experiment demonstrates that the 4H11 and 18C6 anti-MUC16 BsAbs can induce potent and specific killing of a MUC16 +  cancer cell line. 
     Example 11: Therapy of Human MUC16 +  Metastatic Ovarian Cancer in NSG Mice 
     In this example, the in vivo therapeutic efficacy of the 4H11 and 18C6 anti-MUC16 BsAbs in a mouse xenograft model of metastatic ovarian cancer is assessed. Female NSG mice between 6-8 weeks old are injected on day 0 (DO) intraperitoneally (i.p.) with 3×10 6  SKOV3-MUC-CD tumor cells that are modified to express MUC16-C114 and GFP-LUC. These mice are then treated intravenously (i.v.) with 1×10 7  human T cells on day 7 (D7) and i.p with 5 μg of the 4H11 or 18C6 anti-MUC16 BsAb. Additional treatments with 5 μg of the BsAb were administered i.p. on D9, D11, D14, D16, and D18 for a total of six BsAb treatments. Animals are imaged on D14, D21, D28, and D42. 
     Animals treated with the anti-MUC16 BsAb are expected to exhibit delayed disease progression compared to untreated mice or mice treated with T-cells alone. Treatment with the anti-MUC16 BsAb is expected to significantly prolong survival in tumor-bearing mice compared to T-cell-only therapy or no treatment. Tumor-bearing mice treated with T-cells and anti-MUC16 BsAbs are expected to show significantly elevated levels of systemic IL-2 and IFN-γ 7 days after treatment indicating an induction of an anti-tumor immune response. These results demonstrate that administration of anti-MUC16 BsAb delays disease progression and improves survival in a xenogeneic model of MUC16+ metastatic ovarian cancer. 
     Example 12: Generation of Anti-MUC16 Chimeric Antigen Receptors (CAR) 
     This example describes the generation of anti-MUC16 Chimeric Antigen Receptors (CARs) from humanized 4H11 and 18C6 anti-MUC16 scFvs. CAR T cells expressing CARs comprising anti-CD19 scFvs have previously been made using standard recombinant techniques and initial publications on the methods to create them and to characterize their activity are described (Brentjens et al.,  Sci. Trans. Med.  5(177):177ra38 (2013), Pegram et al.  Leukemia  29(2):415-22 (2015)). The 4H11 and 18C6 anti-MUC16 CAR T cell will be made and characterized similarly. 
     The 4H11 and 18C6 anti-MUC16 scFv sequences (e.g., scFv sequences comprising any one of SEQ ID NOS: 53-56 or 61-64 (4H11) and 57-60 or 65-68 (18C6)) are utilized to generate the antigen binding domain of the CARs. The variable heavy and light chains of the scFv are connected via a (Gly4Ser) 3  linker (SEQ ID NO: 179). A leader peptide (e.g., a CD8 signal sequence; e.g., SEQ ID NO: 76) is added to the N-terminus of the scFv for localization. In alternative embodiments, a c-Myc tag can be added to allow detection of the CAR by flow cytometry. A CD8 transmembrane domain (e.g., SEQ ID NO: 77) follows the antigen binding domain. On the cytoplasmic side of the CAR, 4-1BB (e.g., SEQ ID NO: 78) is used as a costimulatory element due to the increased persistence of 4-1BB CAR T cells (Oka et al.  PNAS.  101:13885-90 (2004)). The CAR can be optimized to include a spacer domain upstream of the CD8 transmembrane domain if desired. The nucleic acid encoding the CAR can be cloned into an SFG retroviral vector containing the 4-1BB signaling (e.g., SEQ ID NO: 78) and CD3ζ activation domains (e.g., SEQ ID NO: 79), forming a second generation CAR (Brentjens et al.  Clin Cancer Res.  13(18 Pt 1):5426-35 (2007)). A clinical grade construct, without the c-Myc tag, can also be generated, for which an anti-idiotype mAb to allow detection of the CAR, can be generated. 
     Stable HEK293T viral producing cell lines are generated, subcloned and used to transduce primary human T cells as described previously (Curran et al.  American Society of Gene Therapy  23(4):769-78 (2015)). Following transduction, CAR expression is verified by flow cytometry, using an anti-idiotype antibody to detect the anti-MUC16 scFv. 
     Example 13: Characterization of Anti-MUC16 Chimeric Antigen Receptors (CAR) 
     In this example, the ability of CART cells expressing a CAR comprising a 4H11 or 18C6 anti-MUC16 scFv to induce MUC16-specific cell toxicity is assessed. Activated 4H11 anti-MUC16 CART cells or 18C6 anti-MUC16 CART cells are incubated with either the MUC16 +  OVCAR3 target cell line or the MUC16 −  SKOV3 target cell line at an effector: target (E:T) ratio of 5:1 for 16 hours. The cytotoxicity is measured by lactate dehydrogenase (LDH) release assay. The 4H11 anti-MUC16 CART cells or 18C6 anti-MUC16 CART cells are expected to be able to induce cell lysis of OVCAR3 cells, while cell lysis of SKOV3 is expected to be minimal, indicating that the MUC16 +  target specificity is required for the T cell activation. The experiment demonstrates that the 4H11 anti-MUC16 CART cells or 18C6 anti-MUC16 CART cells can induce potent and specific killing of a MUC16 +  cancer cell line. 
     Example 14: Therapy of Human MUC16 +  Metastatic Ovarian Cancer in NSG Mice 
     In this example, the in vivo therapeutic efficacy of CART cells expressing a CAR comprising a 4H11 or 18C6 anti-MUC16 scFv in a mouse xenograft model of metastatic ovarian cancer is assessed. Female NSG mice between 6-8 weeks old are injected on day 0 (DO) intraperitoneally (i.p.) with 3×10 6  SKOV3-MUC-CD tumor cells that are modified to express MUC16-C114 and GFP-LUC. These mice are then treated intravenously (i.v.) with 1×10 7  4H11 anti-MUC16 CART cells or 18C6 anti-MUC16 CART cells or control T-cells. Additional treatments with of the 4H11 anti-MUC16 CART cells or 18C6 anti-MUC16 CART cells can be administered intravenously at subsequence interval for multiple treatments. Animals are imaged on D14, D21, D28, and D42. 
     Animals treated with the 4H11 anti-MUC16 CART cells or 18C6 anti-MUC16 CART cells are expected to exhibit delayed disease progression compared to untreated mice or mice treated with control T-cells. Treatment with the 4H11 anti-MUC16 CART cells or 18C6 anti-MUC16 CART cells is expected to significantly prolong survival in tumor-bearing mice compared to T-cell-only therapy or no treatment. Tumor-bearing mice treated with 4H11 anti-MUC16 CART cells or 18C6 anti-MUC16 CART cells are expected to show significantly elevated levels of systemic IL-2 and IFN-γ 7 days after treatment indicating an induction of an anti-tumor immune response. These results demonstrate that administration of 4H11 anti-MUC16 CART cells or 18C6 anti-MUC16 CART cells delays disease progression and improves survival in a xenogeneic model of MUC16+ metastatic ovarian cancer. 
     EXEMPLARY EMBODIMENTS 
     The present disclosure may be described in terms of the following non-limiting embodiments: 
     Embodiment 1: The present application in one aspect provides an anti-mucin 16 (MUC16) construct comprising an antibody moiety that immunospecifically recognizes a mucin 16 (MUC16) polypeptide. In some embodiments, the antibody moiety comprises: (a) (i) a variable heavy (VH) chain comprising a heavy chain complementarity determining region 1 (HC-CDR1), HC-CDR2, and HC-CDR3 of SEQ ID NOS: 17, 18, and 19, respectively, and a heavy chain framework region 1 (HC-FW1), HC-FW2, and HC-FW3 of SEQ ID NOS: 136, 137, and 138, respectively, wherein one or more amino acids selected from amino acid positions 1, 3, 5, 11 and 19 of SEQ ID NO: 136, amino acid positions 5, 7, 8, and 9 of SEQ ID NO: 137, and amino acid positions 12, 14, 18, 22, and 23 of SEQ ID NO: 138 is humanized relative to a mouse HC-FW1, HC-FW2, and HC-FW3 of SEQ ID NOS: 124, 125, and 126, respectively; and (ii) a variable light (VL) chain comprising a light chain complementarity determining region 1 (LC-CDR1), LC-CDR2, and LC-CDR3 of SEQ ID NOS: 14, 15, and 16, respectively, and a light chain framework region 1 (LC-FW1), LC-FW2, LC-FW3, and LC-FW4 of SEQ ID NOS: 120, 121, 122, and 123, respectively, wherein one or more amino acids selected from positions 3, 9, 15, 18, and 22 of SEQ ID NO: 120, amino acid positions 7 and 27 of SEQ ID NO: 122, and amino acid positions 3 and 9 of SEQ ID NO: 123, is humanized relative to a mouse LC-FW1, LC-FW2, LC-FW3, and LC-FW4 of SEQ ID NOS: 104, 105, 106 and 107, respectively; or (b) (i) a variable heavy (VH) chain comprising SEQ ID NO: 4 or 5; and (ii) a variable light (VL) chain comprising SEQ ID NO: 2 or 3; or (c) (i) a variable heavy (VH) chain comprising a heavy chain complementarity determining region 1 (HC-CDR1), HC-CDR2, and HC-CDR3 of SEQ ID NOS: 35, 36, and 37, respectively, and a heavy chain framework region 1 (HC-FW1), HC-FW2, HC-FW3, and HC-FW4 of SEQ ID NOS: 175, 176, 177 and 178, respectively, wherein one or more amino acids selected from amino acid positions 10, 11, 12, 13, 15, 19, and 23 of SEQ ID NO: 175, amino acid positions 5, 14, 16, 18, 22, and 23 of SEQ ID NO: 177, and amino acid position 6 of SEQ ID NO: 178 is humanized relative to a mouse HC-FW1, HC-FW2, HC-FW3, and HC-FW4 of SEQ ID NOS: 159, 160, 161, and 162, respectively; and (ii) a variable light (VL) chain comprising a light chain complementarity determining region 1 (LC-CDR1), LC-CDR2, and LC-CDR3 of SEQ ID NOS: 32, 33, and 34, respectively, and a light chain framework region 1 (LC-FW1), LC-FW2, LC-FW3, and LC-FW4 of SEQ ID NOS: 155, 156, 157, and 158, respectively, wherein one or more amino acids selected from positions 7, 9, 11, and 18 of SEQ ID NO: 155, amino acid position 5 of SEQ ID NO: 156, and amino acid positions 9 and 18 of SEQ ID NO: 157, is humanized relative to a mouse LC-FW1, LC-FW2, LC-FW3, and LC-FW4 of SEQ ID NOS: 139, 140, 141, and 142, respectively; or (d) (i) a variable heavy (VH) chain comprising SEQ ID NO: 22 or 23; and (ii) a variable light (VL) chain comprising SEQ ID NO: 20 or 21. 
     Embodiment 2: The anti-MUC16 construct of Embodiment 1, wherein HC-FW1 of (a)(i) comprises SEQ ID NO: 130; the HC-FW2 of (a)(i) comprises SEQ ID NO: 131; the HC-FW3 of (a)(i) comprises SEQ ID NO: 132; the LC-FW1 of (a)(ii) comprises SEQ ID NO: 112; the LC-FW2 of (a)(ii) comprises SEQ ID NO: 113; the LC-FW3 of (a)(ii) comprises SEQ ID NO: 114; and/or the LC-FW4 of (a)(ii) comprises SEQ ID NO: 115. 
     Embodiment 3: The anti-MUC16 construct of Embodiment 1, wherein the HC-FW1 of (a)(i) comprises SEQ ID NO: 130; the HC-FW2 of (a)(i) comprises SEQ ID NO: 131; the HC-FW3 of (a)(i) comprises SEQ ID NO: 132; the LC-FW1 of (a)(ii) comprises SEQ ID NO: 112; the LC-FW2 of (a)(ii) comprises SEQ ID NO: 113; the LC-FW3 of (a)(ii) comprises SEQ ID NO: 114; and the LC-FW4 of (a)(ii) comprises SEQ ID NO: 115. 
     Embodiment 4: The anti-MUC16 construct of Embodiment 1, wherein the HC-FW1 of (a)(i) comprises SEQ ID NO: 133; the HC-FW2 of (a)(i) comprises SEQ ID NO: 134; the HC-FW3 of (a)(i) comprises SEQ ID NO: 135; the LC-FW1 of (a)(ii) comprises SEQ ID NO: 116; the LC-FW2 of (a)(ii) comprises SEQ ID NO: 117; the LC-FW3 of (a)(ii) comprises SEQ ID NO: 118; and/or the LC-FW4 of (a)(ii) comprises SEQ ID NO: 119. 
     Embodiment 5: The anti-MUC16 construct of Embodiment 1, wherein the HC-FW1 of (a)(i) comprises SEQ ID NO: 133; the HC-FW2 of (a)(i) comprises SEQ ID NO: 134; the HC-FW3 of (a)(i) comprises SEQ ID NO: 135; the LC-FW1 of (a)(ii) comprises SEQ ID NO: 116; the LC-FW2 of (a)(ii) comprises SEQ ID NO: 117; the LC-FW3 of (a)(ii) comprises SEQ ID NO: 118; and the LC-FW4 of (a)(ii) comprises SEQ ID NO: 119 
     Embodiment 6: The anti-MUC16 construct of Embodiment 1, wherein the HC-FW1 of (c)(i) comprises SEQ ID NO: 167; the HC-FW2 of (c)(i) comprises SEQ ID NO: 168; the HC-FW3 of (c)(i) comprises SEQ ID NO: 169; the HC-FW4 of (c)(i) comprises SEQ ID NO: 170; the LC-FW1 of (c)(ii) comprises SEQ ID NO: 147; the LC-FW2 of (c)(ii) comprises SEQ ID NO: 148; the LC-FW3 of (c)(ii) comprises SEQ ID NO: 149; and/or the LC-FW4 of (c)(ii) comprises SEQ ID NO: 150. 
     Embodiment 7: The anti-MUC16 construct of Embodiment 1, wherein the HC-FW1 of (c)(i) comprises SEQ ID NO: 167; the HC-FW2 of (c)(i) comprises SEQ ID NO: 168; the HC-FW3 of (c)(i) comprises SEQ ID NO: 169; the HC-FW4 of (c)(i) comprises SEQ ID NO: 170; the LC-FW1 of (c)(ii) comprises SEQ ID NO: 147; the LC-FW2 of (c)(ii) comprises SEQ ID NO: 148; the LC-FW3 of (c)(ii) comprises SEQ ID NO: 149; and the LC-FW4 of (c)(ii) comprises SEQ ID NO: 150 
     Embodiment 8: The anti-MUC16 construct of Embodiment 1, the HC-FW1 of (c)(i) comprises SEQ ID NO: 171; the HC-FW2 of (c)(i) comprises SEQ ID NO: 172; the HC-FW3 of (c)(i) comprises SEQ ID NO: 173; the HC-FW4 of (c)(i) comprises SEQ ID NO: 174; the LC-FW1 of (c)(ii) comprises SEQ ID NO: 151; the LC-FW2 of (c)(ii) comprises SEQ ID NO: 152; the LC-FW3 of (c)(ii) comprises SEQ ID NO: 153; and/or the LC-FW4 of (c)(ii) comprises SEQ ID NO: 154. 
     Embodiment 9: The anti-MUC16 construct of Embodiment 1, wherein the HC-FW1 of (c)(i) comprises SEQ ID NO: 171; the HC-FW2 of (c)(i) comprises SEQ ID NO: 172; the HC-FW3 of (c)(i) comprises SEQ ID NO: 173; the HC-FW4 of (c)(i) comprises SEQ ID NO: 174; the LC-FW1 of (c)(ii) comprises SEQ ID NO: 151; the LC-FW2 of (c)(ii) comprises SEQ ID NO: 152; the LC-FW3 of (c)(ii) comprises SEQ ID NO: 153; and the LC-FW4 of (c)(ii) comprises SEQ ID NO: 154 
     Embodiment 10: The anti-MUC16 construct of any one of embodiments 1-7, wherein the antibody moiety immunospecifically binds to the ectodomain of MUC16. 
     Embodiment 11: The anti-MUC16 construct of any one of embodiments 1-9 wherein the MUC16 is a human MUC16. 
     Embodiment 12: The anti-MUC16 construct of any one of Embodiments 1-11, wherein the antibody moiety is a full-length antibody, a Fab, a Fab′, a F(ab′)2, an Fv, or a single chain Fv (scFv). 
     Embodiment 13: The anti-MUC16 construct of Embodiment 12, wherein the antibody moiety is a single chain Fv (scFv), and the scFv comprises any one of SEQ ID NOs: 53-68. 
     Embodiment 14: The anti-MUC16 construct of any one of Embodiments 1-13, wherein the VH chain and the VL chain are humanized VH chain and VL chain. 
     Embodiment 15: The anti-MUC16 construct of any one of Embodiments 1-14, wherein the antibody moiety immunospecifically binds to a MUC16 c114 polypeptide comprising the amino acid sequence of SEQ ID NO: 44 or 180. 
     Embodiment 16: The anti-MUC16 construct of any one of Embodiments 1-15, wherein the anti-MUC16 construct inhibits in vitro invasion of a tumor cell that expresses MUC16 in a Matrigel invasion assay. 
     Embodiment 17: The anti-MUC16 construct of Embodiment 16, wherein the tumor cell may include an ovarian tumor cell. 
     Embodiment 18: The anti-MUC16 construct of Embodiment 16 or 17, wherein the MUC16 may be glycosylated. 
     Embodiment 19: The anti-MUC16 construct of Embodiment 18, wherein the MUC16 is N-glycosylated at N24 or N30 relative to SEQ ID NO: 44 or 180. 
     Embodiment 20: The anti-MUC16 construct of any one of Embodiments 1-19, wherein the antibody moiety is a monoclonal antibody. 
     Embodiment 21: The anti-MUC16 construct of any one of Embodiments 1-20, wherein the antibody moiety comprises human-derived heavy and light chain constant regions. 
     Embodiment 22: The anti-MUC16 construct of Embodiment 21, wherein the heavy chain constant region has an isotype selected from the group consisting of gamma 1, gamma 2, gamma 3, and gamma 4. 
     Embodiment 23: The anti-MUC16 construct of any one of Embodiment 21 or 22, wherein the light chain constant region has an isotype selected from the group consisting of kappa and lambda. 
     Embodiment 24: The anti-MUC16 construct of any one of Embodiments 1-23, wherein the antibody moiety is an immunoglobulin comprising two identical heavy chains and two identical light chains. 
     Embodiment 25: The anti-MUC16 construct of Embodiment 24, wherein the immunoglobulin is an IgG. 
     Embodiment 26: The anti-MUC16 construct of any one of Embodiments 1-24, wherein the anti-MUC16 construct is monospecific. 
     Embodiment 27: The anti-MUC16 construct of any one of Embodiments 1-24, wherein the anti-MUC16 construct is multispecific. 
     Embodiment 28: The anti-MUC16 construct of any one of Embodiments 1-24, wherein the anti-MUC16 construct is multispecific. 
     Embodiment 29: The anti-MUC16 construct of Embodiment 21 or Embodiment 28, wherein the multispecific or bispecific anti-MUC16 construct further may comprise an anti-CD3 antibody moiety. 
     Embodiment 30: The anti-MUC16 construct of any one of Embodiments 1-24, wherein the anti-MUC16 construct is a tandem scFv, a diabody (db), a single chain diabody (scDb), a dual-affinity retargeting (DART) antibody, a F(ab′)2, a dual variable domain (DVD) antibody, a knob-into-hole (KiH) antibody, a dock and lock (DNL) antibody, a chemically cross-linked antibody, a heteromultimeric antibody, or a heteroconjugate antibody. 
     Embodiment 31: The anti-MUC16 construct of Embodiment 30, wherein the construct is a tandem scFv comprising two scFvs linked by a peptide linker. 
     Embodiment 32: The anti-MUC16 construct of any one of Embodiments 27-31, wherein the antibody moiety that immunospecifically recognizes MUC16 is a first antibody moiety, and wherein the anti-MUC16 construct further comprises a second antibody moiety that immunospecifically recognizes a second antigen. 
     Embodiment 33: The anti-MUC16 construct of Embodiment Error! Reference source not found., wherein the second antigen is an antigen on the surface of a T cell. 
     Embodiment 34: The anti-MUC16 construct of Embodiment 33, wherein the second antigen is a CD3. 
     Embodiment 35: The anti-MUC16 construct of Embodiment 34, wherein the second antigen is selected from the group consisting of CD3γ, CD3δ, CD3ε, and CD3ζ. 
     Embodiment 36: The anti-MUC16 construct of Embodiment 36, wherein the second antigen is CD3ε. 
     Embodiment 37: The anti-MUC16 construct of Embodiment 36, wherein the anti-MUC16 construct comprises any one of SEQ ID NOS: 42, 69-75, and 88-95. 
     Embodiment 38: The anti-MUC16 construct of any one of Embodiments 1-19, wherein the anti-MUC16 construct is a chimeric antigen receptor (CAR). 
     Embodiment 39: The anti-MUC16 construct of claim Error! Reference source not found., wherein the CAR comprises a co-stimulatory domain. 
     Embodiment 40: The anti-MUC16 construct of Embodiments 38 or 39, wherein the CAR comprises a CD3 zeta (ζ) chain cytoplasmic signaling domain. 
     Embodiment 41: The anti-MUC16 construct of any one of Embodiments 38-40, wherein the CAR comprises an scFv of any one of SEQ ID NOS: 53-68. 
     Embodiment 42: The anti-MUC16 construct of any one of Embodiments 38-41, wherein the CAR comprises any one of SEQ ID NOS: 80-87 and 97-103. 
     Embodiment 43: The anti-MUC16 construct of any one of Embodiments 1-42 wherein the anti-MUC16 construct is further conjugated to a peptide agent, a detection agent, an imaging agent, a therapeutic agent, or a cytotoxic agent. 
     Embodiment 44: A polypeptide comprising an amino acid sequence of one or more of SEQ ID NOs: 2-5, 10-13, 20-23 and 28-31, or an amino acid sequence of the anti-MUC16 construct of any one of Embodiments 1-43. 
     Embodiment 45: A polynucleotide comprising a nucleic acid sequence encoding one or more polypeptides of Embodiment 44. 
     Embodiment 46: A vector comprising the polynucleotide of Embodiment 45 operably linked to a promoter. 
     Embodiment 47: A cell comprising the anti-MUC16 construct of any one of Embodiments 1-43, the polypeptide of Embodiment 44, the polynucleotide of Embodiment 45, or the vector of Embodiment 46. 
     Embodiment 48: The cell of Embodiment 47, wherein the cell is a mammalian cell. 
     Embodiment 49: The cell of Embodiment 48, wherein the cell is an immune cell. 
     Embodiment 50: The cell of Embodiment 49, wherein the cell is a lymphocyte. 
     Embodiment 51: The cell of Embodiment 50, wherein the cell is a T cell or a B cell. 
     Embodiment 52: A pharmaceutical composition comprising: a therapeutically effective amount of the anti-MUC16 construct of any one of Embodiments 1-43, the polypeptide of Embodiments 31, the polynucleotide of Embodiment 45, the vector of Embodiment 46, or the cell of any one of Embodiments 47-51; and a pharmaceutically acceptable carrier. 
     Embodiment 53: A method of treating a MUC16-associated disease or disorder in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of the anti-MUC16 construct of any one of Embodiments 1-43 or the pharmaceutical composition of Embodiment 52. 
     Embodiment 54: The method of Embodiment 53, wherein said MUC16-associated disease or disorder is a cancer. 
     Embodiment 55: The method of Embodiment 41, wherein said cancer is a cancer of the ovary, lung, pancreas, breast, uterine, fallopian tube, or primary peritoneum. 
     Embodiment 56: The method of Embodiment 41 or 55, wherein said cancer is a metastatic cancer. 
     Embodiment 57: The method of any one of Embodiments 53-56, wherein the pharmaceutical composition inhibits or reduces metastasis in the patient. 
     Embodiment 58: The method of any one of Embodiments 53-57, wherein said patient is a human patient. 
     Embodiment 59: A method of producing an effector cell, comprising genetically modifying a cell with one or more nucleic acids encoding the anti-MUC16 construct of any one of Embodiments 1-43 or the polypeptide of Embodiment 44. 
     Embodiment 60: A method of treatment comprising introducing one or more nucleic acids encoding the anti-MUC16 construct of any one of Embodiments 1-43 or the polypeptide of Embodiment 44 into one or more primary cells isolated from a patient and administering cells comprising the one or more nucleic acids to the patient. 
     Embodiment 61: The method of Embodiment 60, further comprising expanding the cells prior to administering the cells to the patient. 
     Embodiment 62: The method Embodiment 60 or 61, wherein the primary cells are lymphocytes. 
     Embodiment 63: The method of Embodiment 62, wherein the primary cells are T cells. 
     Embodiment 64: The method of any one of Embodiments 53-63, wherein the method further comprises administering a therapeutically effective amount of an additional therapeutic agent to the patient. 
     Embodiment 65: The method of any one of claims Error! Reference source not found.-Error! Reference source not found., wherein the anti-MUC16 construct is the anti-MUC16 construct of any one of Embodiments 1-43. 
     Embodiment 66: A method of detecting MUC16 in a sample, comprising: (a) contacting the sample with the anti-MUC16 construct of any one of Embodiments 1-31; and (b) detecting the binding, directly or indirectly, between the anti-MUC16 construct and any MUC16 in the sample. 
     Embodiment 67: The method of Embodiment Error! Reference source not found., wherein the anti-MUC16 construct is conjugated to a detectable label. 
     Embodiment 68: The method of Embodiment Error! Reference source not found., wherein the detectable label is a chromogenic, enzymatic, radioisotopic, isotopic, fluorescent, toxic, chemiluminescent, nuclear magnetic resonance contrast agent. 
     Embodiment 69: The method of Embodiment 67 or 68, wherein the binding between the anti-MUC16 construct and any MUC16 in the sample is detected directly by detecting the detectable label. 
     Embodiment 70: The method of Embodiment 66, wherein the binding between the anti-MUC16 construct and any MUC16 in the sample is detected indirectly using a secondary antibody. 
     Embodiment 71: A method of diagnosing an individual suspected of having a MUC16-associated disease or disorder, comprising: a) administering an effective amount of the anti-MUC16 construct of any one of Embodiments 1-31 to the individual; and b) determining the level of the binding, directly or indirectly, between the anti-MUC16 construct and any MUC16 in the individual, wherein a level of the binding above a threshold level indicates that the individual has the MUC16-associated disease or disorder. 
     Embodiment 72: A method of diagnosing an individual suspected of having a MUC16-associated disease or disorder, comprising: a) contacting a sample comprising cells derived from the individual with the anti-MUC16 construct of any one of Embodiments 1-31; and b) determining the number of cells in the sample bound to the anti-MUC16 construct, wherein a value for the number of cells bound to the anti-MUC16 construct above a threshold level indicates that the individual has the MUC16-associated disease or disorder. 
     Embodiment 73: Use of the anti-MUC16 construct of any one of Embodiments 1-43, the polypeptide of Embodiment 44, the polynucleotide of Embodiment 45, the vector of Embodiment 46, or the cell of any one of Embodiments 47-51 for the treatment of a disease or disorder associated with positive MUC16 expression. 
     Embodiment 74: Use of the anti-MUC16 construct of any one of Embodiments 1-43, the polypeptide of Embodiment 44, the polynucleotide of Embodiment 45, the vector of Embodiment 46, or the cell of any one of Embodiments 47-51 in the manufacture of a medicament for the treatment of a disease or disorder associated with positive MUC16 expression. 
     Embodiment 75: Use of the anti-MUC16 construct of any one of Embodiments 1-31 for the diagnosis of a disease or disorder associated with positive MUC16 expression. 
     Embodiment 76: The use of any one of Embodiments 62-75, wherein the disease or disorder associated with positive MUC16 expression is a cancer. 
     Embodiment 77: The use of Embodiment 76, wherein the cancer is ovarian cancer. 
     Embodiment 78: A kit comprising an anti-MUC16 construct of any one of Embodiments 1-43, a murine anti-MUC16 antibody or antigen binding fragment thereof, and instructions for use, wherein the murine anti-MUC16 antibody or antigen binding fragment includes (a) a variable heavy (VH) chain comprising a heavy chain complementarity determining region 1 (HC-CDR1), HC-CDR2, and HC-CDR3 of SEQ ID NOS: 17, 18, and 19, respectively, and a variable light (VL) chain comprising a light chain complementarity determining region 1 (LC-CDR1), LC-CDR2, and LC-CDR3 of SEQ ID NOS: 14, 15, and 16, respectively; or (b) a variable heavy (VH) chain comprising a heavy chain complementarity determining region 1 (HC-CDR1), HC-CDR2, and HC-CDR3 of SEQ ID NOS: 35, 36, and 37, respectively, and a variable light (VL) chain comprising a light chain complementarity determining region 1 (LC-CDR1), LC-CDR2, and LC-CDR3 of SEQ ID NOS: 32, 33, and 34, respectively. 
     Embodiment 79: The kit of Embodiment 78, wherein the murine anti-MUC16 antibody or antigen binding fragment is used to identify a patient that is responsive to treatment with the anti-MUC16 construct. 
     Embodiment 80: The kit of Embodiment 79, wherein the murine anti-MUC16 antibody or antigen binding fragment is used to detect MUC16-expressing tumors in a sample obtained from the patient via western blotting, immunohistochemistry, high-performance liquid chromatography (HPLC), liquid chromatography-mass spectrometry (LC/MS), enzyme-linked immunosorbent assay (ELISA), immunoprecipitation, or immunoelectrophoresis. 
     Embodiment 81: The anti-MUC16 construct of Embodiment 68, wherein the anti-MUC16 construct is conjugated to an alpha emitter, an Auger-emitter, a beta-emitter, a gamma-emitter, a positron-emitters, or an x-ray emitter, optionally wherein the positron-emitter is  89 Zr-desferrioxamine B (DFO). 
     Embodiment 82: A method for detecting cancer in a subject in vivo comprising (a) administering to the subject an effective amount of the anti-MUC16 construct of any one of Embodiments 1-31, wherein the anti-MUC16 construct is configured to localize to a cancer cell expressing MUC16 and is labeled with a radioisotope; and (b) detecting the presence of a tumor in the subject by detecting radioactive levels emitted by the anti-MUC16 construct that are higher than a reference value, optionally wherein the radioisotope is  89 Zr-desferrioxamine B (DFO). 
     Embodiment 83: The method of Embodiment 82, wherein the subject is diagnosed with or is suspected of having cancer. 
     Embodiment 84: The method of Embodiment 82 or 83, wherein the radioactive levels emitted by the anti-MUC16 construct are detected using positron emission tomography or single photon emission computed tomography. 
     Embodiment 85: The method of any one of Embodiments 82-84, further comprising administering to the subject an effective amount of an immunoconjugate comprising the anti-MUC16 construct of any one of claims  1 - 31  conjugated to a radionuclide. 
     Embodiment 86: The method of any one of Embodiments 82-85, wherein the radionuclide is an alpha particle-emitting isotope, a beta particle-emitting isotope, an Auger-emitter, or any combination thereof. 
     EQUIVALENTS 
     The present technology is not to be limited in terms of the particular embodiments described in this application, which are intended as single illustrations of individual aspects of the present technology. Many modifications and variations of this present technology can be made without departing from its spirit and scope, as will be apparent to those skilled in the art. Functionally equivalent methods and apparatuses within the scope of the present technology, in addition to those enumerated herein, will be apparent to those skilled in the art from the foregoing descriptions. Such modifications and variations are intended to fall within the scope of the present technology. It is to be understood that this present technology is not limited to particular methods, reagents, compounds compositions or biological systems, which can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting. 
     In addition, where features or aspects of the disclosure are described in terms of Markush groups, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group. 
     As will be understood by one skilled in the art, for any and all purposes, particularly in terms of providing a written description, all ranges disclosed herein also encompass any and all possible subranges and combinations of subranges thereof. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc. As will also be understood by one skilled in the art all language such as “up to,” “at least,” “greater than,” “less than,” and the like, include the number recited and refer to ranges which can be subsequently broken down into subranges as discussed above. Finally, as will be understood by one skilled in the art, a range includes each individual member. Thus, for example, a group having 1-3 cells refers to groups having 1, 2, or 3 cells. Similarly, a group having 1-5 cells refers to groups having 1, 2, 3, 4, or 5 cells, and so forth. 
     All patents, patent applications, provisional applications, and publications referred to or cited herein are incorporated by reference in their entirety, including all figures and tables, to the extent they are not inconsistent with the explicit teachings of this specification. 
     
       
         
           
               
             
               
                 TABLE 7 
               
             
            
               
                   
               
               
                 Table of Sequences 
               
            
           
           
               
               
               
            
               
                 SEQ 
                   
                   
               
               
                 ID 
                   
                   
               
               
                 NO 
                 Description 
                 Sequence 
               
               
                   
               
            
           
           
               
               
               
            
               
                 1 
                 hMUC16 
                 MLKPSGLPGSSSPTRSLMTGSRSTKATPEMDSGLTGATLSPKTSTGA 
               
               
                   
                 (Immature) 
                 IVVTEHTLPFTSPDKTLASPTSSVVGRTTQSLGVMSSALPESTSRGM 
               
               
                   
                   
                 THSEQRTSPSLSPQVNGTPSRNYPATSMVSGLSSPRTRTSSTEGNFT 
               
               
                   
                   
                 KEASTYTLTVETTSGPVTEKYTVPTETSTTEGDSTETPWDTRYIPVK 
               
               
                   
                   
                 ITSPMKTFADSTASKENAPVSMTPAETTVTDSHTPGRTNPSFGTLYS 
               
               
                   
                   
                 SFLDLSPKGTPNSRGETSLELILSTTGYPFSSPEPGSAGHSRISTSAPL 
               
               
                   
                   
                 SSSASVLDNKISETSIFSGQSLTSPLSPGVPEARASTMPNSAIPFSMTL 
               
               
                   
                   
                 SNAETSAERVRSTISSLGTPSISTKQTAETILTFHAFAETMDIPSTHIA 
               
               
                   
                   
                 KTLASEWLGSPGTLGGTSTSALTTTSPSTTLVSEETNTHEISTSGKET 
               
               
                   
                   
                 EGTLNTSMTPLETSAPGEESEMTATLVPTLGFTTLDSKIRSPSQVSSS 
               
               
                   
                   
                 HPTRELRTTGSTSGRQSSSTAAHGSSDILRATTSSTSKASSWTSESTA 
               
               
                   
                   
                 QQFSEPQHTQWVETSPSMKTERPPASTSVAAPITTSVPSVVSGFTTL 
               
               
                   
                   
                 KTSSTKGIWLEETSADTLIGESTAGPTTHQFAVPTGISMTGGSSTRG 
               
               
                   
                   
                 SQGTTHLLTRATASSETSADLTLATNGVPVSVSPAVSKTAAGSSPPG 
               
               
                   
                   
                 GTKPSYTMVSSVIPETSSLQSSAFREGTSLGLTPLNTRHPFSSPEPDS 
               
               
                   
                   
                 AGHTKISTSIPLLSSASVLEDKVSATSTFSHHKATSSITTGTPEISTKT 
               
               
                   
                   
                 KPSSAVLSSMTLSNAATSPERVRNATSPLTHPSPSGEETAGSVLTLS 
               
               
                   
                   
                 TSAETTDSPNIHPTGTLTSESSESPSTLSLPSVSGVKTTFSSSTPSTHLF 
               
               
                   
                   
                 TSGEETEETSNPSVSQPETSVSRVRTTLASTSVPTPVFPTMDTWPTR 
               
               
                   
                   
                 SAQFSSSHLVSELRATSSTSVTNSTGSALPKISHLTGTATMSQTNRD 
               
               
                   
                   
                 TFNDSAAPQSTTWPETSPRFKTGLPSATTTVSTSATSLSATVMVSKF 
               
               
                   
                   
                 TSPATSSMEATSIREPSTTILTTETTNGPGSMAVASTNIPIGKGYITEG 
               
               
                   
                   
                 RLDTSHLPIGTTASSETSMDFTMAKESVSMSVSPSQSMDAAGSSTP 
               
               
                   
                   
                 GRTSQFVDTFSDDVYHLTSREITIPRDGTSSALTPQMTATHPPSPDP 
               
               
                   
                   
                 GSARSTWLGILSSSPSSPTPKVTMSSTFSTQRVTTSMIMDTVETSRW 
               
               
                   
                   
                 NMPNLPSTTSLTPSNIPTSGAIGKSTLVPLDTPSPATSLEASEGGLPTL 
               
               
                   
                   
                 STYPESTNTPSIHLGAHASSESPSTIKLTMASVVKPGSYTPLTFPSIET 
               
               
                   
                   
                 HIHVSTARMAYSSGSSPEMTAPGETNTGSTWDPTTYITTTDPKDTSS 
               
               
                   
                   
                 AQVSTPHSVRTLRTTENHPKTESATPAAYSGSPKISSSPNLTSPATK 
               
               
                   
                   
                 AWTITDTTEHSTQLHYTKLAEKSSGFETQSAPGPVSVVIPTSPTIGSS 
               
               
                   
                   
                 TLELTSDVPGEPLVLAPSEQTTITLPMATWLSTSLTEEMASTDLDISS 
               
               
                   
                   
                 PSSPMSTFAIFPPMSTPSHELSKSEADTSAIRNTDSTTLDQHLGIRSLG 
               
               
                   
                   
                 RTGDLTTVPITPLTTTWTSVIEHSTQAQDTLSATMSPTHVTQSLKDQ 
               
               
                   
                   
                 TSIPASASPSHLTEVYPELGTQGRSSSEATTFWKPSTDTLSREIETGP 
               
               
                   
                   
                 TNIQSTPPMDNTTTGSSSSGVTLGIAHLPIGTSSPAETSTNMALERRS 
               
               
                   
                   
                 STATVSMAGTMGLLVTSAPGRSISQSLGRVSSVLSESTTEGVTDSSK 
               
               
                   
                   
                 GSSPRLNTQGNTALSSSLEPSYAEGSQMSTSIPLTSSPTTPDVEFIGGS 
               
               
                   
                   
                 TFWTKEVTTVMTSDISKSSARTESSSATLMSTALGSTENTGKEKLR 
               
               
                   
                   
                 TASMDLPSPTPSMEVTPWISLTLSNAPNTTDSLDLSHGVHTSSAGTL 
               
               
                   
                   
                 ATDRSLNTGVTRASRLENGSDTSSKSLSMGNSTHTSMTYTEKSEVS 
               
               
                   
                   
                 SSIHPRPETSAPGAETTLTSTPGNRAISLTLPFSSIPVEEVISTGITSGPD 
               
               
                   
                   
                 INSAPMTHSPITPPTIVWTSTGTIEQSTQPLHAVSSEKVSVQTQSTPY 
               
               
                   
                   
                 VNSVAVSASPTHENSVSSGSSTSSPYSSASLESLDSTISRRNAITSWL 
               
               
                   
                   
                 WDLTTSLPTTTWPSTSLSEALSSGHSGVSNPSSTTTEFPLFSAASTSA 
               
               
                   
                   
                 AKQRNPETETHGPQNTAASTLNTDASSVTGLSETPVGASISSEVPLP 
               
               
                   
                   
                 MAITSRSDVSGLTSESTANPSLGTASSAGTKLTRTISLPTSESLVSFR 
               
               
                   
                   
                 MNKDPWTVSIPLGSHPTTNTETSIPVNSAGPPGLSTVASDVIDTPSD 
               
               
                   
                   
                 GAESIPTVSFSPSPDTEVTTISHFPEKTTHSFRTISSLTHELTSRVTPIP 
               
               
                   
                   
                 GDWMSSAMSTKPTGASPSITLGERRTITSAAPTTSPIVLTASFTETST 
               
               
                   
                   
                 VSLDNETTVKTSDILDARKTNELPSDSSSSSDLINTSIASSTMDVTKT 
               
               
                   
                   
                 ASISPTSISGMTASSSPSLFSSDRPQVPTSTTETNTATSPSVSSNTYSL 
               
               
                   
                   
                 DGGSNVGGTPSTLPPFTITHPVETSSALLAWSRPVRTFSTMVSTDTA 
               
               
                   
                   
                 SGENPTSSNSVVTSVPAPGTWTSVGSTTDLPAMGFLKTSPAGEAHS 
               
               
                   
                   
                 LLASTIEPATAFTPHLSAAVVTGSSATSEASLLTTSESKAIHSSPQTPT 
               
               
                   
                   
                 TPTSGANWETSATPESLLVVTETSDTTLTSKILVTDTILFSTVSTPPS 
               
               
                   
                   
                 KFPSTGTLSGASFPTLLPDTPAIPLTATEPTSSLATSFDSTPLVTIASDS 
               
               
                   
                   
                 LGTVPETTLTMSETSNGDALVLKTVSNPDRSIPGITIQGVTESPLHPS 
               
               
                   
                   
                 STSPSKIVAPRNTTYEGSITVALSTLPAGTTGSLVFSQSSENSETTAL 
               
               
                   
                   
                 VDSSAGLERASVMPLTTGSQGMASSGGIRSGSTHSTGTKTFSSLPLT 
               
               
                   
                   
                 MNPGEVTAMSEITTNRLTATQSTAPKGIPVKPTSAESGLLTPVSASS 
               
               
                   
                   
                 SPSKAFASLTTAPPTWGIPQSTLTFEFSEVPSLDTKSASLPTPGQSLN 
               
               
                   
                   
                 TIPDSDASTASSSLSKSPEKNPRARMMTSTKAISASSFQSTGFTETPE 
               
               
                   
                   
                 GSASPSMAGHEPRVPTSGTGDPRYASESMSYPDPSKASSAMTSTSL 
               
               
                   
                   
                 ASKLTTLFSTGQAARSGSSSSPISLSTEKETSFLSPTASTSRKTSLFLG 
               
               
                   
                   
                 PSMARQPNILVHLQTSALTLSPTSTLNMSQEEPPELTSSQTIAEEEGT 
               
               
                   
                   
                 TAETQTLTFTPSETPTSLLPVSSPTEPTARRKSSPETWASSISVPAKTS 
               
               
                   
                   
                 LVETTDGTLVTTIKMSSQAAQGNSTWPAPAEETGSSPAGTSPGSPE 
               
               
                   
                   
                 MSTTLKIMSSKEPSISPEIRSTVRNSPWKTPETTVPMETTVEPVTLQS 
               
               
                   
                   
                 TALGSGSTSISHLPTGTTSPTKSPTENMLATERVSLSPSPPEAWTNLY 
               
               
                   
                   
                 SGTPGGTRQSLATMSSVSLESPTARSITGTGQQSSPELVSKTTGMEF 
               
               
                   
                   
                 SMWHGSTGGTTGDTHVSLSTSSNILEDPVTSPNSVSSLTDKSKHKT 
               
               
                   
                   
                 ETWVSTTAIPSTVLNNKIMAAEQQTSRSVDEAYSSTSSWSDQTSGS 
               
               
                   
                   
                 DITLGASPDVTNTLYITSTAQTTSLVSLPSGDQGITSLTNPSGGKTSS 
               
               
                   
                   
                 ASSVTSPSIGLETLRANVSAVKSDIAPTAGHLSQTSSPAEVSILDVTT 
               
               
                   
                   
                 APTPGISTTITTMGTNSISTTTPNPEVGMSTMDSTPATERRTTSTEHP 
               
               
                   
                   
                 STWSSTAASDSWTVTDMTSNLKVARSPGTISTMHTTSFLASSTELD 
               
               
                   
                   
                 SMSTPHGRITVIGTSLVTPSSDASAVKTETSTSERTLSPSDTTASTPIS 
               
               
                   
                   
                 TFSRVQRMSISVPDILSTSWTPSSTEAEDVPVSMVSTDHASTKTDPN 
               
               
                   
                   
                 TPLSTFLFDSLSTLDWDTGRSLSSATATTSAPQGATTPQELTLETMIS 
               
               
                   
                   
                 PATSQLPFSIGHITSAVTPAAMARSSGVTFSRPDPTSKKAEQTSTQLP 
               
               
                   
                   
                 TTTSAHPGQVPRSAATTLDVIPHTAKTPDATFQRQGQTALTTEARA 
               
               
                   
                   
                 TSDSWNEKEKSTPSAPWITEMMNSVSEDTIKEVTSSSSVLRTLNTLD 
               
               
                   
                   
                 INLESGTTSSPSWKSSPYERIAPSESTTDKEAIHPSTNTVETTGWVTS 
               
               
                   
                   
                 SEHASHSTIPAHSASSKLTSPVVTTSTREQAIVSMSTTTWPESTRART 
               
               
                   
                   
                 EPNSFLTIELRDVSPYMDTSSTTQTSIISSPGSTAITKGPRTEITSSKRIS 
               
               
                   
                   
                 SSFLAQSMRSSDSPSEAITRLSNFPAMTESGGMILAMQTSPPGATSL 
               
               
                   
                   
                 SAPTLDTSATASWTGTPLATTQRFTYSEKTTLFSKGPEDTSQPSPPS 
               
               
                   
                   
                 VEETSSSSSLVPIHATTSPSNILLTSQGHSPSSTPPVTSVFLSETSGLG 
               
               
                   
                   
                 KTTDMSRISLEPGTSLPPNLSSTAGEALSTYEASRDTKAIHHSADTA 
               
               
                   
                   
                 VTNMEATSSEYSPIPGHTKPSKATSPLVTSHEVIGDITSSTSVFGSSET 
               
               
                   
                   
                 TEIETVSSVNQGLQERSTSQVASSATETSTVITHVSSGDATTHVTKT 
               
               
                   
                   
                 QATFSSGTSISSPHQFITSTNTFTDVSTNPSTSLIMTESSGVTITTQTGP 
               
               
                   
                   
                 TGAATQGPYLLDTSTMPYLTETPLAVTPDFMQSEKTTLISKGPKDV 
               
               
                   
                   
                 SWTSPPSVAETSYPSSLTPFLVTTIPPATSTLQGQHTSSPVSATSVLTS 
               
               
                   
                   
                 GLVKTTDMLNTSMEPVTNSPQNLNNPSNEILATLAATTDIETIHPSI 
               
               
                   
                   
                 NKAVTNMGTASSAHVLHSTLPVSSEPSTATSPMVPASSMGDALASI 
               
               
                   
                   
                 SIPGSETTDIEGEPTSSLTAGRKENSTLQEMNSTTESNIILSNVSVGAI 
               
               
                   
                   
                 TEATKMEVPSFDATFIPTPAQSTKFPDIFSVASSRLSNSPPMTISTHM 
               
               
                   
                   
                 TTTQTGSSGATSKIPLALDTSTLETSAGTPSVVTEGFAHSKITTAMN 
               
               
                   
                   
                 NDVKDVSQTNPPFQDEASSPSSQAPVLVTTLPSSVAFTPQWHSTSSP 
               
               
                   
                   
                 VSMSSVLTSSLVKTAGKVDTSLETVTSSPQSMSNTLDDISVTSAATT 
               
               
                   
                   
                 DIETTHPSINTVVTNVGTTGSAFESHSTVSAYPEPSKVTSPNVTTST 
               
               
                   
                   
                 MEDTTISRSIPKSSKTTRTETETTSSLTPKLRETSISQEITSSTETSTVP 
               
               
                   
                   
                 YKELTGATTEVSRTDVTSSSSTSFPGPDQSTVSLDISTETNTRLSTSPI 
               
               
                   
                   
                 MTESAEITITTQTGPHGATSQDTFTMDPSNTTPQAGIHSAMTHGFSQ 
               
               
                   
                   
                 LDVTTLMSRIPQDVSWTSPPSVDKTSSPSSFLSSPAMTTPSLISSTLPE 
               
               
                   
                   
                 DKLSSPMTSLLTSGLVKITDILRTRLEPVTSSLPNFSSTSDKILATSKD 
               
               
                   
                   
                 SKDTKEIFPSINTEETNVKANNSGHESHSPALADSETPKATTQMVIT 
               
               
                   
                   
                 TTVGDPAPSTSMPVHGSSETTNIKREPTYFLTPRLRETSTSQESSFPT 
               
               
                   
                   
                 DTSFLLSKVPTGTITEVSSTGVNSSSKISTPDHDKSTVPPDTFTGEIPR 
               
               
                   
                   
                 VFTSSIKTKSAEMTITTQASPPESASHSTLPLDTSTTLSQGGTHSTVT 
               
               
                   
                   
                 QGFPYSEVTTLMGMGPGNVSWMTTPPVEETSSVSSLMSSPAMTSPS 
               
               
                   
                   
                 PVSSTSPQSIPSSPLPVTALPTSVLVTTTDVLGTTSPESVTSSPPNLSSI 
               
               
                   
                   
                 THERPATYKDTAHTEAAMHHSTNTAVTNVGTSGSGHKSQSSVLAD 
               
               
                   
                   
                 SETSKATPLMSTTSTLGDTSVSTSTPNISQTNQIQTEPTASLSPRLRES 
               
               
                   
                   
                 STSEKTSSTTETNTAFSYVPTGAITQASRTEISSSRTSISDLDRPTIAPD 
               
               
                   
                   
                 ISTGMITRLFTSPEVITKSAEMTVTTQTTTPGATSQGILPWDTSTTLFQ 
               
               
                   
                   
                 GGTHSTVSQGFPHSEITTLRSRTPGDVSWMTTPPVEETSSGFSLMSP 
               
               
                   
                   
                 SMTSPSPVSSTSPESIPSSPLPVTALLTSVLVTTTNVLGTTSPEPVTSS 
               
               
                   
                   
                 PPNLSSPTQERLTTYKDTAHTEAMHASMHTNTAVANVGTSISGHES 
               
               
                   
                   
                 QSSVPADSHTSKATSPMGITFAMGDTSVSTSTPAFFETRIQTESTSSL 
               
               
                   
                   
                 IPGLRDTRTSEEINTVTETSTVLSEVPTTTTTEVSRTEVITSSRTTISGP 
               
               
                   
                   
                 DHSKMSPYISTETITRLSTFPFVTGSTEMAITNQTGPIGTISQATLTLD 
               
               
                   
                   
                 TSSTASWEGTHSPVTQRFPHSEETTTMSRSTKGVSWQSPPSVEETSS 
               
               
                   
                   
                 PSSPVPLPAITSHSSLYSAVSGSSPTSALPVTSLLTSGRRKTIDMLDT 
               
               
                   
                   
                 HSELVTSSLPSASSFSGEILTSEASTNTETIHFSENTAETNMGTTNSM 
               
               
                   
                   
                 HKLHSSVSIHSQPSGHTPPKVTGSMMEDAIVSTSTPGSPETKNVDRD 
               
               
                   
                   
                 STSPLTPELKEDSTALVMNSTTESNTVFSSVSLDAATEVSRAEVTYY 
               
               
                   
                   
                 DPTFMPASAQSTKSPDISPEASSSHSNSPPLTISTHKTIATQTGPSGVT 
               
               
                   
                   
                 SLGQLTLDTSTIATSAGTPSARTQDFVDSETTSVMNNDLNDVLKTS 
               
               
                   
                   
                 PFSAEEANSLSSQAPLLVTTSPSPVTSTLQEHSTSSLVSVTSVPTPTL 
               
               
                   
                   
                 AKITDMDTNLEPVTRSPQNLRNTLATSEATTDTHTMHPSINTAVAN 
               
               
                   
                   
                 VGTTSSPNEFYFTVSPDSDPYKATSAVVITSTSGDSIVSTSMPRSSAM 
               
               
                   
                   
                 KKIESETTFSLIFRLRETSTSQKIGSSSDTSTVFDKAFTAATTEVSRTE 
               
               
                   
                   
                 LTSSSRTSIQGTEKPTMSPDTSTRSVTMLSTFAGLTKSEERTIATQTG 
               
               
                   
                   
                 PHRATSQGTLTWDTSITTSQAGTHSAMTHGFSQLDLSTLTSRVPEYI 
               
               
                   
                   
                 SGTSPPSVEKTSSSSSLLSLPAITSPSPVPTTLPESRPSSPVHLTSLPTS 
               
               
                   
                   
                 GLVKTTDMLASVASLPPNLGSTSHKIPTTSEDIKDTEKMYPSTNIAV 
               
               
                   
                   
                 TNVGTTTSEKESYSSVPAYSEPPKVTSPMVTSFNIRDTIVSTSMPGSS 
               
               
                   
                   
                 EITRIEMESTFSLAHGLKGTSTSQDPIVSTEKSAVLHKLTTGATETSR 
               
               
                   
                   
                 TEVASSRRTSIPGPDHSTESPDISTEVIPSLPISLGITESSNMTIITRTGP 
               
               
                   
                   
                 PLGSTSQGTFTLDTPTTSSRAGTHSMATQEFPHSEMTTVMNKDPEIL 
               
               
                   
                   
                 SWTIPPSIEKTSFSSSLMPSPAMTSPPVSSTLPKTIHTTPSPMTSLLTPS 
               
               
                   
                   
                 LVMTTDTLGTSPEPTTSSPPNLSSTSHEILTTDEDTTAIEAMHPSTST 
               
               
                   
                   
                 AATNVETTSSGHGSQSSVLADSEKTKATAPMDTTSTMGHTTVSTS 
               
               
                   
                   
                 MSVSSETTKIKRESTYSLTPGLRETSISQNASFSTDTSIVLSEVPTGTT 
               
               
                   
                   
                 AEVSRTEVTSSGRTSIPGPSQSTVLPEISTRTMTRLFASPTMTESAEM 
               
               
                   
                   
                 TIPTQTGPSGSTSQDTLTLDTSTTKSQAKTHSTLTQRFPHSEMTTLM 
               
               
                   
                   
                 SRGPGDMSWQSSPSLENPSSLPSLLSLPATTSPPPISSTLPVTISSSPLP 
               
               
                   
                   
                 VTSLLTSSPVTTTDMLHTSPELVTSSPPKLSHTSDERLTTGKDTTNT 
               
               
                   
                   
                 EAVHPSTNTAASNVEIPSSGHESPSSALADSETSKATSPMFITSTQED 
               
               
                   
                   
                 TTVAISTPHFLETSRIQKESISSLSPKLRETGSSVETSSAIETSAVLSEV 
               
               
                   
                   
                 SIGATTEISRTEVTSSSRTSISGSAESTMLPEISTTRKIIKEPTSPILAESS 
               
               
                   
                   
                 EMTIKTQTSPPGSTSESTFTLDTSTTPSLVITHSTMTQRLPHSEITTLV 
               
               
                   
                   
                 SRGAGDVPRPSSLPVEETSPPSSQLSLSAMISPSPVSSTLPASSHSSSA 
               
               
                   
                   
                 SVTSLLTPGQVKTTEVLDASAEPETSSPPSLSSTSVEILATSEVTTDT 
               
               
                   
                   
                 EKIHPFSNTAVTKVGTSSSGHESPSSVLPDSETTKATSAMGTISIMGD 
               
               
                   
                   
                 TSVSTLTPALSNTRKIQSEPASSLTTRLRETSTSEETSLATEANTVLS 
               
               
                   
                   
                 KVSTGATTEVSRTEAISFSRTSMSGPEQSTMSQDISIGTIPRISASSVL 
               
               
                   
                   
                 TESAKMTITTQTGPSESTLESTLNLNTATTPSWVETHSIVIQGFPHPE 
               
               
                   
                   
                 MTTSMGRGPGGVSWPSPPFVKETSPPSSPLSLPAVTSPHPVSTTFLA 
               
               
                   
                   
                 HIPPSPLPVTSLLTSGPATTTDILGTSTEPGTSSSSSLSTTSHERLTTYK 
               
               
                   
                   
                 DTAHTEAVHPSTNTGGTNVATTSSGYKSQSSVLADSSPMCTTSTM 
               
               
                   
                   
                 GDTSVLTSTPAFLETRRIQTELASSLTPGLRESSGSEGTSSGTKMSTV 
               
               
                   
                   
                 LSKVPTGATTEISKEDVTSIPGPAQSTISPDISTRTVSWFSTSPVMTES 
               
               
                   
                   
                 AEITMNTHTSPLGATTQGTSTLDTSSTTSLTMTHSTISQGFSHSQMS 
               
               
                   
                   
                 TLMRRGPEDVSWMSPPLLEKTRPSFSLMSSPATTSPSPVSSTLPESIS 
               
               
                   
                   
                 SSPLPVTSLLTSGLAKTTDMLHKSSEPVTNSPANLSSTSVEILATSEV 
               
               
                   
                   
                 TTDTEKTHPSSNRTVTDVGTSSSGHESTSFVLADSQTSKVTSPMVIT 
               
               
                   
                   
                 STMEDTSVSTSTPGFFETSRIQTEPTSSLTLGLRKTSSSEGTSLATEM 
               
               
                   
                   
                 STVLSGVPTGATAEVSRTEVTSSSRTSISGFAQLTVSPETSTETITRLP 
               
               
                   
                   
                 TSSIMTESAEMMIKTQTDPPGSTPESTHTVDISTTPNWVETHSTVTQ 
               
               
                   
                   
                 RFSHSEMTTLVSRSPGDMLWPSQSSVEETSSASSLLSLPATTSPSPVS 
               
               
                   
                   
                 STLVEDFPSASLPVTSLLNPGLVITTDRMGISREPGTSSTSNLSSTSRE 
               
               
                   
                   
                 RLTTLEDTVDTEDMQPSTHTAVTNVRTSISGHESQSSVLSDSETPKA 
               
               
                   
                   
                 TSPMGTTYTMGETSVSISTSDFFETSRIQIEPTSSLTSGLRETSSSERIS 
               
               
                   
                   
                 SATEGSTVLSEVPSGATTEVSRTEVISSRGTSMSGPDQFTISPDISTEA 
               
               
                   
                   
                 ITRLSTSPIMTESAESAITIETGSPGATSEGTLTLDTSTTTFWSGTHST 
               
               
                   
                   
                 ASPGFSHSEMTTLMSRTPGDVPWPSLPSVEEASSVSSSLSSPAMTST 
               
               
                   
                   
                 SFFSTLPESISSSPHPVTALLTLGPVKTTDMLRTSSEPETSSPPNLSSTS 
               
               
                   
                   
                 AEILATSEVTKDREKIHPSSNTPVVNVGTVIYKHLSPSSVLADLVTT 
               
               
                   
                   
                 KPTSPMATTSTLGNTSVSTSTPAFPETMMTQPTSSLTSGLREISTSQE 
               
               
                   
                   
                 TSSATERSASLSG1VIPTGATTKVSRTEALSLGRTSTPGPAQSTISPEIS 
               
               
                   
                   
                 TETITRISTPLTTTGSAEMTITPKTGHSGASSQGTFTLDTSSRASWPG 
               
               
                   
                   
                 THSAATHRSPHSGMTTPMSRGPEDVSWPSRPSVEKTSPPSSLVSLSA 
               
               
                   
                   
                 VTSPSPLYSTPSESSHSSPLRVTSLFTPVMMKTTDMLDTSLEPVTTSP 
               
               
                   
                   
                 PSMNITSDESLATSKATMETEAIQLSENTAVTQMGTISARQEFYSSY 
               
               
                   
                   
                 PGLPEPSKVTSPVVTSSTIKDIVSTTIPASSEITRIEMESTSTLTPTPRET 
               
               
                   
                   
                 STSQEIHSATKPSTVPYKALTSATIEDSMTQVMSSSRGPSPDQSTMS 
               
               
                   
                   
                 QDISTEVITRLSTSPIKTESTEMTITTQTGSPGATSRGTLTLDTSTTFM 
               
               
                   
                   
                 SGTHSTASQGFSHSQMTALMSRTPGDVPWLSHPSVEEASSASFSLSS 
               
               
                   
                   
                 PVMTSSSPVSSTLPDSIHSSSLPVTSLLTSGLVKTTELLGTSSEPETSS 
               
               
                   
                   
                 PPNLSSTSAEILAITEVTTDTEKLEMTNVVTSGYTHESPSSVLADSVT 
               
               
                   
                   
                 TKATSSMGITYPTGDTNVLTSTPAFSDTSRIQTKSKLSLTPGLMETSI 
               
               
                   
                   
                 SEETSSATEKSTVLSSVPTGATTEVSRTEAISSSRTSIPGPAQSTMSSD 
               
               
                   
                   
                 TSMETITRISTPLTRKESTDMAITPKTGPSGATSQGTFTLDSSSTASW 
               
               
                   
                   
                 PGTHSATTQRFPQSVVTTPMSRGPEDVSWPSPLSVEKNSPPSSLVSS 
               
               
                   
                   
                 SSVTSPSPLYSTPSGSSHSSPVPVTSLFTSIMMKATDMLDASLEPETT 
               
               
                   
                   
                 SAPNMNITSDESLAASKATTETEAIHVFENTAASHVETTSATEELYS 
               
               
                   
                   
                 SSPGFSEPTKVISPVVTSSSIRDNMVSTTMPGSSGITRIEIESMSSLTPG 
               
               
                   
                   
                 LRETRTSQDITSSTETSTVLYKMPSGATPEVSRTEVMPSSRTSIPGPA 
               
               
                   
                   
                 QSTMSLDISDEVVTRLSTSPIMTESAEITITTQTGYSLATSQVTLPLG 
               
               
                   
                   
                 TSMTFLSGTHSTMSQGLSHSEMTNLMSRGPESLSWTSPRFVETTRS 
               
               
                   
                   
                 SSSLTSLPLTTSLSPVSSTLLDSSPSSPLPVTSLILPGLVKTTEVLDTSS 
               
               
                   
                   
                 EPKTSSSPNLSSTSVEIPATSEIMTDTEKIHPSSNTAVAKVRTSSSVHE 
               
               
                   
                   
                 SHSSVLADSETTITIPSMGITSAVDDTTVETSNPAFSETRRIPTEPTESL 
               
               
                   
                   
                 TPGFRETSTSEETTSITETSAVLYGVPTSATTEVSMTEIMSSNRIHIPD 
               
               
                   
                   
                 SDQSTMSPDIITEVITRLSSSSMMSESTQMTITTQKSSPGATAQSTLT 
               
               
                   
                   
                 LATTTAPLARTHSTVPPRFLHSEMTTLMSRSPENPSWKSSLFVEKTS 
               
               
                   
                   
                 SSSSLLSLPVTTSPSVSSTLPQSIPSSSFSVTSLLTPGMVKTTDTSTEPG 
               
               
                   
                   
                 TSLSPNLSGTSVEILAASEVTTDTEKIHPSSSMAVTNVGTTSSGHELY 
               
               
                   
                   
                 SSVSIHSEPSKATYPVGTPSSMAETSISTSMPANFETTGFEAEPFSHL 
               
               
                   
                   
                 TSGFRKTNMSLDTSSVTPTNTPSSPGSTHLLQSSKTDFTSSAKTSSPD 
               
               
                   
                   
                 WPPASQYTEIPVDIITPFNASPSITESTGITSFPESRFTMSVTESTHHLS 
               
               
                   
                   
                 TDLLPSAETISTGTVMPSLSEAMTSFATTGVPRAISGSGSPFSRTESG 
               
               
                   
                   
                 PGDATLSTIAESLPSSTPVPFSSSTFTTTDSSTIPALHEITSSSATPYRV 
               
               
                   
                   
                 DTSLGTESSTTEGRLVMVSTLDTSSQPGRTSSSPILDTRMTESVELG 
               
               
                   
                   
                 TVTSAYQVPSLSTRLTRTDGIMEHITKIPNEAAHRGTIRPVKGPQTST 
               
               
                   
                   
                 SPASPKGLHTGGTKRMETTTTALKTTTTALKTTSRATLTTSVYTPTL 
               
               
                   
                   
                 GTLTPLNASMQMASTIPTEMMITTPYVFPDVPETTSSLATSLGAETS 
               
               
                   
                   
                 TALPRTTPSVFNRESETTASLVSRSGAERSPVIQTLDVSSSEPDTTAS 
               
               
                   
                   
                 WVIHPAETIPTVSKTTPNFEHSELDTVSSTATSHGADVSSAIPTNISPS 
               
               
                   
                   
                 ELDALTPLVTISGTDTSTTEPTLTKSPHETETRTTWLTHPAETSSTIPR 
               
               
                   
                   
                 TIPNESHHESDATPSIATSPGAETSSAIPEVITVSPGAEDLVTSQVTSSG 
               
               
                   
                   
                 TDRNMTIPTLTLSPGEPKTIASLVTHPEAQTSSAIPTSTISPAVSRLVT 
               
               
                   
                   
                 SMVTSLAAKTSTTNRALTNSPGEPATTVSLVTHPAQTSPTVPWTTSI 
               
               
                   
                   
                 FFHSKSDTTPSMTTSHGAESSSAVPTPTVSTEVPGVVTPLVTSSRAVI 
               
               
                   
                   
                 STTIPILTLSPGEPETTPSMATSHGEEASSAIPTPTVSPGVPGVVTSLV 
               
               
                   
                   
                 TSSRAVTSTTIPILTFSLGEPETTPSMATSHGTEAGSAVPTVLPEVPG 
               
               
                   
                   
                 MVTSLVASSRAVTSTTLPTLTLSPGEPETTPSMATSHGAEASSTVPT 
               
               
                   
                   
                 VSPEVPGVVTSLVTSSSGVNSTSIPTLILSPGELETTPSMATSHGAEA 
               
               
                   
                   
                 SSAVPTPTVSPGVSGVVTPLVTSSRAVTSTTIPILTLSSSEPETTPSMA 
               
               
                   
                   
                 TSHGVEASSAVLTVSPEVPGMVTSLVTSSRAVTSTTIPTLTISSDEPE 
               
               
                   
                   
                 TTTSLVTHSEAKMISAIPTLAVSPTVQGLVTSLVTSSGSETSAFSNLT 
               
               
                   
                   
                 VASSQPETIDSWVAHPGTEASSVVPTLTVSTGEPFTNISLVTHPAESS 
               
               
                   
                   
                 STLPRTTSRFSHSELDTMPSTVTSPEAESSSAISTTISPGIPGVLTSLVT 
               
               
                   
                   
                 SSGRDISATFPTVPESPHESEATASWVTHPAVTSTTVPRTTPNYSHSE 
               
               
                   
                   
                 PDTTPSIATSPGAEATSDFPTITVSPDVPDMVTSQVTSSGTDTSITIPT 
               
               
                   
                   
                 LTLSSGEPETTTSFITYSETHTSSAIPTLPVSPGASKMLTSLVISSGTDS 
               
               
                   
                   
                 TTTEPTLTETPYEPETTAIQUHPAETNTMVPRTTPKESHSKSDTTLP 
               
               
                   
                   
                 VAITSPGPEASSAVSTTTISPDMSDLVTSLVPSSGTDTSTTFPTLSETP 
               
               
                   
                   
                 YEPETTATWLTHPAETSTTVSGTIPNFSHRGSDTAPSMVTSPGVDTR 
               
               
                   
                   
                 SGVPTTTIPPSIPGVVTSQVTSSATDTSTAIPTLTPSPGEPETTASSAT 
               
               
                   
                   
                 HPGTQTGFTVPIRTVPSSEPDTMASWVTHPPQTSTPVSRTTSSFSHSS 
               
               
                   
                   
                 PDATPVMATSPRTEASSAVLTTISPGAPEMVTSQITSSGAATSTTVPT 
               
               
                   
                   
                 LTHSPGMPETTALLSTHPRTETSKTFPASTVFPQVSETTASLTIRPGA 
               
               
                   
                   
                 ETSTALPTQTTSSLFTLLVTGTSRVDLSPTASPGVSAKTAPLSTHPGT 
               
               
                   
                   
                 ETSTMIPTSTLSLGLLETTGLLATSSSAETSTSTLTLTVSPAVSGLSSA 
               
               
                   
                   
                 SITTDKPQTVTSWNTETSPSVTSVGPPEFSRTVTGTTMTLIPSEMPTP 
               
               
                   
                   
                 PKTSHGEGVSPTTILRTTMVEATNLATTGSSPTVAKTTTTFNTLAGS 
               
               
                   
                   
                 LFTPLTTPGMSTLASESVTSRTSYNHRSWISTTSSYNRRYWTPATST 
               
               
                   
                   
                 PVTSTFSPGISTSSIPSSTAATVPFMVPFTLNFTITNLQYEEDMRHPGS 
               
               
                   
                   
                 RKFNATERELQGLLKPLFRNSSLEYLYSGCRLASLRPEKDSSATAV 
               
               
                   
                   
                 DAICTHRPDPEDLGLDRERLYWELSNLTNGIQELGPYTLDRNSLYV 
               
               
                   
                   
                 NGETHRSSMPTTSTPGTSTVDVGTSGTPSSSPSPTTAGPLLMPFTLNF 
               
               
                   
                   
                 TITNLQYEEDMRRTGSRKENTMESVLQGLLKPLEKNTSVGPLYSGC 
               
               
                   
                   
                 RLTLLRPEKDGAATGVDAICTHRLDPKSPGLNREQLYWELSKLTND 
               
               
                   
                   
                 IEELGPYTLDRNSLYVNGFTHQSSVSTTSTPGTSTVDLRTSGTPSSLS 
               
               
                   
                   
                 SPTIMAAGPLLVPFTLNETITNLQYGEDMGHPGSRKENTTERVLQG 
               
               
                   
                   
                 LLGPIFKNTSVGPLYSGCRLTSLRSEKDGAATGVDAICIHHLDPKSP 
               
               
                   
                   
                 GLNRERLYWELSQLTNGIKELGPYTLDRNSLYVNGFTHRTSVPTSS 
               
               
                   
                   
                 TPGTSTVDLGTSGTPFSLPSPATAGPLLVLFTLNFTITNLKYEEDMH 
               
               
                   
                   
                 RPGSRKFNTTERVLQTLLGPMFKNTSVGLLYSGCRLTLLRSEKDGA 
               
               
                   
                   
                 ATGVDAICTHRLDPKSPGVDREQLYWELSQLTNGIKELGPYTLDRN 
               
               
                   
                   
                 SLYVNGFTHWIPVPTSSTPGTSTVDLGSGTPSSLPSPTTAGPLLVPFT 
               
               
                   
                   
                 LNETITNLKYEEDMHCPGSRKENTTERVLQSLLGPMFKNTSVGPLY 
               
               
                   
                   
                 SGCRLTLLRSEKDGAATGVDAICTHRLDPKSPGVDREQLYWELSQL 
               
               
                   
                   
                 TNGIKELGPYTLDRNSLYVNGFTHQTSAPNTSTPGTSTVDLGTSGTP 
               
               
                   
                   
                 SSLPSPTSAGPLLVPFTLNETITNLQYEEDMHHPGSRKENTTERVLQ 
               
               
                   
                   
                 GLLGPMEKNTSVGLLYSGCRLTLLRPEKNGAATGMDAICSHRLDP 
               
               
                   
                   
                 KSPGLNREQLYWELSQLTHGIKELGPYTLDRNSLYVNGFTHRSSVA 
               
               
                   
                   
                 PTSTPGTSTVDLGTSGTPSSLPSPTTAVPLLVPFTLNFTITNLQYGED 
               
               
                   
                   
                 MRHPGSRKFNTTERVLQGLLGPLFKNSSVGPLYSGCRLISLRSEKD 
               
               
                   
                   
                 GAATGVDAICTHHLNPQSPGLDREQLYWQLSQMTNGIKELGPYTL 
               
               
                   
                   
                 DRNSLYVNGFTHRSSGLTTSTPWTSTVDLGTSGTPSPVPSPTTTGPL 
               
               
                   
                   
                 LVPFTLNETITNLQYEENMGHPGSRKFNITESVLQGLLKPLEKSTSV 
               
               
                   
                   
                 GPLYSGCRLTLLRPEKDGVATRVDAICTHRPDPKIPGLDRQQLYWE 
               
               
                   
                   
                 LSQLTHSITELGPYTLDRDSLYVNGFTQRSSVPTTSTPGTFTVQPETS 
               
               
                   
                   
                 ETPSSLPGPTATGPVLLPFTLNFTITNLQYEEDMRRPGSRKFNTTER 
               
               
                   
                   
                 VLQGLLMPLFKNTSVSSLYSGCRLTLLRPEKDGAATRVDAVCTHRP 
               
               
                   
                   
                 DPKSPGLDRERLYWKLSQLTHGITELGPYTLDRHSLYVNGFTHQSS 
               
               
                   
                   
                 MTTTRTPDTSTMHLATSRTPASLSGPMTASPLLVLFTINFTITNLRYE 
               
               
                   
                   
                 ENMHHPGSRKFNTTERVLQGLLRPVFKNTSVGPLYSGCRLTLLRPK 
               
               
                   
                   
                 KDGAATKVDAICTYRPDPKSPGLDREQLYWELSQLTHSITELGPYT 
               
               
                   
                   
                 LDRDSLYVNGFTQRSSVPTTSIPGTPTVDLGTSGTPVSKPGPSAASPL 
               
               
                   
                   
                 LVLFTLNFTITNLRYEENIVIQHPGSRKFNTTERVLQGLLRSLFKSTSV 
               
               
                   
                   
                 GPLYSGCRLTLLRPEKDGTATGVDAICTHHPDPKSPRLDREQLYWE 
               
               
                   
                   
                 LSQLTHNITELGPYALDNDSLFVNGFTHRSSVSTTSTPGTPTVYLGA 
               
               
                   
                   
                 SKTPASIFGPSAASHLLILFTLNFTITNLRYEENIVIWPGSRKFNTTERV 
               
               
                   
                   
                 LQGLLRPLFKNTSVGPLYSGCRLTLLRPEKDGEATGVDAICTHRPD 
               
               
                   
                   
                 PTGPGLDREQLYLELSQLTHSITELGPYTLDRDSLYVNGFTHRSSVP 
               
               
                   
                   
                 TTSTGVVSEEPFTLNFTINNLRYMADMGQPGSLKFNITDNVMQHLL 
               
               
                   
                   
                 SPLFQRSSLGARYTGCRVIALRSVKNGAETRVDLLCTYLQPLSGPG 
               
               
                   
                   
                 LPIKQVFHELSQQTHGITRLGPYSLDKDSLYLNGYNEPGPDEPPTTP 
               
               
                   
                   
                 KPATTFLPPLSEATTAMGYHLKTLTLNFTISNLQYSPDMGKGSATF 
               
               
                   
                   
                 NSTEGVLQHLLRPLFQKSSMGPFYLGCQLISLRPEKDGAATGVDTT 
               
               
                   
                   
                 CTYHPDPVGPGLDIQQLYWELSQLTHGVTQLGFYVLDRDSLFINGY 
               
               
                   
                   
                 APQNLSIRGEYQINFHIVNWNLSNPDPTSSEYITLLRDIQDKVTTLYK 
               
               
                   
                   
                 GSQLHDTFRFCLVTNLTMDSVLVTVKALFSSNLDPSLVEQVFLDKT 
               
               
                   
                   
                 LNASFHWLGSTYQLVDIHVTEMESSVYQPTSSSSTQHFYLNFTITNL 
               
               
                   
                   
                 PYSQDKAQPGTTNYQRNKRNIEDALNQLFRNSSIKSYFSDCQVSTF 
               
               
                   
                   
                 RSVPNRHHTGVDSLCNFSPLARRVDRVAIYEEFLRMTRNGTQLQNF 
               
               
                   
                   
                 TLDRSSVLVDGYSPNRNEPLTGNSDLPFWAVILIGLAGLLGVITCLI 
               
               
                   
                   
                 CGVLVTTRRRKKEGEYNVQQQCPGYYQSHLDLEDLQ 
               
               
                   
               
               
                 2 
                 4H11 
                 DIELTQSPSSLAVSAGERVTMNCKSSQSLLNSRTRKNQLAWYQQKP 
               
               
                   
                 humanized 
                 GQSPELLIYWASTRQSGVPDRFSGSGSGTDFTLTISSVQAEDVAVYY 
               
               
                   
                 light chain 
                 CQQSYNLLTFGPGTKLEIKR 
               
               
                   
                 variable 
                   
               
               
                   
                 region L1 
                   
               
               
                   
               
               
                 3 
                 4H11 
                 DIVLTQSPDSLAVSLGERVTMNCKSSQSLLNSRTRKNQLAWYQQK 
               
               
                   
                 humanized 
                 PGQSPELLIYWASTRQSGVPDRFSGSGSGTDFTLTISSVQAEDVAVY 
               
               
                   
                 light chain 
                 YCQQSYNLLTFGQGTKLEIKR 
               
               
                   
                 variable 
                   
               
               
                   
                 region L2 
                   
               
               
                   
               
               
                 4 
                 4H11 
                 EVKLQESGGGFVKPGGSLRVSCAASGFTFSSYAMSWVRLAPEMRL 
               
               
                   
                 humanized 
                 EWVATISSAGGYIFYSDSVQGRFTISRDNAKNSLHLQMGSLRSGDT 
               
               
                   
                 heavy chain 
                 AMYYCARQGFGNYGDYYAMDYWGQGTTVTVSS 
               
               
                   
                 variable 
                   
               
               
                   
                 region H1 
                   
               
               
                   
               
               
                 5 
                 4H11 
                 EVQLVESGGGLVKPGGSLRVSCAASGFTFSSYAMSWVRLAPGKGL 
               
               
                   
                 humanized 
                 EWVATISSAGGYIFYSDSVQGRFTISRDNAKNSLYLQMNSLRAEDT 
               
               
                   
                 heavy chain 
                 AMYYCARQGFGNYGDYYAMDYWGQGTLVTVSS 
               
               
                   
                 variable 
                   
               
               
                   
                 region H2 
                   
               
               
                   
               
               
                 6 
                 4H11 light 
                 TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNAL 
               
               
                   
                 chain 
                 QSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQ 
               
               
                   
                 constant 
                 GLSSPVTKSFNRGEC 
               
               
                   
                 region L1 
                   
               
               
                   
               
               
                 7 
                 4H11 light 
                 TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNAL 
               
               
                   
                 chain 
                 QSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQ 
               
               
                   
                 constant 
                 GLSSPVTKSFNRGEC 
               
               
                   
                 region L2 
                   
               
               
                   
               
               
                 8 
                 4H11 heavy 
                 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGAL 
               
               
                   
                 chain 
                 TSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTK 
               
               
                   
                 constant 
                 VDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTP 
               
               
                   
                 region H1 
                 EVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR 
               
               
                   
                   
                 VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREP 
               
               
                   
                   
                 QVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYK 
               
               
                   
                   
                 TTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT 
               
               
                   
                   
                 QKSLSLSPGK 
               
               
                   
               
               
                 9 
                 4H11 heavy 
                 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGAL 
               
               
                   
                 chain 
                 TSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTK 
               
               
                   
                 constant 
                 VDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTP 
               
               
                   
                 region H2 
                 EVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR 
               
               
                   
                   
                 VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREP 
               
               
                   
                   
                 QVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYK 
               
               
                   
                   
                 TTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT 
               
               
                   
                   
                 QKSLSLSPGK 
               
               
                   
               
               
                 10 
                 4H11 light 
                 DIELTQSPSSLAVSAGERVTMNCKSSQSLLNSRTRKNQLAWYQQKP 
               
               
                   
                 chain L1 
                 GQSPELLIYWASTRQSGVPDRFSGSGSGTDFTLTISSVQAEDVAVYY 
               
               
                   
                   
                 CQQSYNLLTFGPGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCL 
               
               
                   
                   
                 LNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT 
               
               
                   
                   
                 LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 
               
               
                   
               
               
                 11 
                 4H11 light 
                 DIVLTQSPDSLAVSLGERVTMNCKSSQSLLNSRTRKNQLAWYQQK 
               
               
                   
                 chain L2 
                 PGQSPELLIYWASTRQSGVPDRFSGSGSGTDFTLTISSVQAEDVAVY 
               
               
                   
                   
                 YCQQSYNLLTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVC 
               
               
                   
                   
                 LLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTL 
               
               
                   
                   
                 TLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 
               
               
                   
               
               
                 12 
                 4H11 heavy 
                 EVKLQESGGGFVKPGGSLRVSCAASGFTFSSYAMSWVRLAPEMRL 
               
               
                   
                 chain H1 
                 EWVATISSAGGYIFYSDSVQGRFTISRDNAKNSLHLQMGSLRSGDT 
               
               
                   
                   
                 AMYYCARQGFGNYGDYYAMDYWGQGTTVTVSSASTKGPSVFPL 
               
               
                   
                   
                 APSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL 
               
               
                   
                   
                 QSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC 
               
               
                   
                   
                 DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS 
               
               
                   
                   
                 HEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQ 
               
               
                   
                   
                 DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDE 
               
               
                   
                   
                 LTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS 
               
               
                   
                   
                 FFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 
               
               
                   
               
               
                 13 
                 4H11 heavy 
                 EVQLVESGGGLVKPGGSLRVSCAASGFTFSSYAMSWVRLAPGKGL 
               
               
                   
                 chain H2 
                 EWVATISSAGGYIFYSDSVQGRFTISRDNAKNSLYLQMNSLRAEDT 
               
               
                   
                   
                 AMYYCARQGFGNYGDYYAMDYWGQGTLVTVSSASTKGPSVFPL 
               
               
                   
                   
                 APSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL 
               
               
                   
                   
                 QSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC 
               
               
                   
                   
                 DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS 
               
               
                   
                   
                 HEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQ 
               
               
                   
                   
                 DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDE 
               
               
                   
                   
                 LTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS 
               
               
                   
                   
                 FFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 
               
               
                   
               
               
                 14 
                 4H11 
                 QSLLNSRTRKNQ 
               
               
                   
                 LCDR1 
                   
               
               
                   
               
               
                 15 
                 4H11 
                 WAS 
               
               
                   
                 LCDR2 
                   
               
               
                   
               
               
                 16 
                 4H11 
                 QQSYNLLT 
               
               
                   
                 LCDR3 
                   
               
               
                   
               
               
                 17 
                 4H11 
                 GFTFSSYA 
               
               
                   
                 HCDR1 
                   
               
               
                   
               
               
                 18 
                 4H11 
                 ISSAGGYI 
               
               
                   
                 HCDR2 
                   
               
               
                   
               
               
                 19 
                 4H11 
                 ARQGFGNYGDYYAMDY 
               
               
                   
                 HCDR3 
                   
               
               
                   
               
               
                 20 
                 18C6 
                 DIVMTQSAPSVPVTPGESVSISCRSSKSLLHSNGNTYLYWFLQKPGQ 
               
               
                   
                 humanized 
                 SPQRLIYYMSNLASGVPDRFSGRGSGTDFTLKISRVEAEDVGVYYC 
               
               
                   
                 light chain 
                 MQSLEYPLTFGGGTKLEIKR 
               
               
                   
                 variable 
                   
               
               
                   
                 region L1 
                   
               
               
                   
               
               
                 21 
                 18C6 
                 DIVMTQSALSLPVTPGEPVSISCRSSKSLLHSNGNTYLYWFLQKPGQ 
               
               
                   
                 humanized 
                 SPQRLIYYMSNLASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYC 
               
               
                   
                 light chain 
                 MQSLEYPLTFGGGTKLEIKR 
               
               
                   
                 variable 
                   
               
               
                   
                 region L2 
                   
               
               
                   
               
               
                 22 
                 18C6 heavy 
                 QVTLKESGPGILQPTQTLTLTCTFSGFSLSTVGMGVGWSRQPSGKG 
               
               
                   
                 chain 
                 LEWLAHIWWDDEDKYYNPALKSRLTITKDTSKNQVFLKITNVDTA 
               
               
                   
                 variable 
                 DTATYYCTRIGTAQATDALDYWGQGTLVTVSS 
               
               
                   
                 region H1 
                   
               
               
                   
               
               
                 23 
                 18C6 heavy 
                 QVTLKESGPTLVKPTQTLTLTCTFSGFSLSTVGMGVGWSRQPSGKG 
               
               
                   
                 chain 
                 LEWLAHIWWDDEDKYYNPALKSRLTITKDTSKNQVVLTITNVDPV 
               
               
                   
                 variable 
                 DTATYYCTRIGTAQATDALDYWGQGTLVTVSS 
               
               
                   
                 region H2 
                   
               
               
                   
               
               
                 24 
                 18C6 light 
                 TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNAL 
               
               
                   
                 chain 
                 QSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQ 
               
               
                   
                 constant 
                 GLSSPVTKSFNRGEC 
               
               
                   
                 region L1 
                   
               
               
                   
               
               
                 25 
                 18C6 light 
                 TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNAL 
               
               
                   
                 chain 
                 QSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQ 
               
               
                   
                 constant 
                 GLSSPVTKSFNRGEC 
               
               
                   
                 region L2 
                   
               
               
                   
               
               
                 26 
                 18C6 heavy 
                 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGAL 
               
               
                   
                 chain 
                 TSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTK 
               
               
                   
                 constant 
                 VDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTP 
               
               
                   
                 region H1 
                 EVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR 
               
               
                   
                   
                 VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREP 
               
               
                   
                   
                 QVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYK 
               
               
                   
                   
                 TTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT 
               
               
                   
                   
                 QKSLSLSPGK 
               
               
                   
               
               
                 27 
                 18C6 heavy 
                 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGAL 
               
               
                   
                 chain 
                 TSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTK 
               
               
                   
                 constant 
                 VDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTP 
               
               
                   
                 region H1 
                 EVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR 
               
               
                   
                   
                 VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREP 
               
               
                   
                   
                 QVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYK 
               
               
                   
                   
                 TTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT 
               
               
                   
                   
                 QKSLSLSPGK 
               
               
                   
               
               
                 28 
                 18C6 light 
                 DIVMTQSAPSVPVTPGESVSISCRSSKSLLHSNGNTYLYWFLQKPGQ 
               
               
                   
                 chain L1 
                 SPQRLIYYMSNLASGVPDRFSGRGSGTDFTLKISRVEAEDVGVYYC 
               
               
                   
                   
                 MQSLEYPLTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCL 
               
               
                   
                   
                 LNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT 
               
               
                   
                   
                 LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 
               
               
                   
               
               
                 29 
                 18C6 light 
                 DIVMTQSALSLPVTPGEPVSISCRSSKSLLHSNGNTYLYWFLQKPGQ 
               
               
                   
                 chain L2 
                 SPQRLIYYMSNLASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYC 
               
               
                   
                   
                 MQSLEYPLTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCL 
               
               
                   
                   
                 LNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT 
               
               
                   
                   
                 LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 
               
               
                   
               
               
                 30 
                 18C6 heavy 
                 QVTLKESGPGILQPTQTLTLTCTFSGFSLSTVGMGVGWSRQPSGKG 
               
               
                   
                 chain H1 
                 LEWLAHIWWDDEDKYYNPALKSRLTITKDTSKNQVFLKITNVDTA 
               
               
                   
                   
                 DTATYYCTRIGTAQATDALDYWGQGTLVTVSSASTKGPSVFPLAPS 
               
               
                   
                   
                 SKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS 
               
               
                   
                   
                 GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKT 
               
               
                   
                   
                 HTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHED 
               
               
                   
                   
                 PEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL 
               
               
                   
                   
                 NGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTK 
               
               
                   
                   
                 NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFL 
               
               
                   
                   
                 YSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 
               
               
                   
               
               
                 31 
                 18C6 heavy 
                 QVTLKESGPTLVKPTQTLTLTCTFSGFSLSTVGMGVGWSRQPSGKG 
               
               
                   
                 chain H2 
                 LEWLAHIWWDDEDKYYNPALKSRLTITKDTSKNQVVLTITNVDPV 
               
               
                   
                   
                 DTATYYCTRIGTAQATDALDYWGQGTLVTVSSASTKGPSVFPLAPS 
               
               
                   
                   
                 SKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS 
               
               
                   
                   
                 GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKT 
               
               
                   
                   
                 HTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHED 
               
               
                   
                   
                 PEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL 
               
               
                   
                   
                 NGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTK 
               
               
                   
                   
                 NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFL 
               
               
                   
                   
                 YSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 
               
               
                   
               
               
                 32 
                 18C6 
                 KSLLHSNGNTY 
               
               
                   
                 LCDR1 
                   
               
               
                   
               
               
                 33 
                 18C6 
                 YMS 
               
               
                   
                 LCDR2 
                   
               
               
                   
               
               
                 34 
                 18C6 
                 MQSLEYPLT 
               
               
                   
                 LCDR3 
                   
               
               
                   
               
               
                 35 
                 18C6 
                 GFSLSTVGMG 
               
               
                   
                 HCDR1 
                   
               
               
                   
               
               
                 36 
                 18C6 
                 IWWDDEDK 
               
               
                   
                 HCDR2 
                   
               
               
                   
               
               
                 37 
                 18C6 
                 TRIGTAQATDALDY 
               
               
                   
                 HCDR3 
                   
               
               
                   
               
               
                 38 
                 Leader 
                 MGWSCIILFLVATATG 
               
               
                   
                 Sequence 
                   
               
               
                   
               
               
                 179 
                 GS linker 
                 GGGGSGGGGSGGGGS 
               
               
                   
               
               
                 39 
                 Linker 
                 TSGGGGS 
               
               
                   
               
               
                 40 
                 L2K (anti- 
                 DVQLVQSGAEVKKPGASVKVSCKASGYTFTRYTMHWVRQAPGQG 
               
               
                   
                 CD3) 
                 LEWIGYINPSRGYTNYADSVKGRFTITTDKSTSTAYMELSSLRSEDT 
               
               
                   
                   
                 ATYYCARYYDDHYCLDYWGQGTTVTVSSGEGTSTGSGGSGGSGG 
               
               
                   
                   
                 ADDIVLTQSPATLSLSPGERATLSCRASQSVSYMNWYQQKPGKAP 
               
               
                   
                   
                 KRWIYDTSKVASGVPARFSGSGSGTDYSLTINSLEAEDAATYYCQQ 
               
               
                   
                   
                 WSSNPLTFGGGTKVEIK 
               
               
                   
               
               
                 41 
                 His tag 
                 HHHHHH 
               
               
                   
               
               
                 42 
                 4H11 L1H1- 
                 MGWSCIILFLVATATGKLDIELTQSPSSLAVSAGERVTMNCKSSQSL 
               
               
                   
                 BsAB 
                 LNSRTRKNQLAWYQQKPGQSPELLIYWASTRQSGVPDRFSGSGSG 
               
               
                   
                   
                 TDFTLTISSVQAEDVAVYYCQQSYNLLTFGPGTKLEIKRGGGGSGG 
               
               
                   
                   
                 GGSGGGGSEVKLQESGGGFVKPGGSLRVSCAASGFTFSSYAMSWV 
               
               
                   
                   
                 RLAPEMRLEWVATISSAGGYIFYSDSVQGRFTISRDNAKNSLHLQM 
               
               
                   
                   
                 GSLRSGDTAMYYCARQGFGNYGDYYAMDYWGQGTTVTVSSTSG 
               
               
                   
                   
                 GGGSDVQLVQSGAEVKKPGASVKVSCKASGYTFTRYTMHWVRQA 
               
               
                   
                   
                 PGQGLEWIGYINPSRGYTNYADSVKGRFTITTDKSTSTAYMELSSLR 
               
               
                   
                   
                 SEDTATYYCARYYDDHYCLDYWGQGTTVTVSSGEGTSTGSGGSG 
               
               
                   
                   
                 GSGGADDIVLTQSPATLSLSPGERATLSCRASQSVSYMNWYQQKP 
               
               
                   
                   
                 GKAPKRWIYDTSKVASGVPARFSGSGSGTDYSLTINSLEAEDAATY 
               
               
                   
                   
                 YCQQWSSNPLTFGGGTKVEIKHHHHHH 
               
               
                   
               
               
                 43 
                 MUC16c344 
                 WELSQLTHGVTQLGFYVLDRDSLFINGYAPQNLSIRGEYQINFHIVN 
               
               
                   
                   
                 QNLSNPDPTSSEYITLLRDIQDKVTTLYKGSQLHDTFRFCLVTNLTM 
               
               
                   
                   
                 DSVLVTVKALFSSNLDPSLVEQVFLDKTLNASFHQLGSTYQLVDIH 
               
               
                   
                   
                 VTEMESSVYQPTSSSSTQHFYLNFTITNLPYSQDKAQPGTTNYQRN 
               
               
                   
                   
                 KRNIEDALNQLFRNSSIKSYFSDCQVSTFRSVPNRHHTGVDSLCNFS 
               
               
                   
                   
                 PLARRVDRVAIYEEFLRMTRNGTQLQNFTLDRSSVLVDGYSPNRNE 
               
               
                   
                   
                 PLTGNSDLPFWAVILIGLAGLLGLITCLICGVLVTTRRRKKEGEYNV 
               
               
                   
                   
                 QQQCPGYYQSHLDLEDLQ 
               
               
                   
               
               
                 44 
                 MUC16c114 
                 NFSPLARRVDRVAIYEEFLRMTRNGTQLQNFTLDRSSVLVDGYSPN 
               
               
                   
                   
                 RNEPLTGNSDLPFWAVILIGLAGLLGLITCLICGVLVTTRRRKKEGE 
               
               
                   
                   
                 YNVQQQCPGYYQSHLDLEDLQ 
               
               
                   
               
               
                 45 
                 MUC16c86 
                 NFSPLARRVDRVAIYEEFLRMDLPFWAVILIGLAGLLGLITCLICGV 
               
               
                   
                   
                 LVTTRRRKKEGEYNVQQQCPGYYQSHLDLEDLQ 
               
               
                   
               
               
                 46 
                 MUC16c80 
                 NFSPLARRVDRVAIYEEFLRMTRNGTQLQNFTLDRSSVLVDGYSPN 
               
               
                   
                   
                 RNEPLTGNSDLPFWAVILIGLAGLLGLITCLICGDLEDLQ 
               
               
                   
               
               
                 47 
                 IgG1 heavy 
                 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGAL 
               
               
                   
                 chain 
                 TSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTK 
               
               
                   
                 constant 
                 VDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTP 
               
               
                   
                 region 
                 EVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR 
               
               
                   
                   
                 VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREP 
               
               
                   
                   
                 QVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY 
               
               
                   
                   
                 KTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHY 
               
               
                   
                   
                 TQKSLSLSPGK 
               
               
                   
               
               
                 48 
                 IgG4 heavy 
                 ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALT 
               
               
                   
                 chain 
                 SGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTK 
               
               
                   
                 constant 
                 VDKRVESKYGPPCPSCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVT 
               
               
                   
                 region 
                 CVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVS 
               
               
                   
                   
                 VLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYT 
               
               
                   
                   
                 LPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPP 
               
               
                   
                   
                 VLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSL 
               
               
                   
                   
                 SLSLGK 
               
               
                   
               
               
                 49 
                 Light chain 
                 QPKANPTVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADGS 
               
               
                   
                 constant 
                 PVKAGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHE 
               
               
                   
                 region 
                 GSTVEKTVAPTECS 
               
               
                   
               
               
                 50 
                 MUC16c114 
                 NFSPLARRVDRVAIYEEFLRMTRNGTQLQAFTLDRSSVLVDGYSPN 
               
               
                   
                 N30A 
                 RNEPLTGNSDLPFWAVILIGLAGLLGLITCLICGVLVTTRRRKKEGE 
               
               
                   
                   
                 YNVQQQCPGYYQSHLDLEDLQ 
               
               
                   
               
               
                 51 
                 hMUC16 
                 DKTLASPTSSVVGRTTQSLGVMSSALPESTSRGMTHSEQRTSPSLSP 
               
               
                   
                 (mature) 
                 QVNGTPSRNYPATSMVSGLSSPRTRTSSTEGNFTKEASTYTLTVETT 
               
               
                   
                   
                 SGPVTEKYTVPTETSTTEGDSTETPWDTRYIPVKITSPMKTFADSTA 
               
               
                   
                   
                 SKENAPVSMTPAETTVTDSHTPGRTNPSFGTLYSSFLDLSPKGTPNS 
               
               
                   
                   
                 RGETSLELILSTTGYPFSSPEPGSAGHSRISTSAPLSSSASVLDNKISET 
               
               
                   
                   
                 SIFSGQSLTSPLSPGVPEARASTMPNSAIPFSMTLSNAETSAERVRSTI 
               
               
                   
                   
                 SSLGTPSISTKQTAETILTFHAFAETMDIPSTHIAKTLASEWLGSPGT 
               
               
                   
                   
                 LGGTSTSALTTTSPSTTLVSEETNTHEISTSGKETEGTLNTSMTPLETS 
               
               
                   
                   
                 APGEESEMTATLVPTLGFTTLDSKIRSPSQVSSSHPTRELRTTGSTSG 
               
               
                   
                   
                 RQSSSTAAHGSSDILRATTSSTSKASSWTSESTAQQFSEPQHTQWVE 
               
               
                   
                   
                 TSPSMKTERPPASTSVAAPITTSVPSVVSGFTTLKTSSTKGIWLEETS 
               
               
                   
                   
                 ADTLIGESTAGPTTHQFAVPTGISMTGGSSTRGSQGTTHLLTRATAS 
               
               
                   
                   
                 SETSADLTLATNGVPVSVSPAVSKTAAGSSPPGGTKPSYTMVSSVIP 
               
               
                   
                   
                 ETSSLQSSAFREGTSLGLTPLNTRHPFSSPEPDSAGHTKISTSIPLLSS 
               
               
                   
                   
                 ASVLEDKVSATSTFSHHKATSSITTGTPEISTKTKPSSAVLSSMTLSN 
               
               
                   
                   
                 AATSPERVRNATSPLTHPSPSGEETAGSVLTLSTSAETTDSPNIHPTG 
               
               
                   
                   
                 TLTSESSESPSTLSLPSVSGVKTTESSSTPSTHLFTSGEETEETSNPSVS 
               
               
                   
                   
                 QPETSVSRVRTTLASTSVPTPVEPTMDTWPTRSAQESSSHLVSELRA 
               
               
                   
                   
                 TSSTSVTNSTGSALPKISHLTGTATMSQTNRDTFNDSAAPQSTTWPE 
               
               
                   
                   
                 TSPREKTGLPSATTTVSTSATSLSATVMVSKFTSPATSSMEATSIREP 
               
               
                   
                   
                 STTILTTETTNGPGSMAVASTNIPIGKGYITEGRLDTSHLPIGTTASSE 
               
               
                   
                   
                 TSMDFTMAKESVSMSVSPSQSMDAAGSSTPGRTSQFVDTFSDDVY 
               
               
                   
                   
                 HLTSREITIPRDGTSSALTPQMTATHPPSPDPGSARSTWLGILSSSPSS 
               
               
                   
                   
                 PTPKVTMSSTFSTQRVTTSMIMDTVETSRWNMPNLPSTTSLTPSNIP 
               
               
                   
                   
                 TSGAIGKSTLVPLDTPSPATSLEASEGGLPTLSTYPESTNTPSIHLGA 
               
               
                   
                   
                 HASSESPSTIKLTMASVVKPGSYTPLTFPSIETHIHVSTARMAYSSGS 
               
               
                   
                   
                 SPEMTAPGETNTGSTWDPTTYITTTDPKDTSSAQVSTPHSVRTLRTT 
               
               
                   
                   
                 ENHPKTESATPAAYSGSPKISSSPNLTSPATKAWTITDTTEHSTQLH 
               
               
                   
                   
                 YTKLAEKSSGFETQSAPGPVSVVIPTSPTIGSSTLELTSDVPGEPLVL 
               
               
                   
                   
                 APSEQTTITLPMATWLSTSLTEEMASTDLDISSPSSPMSTFAIFPPMS 
               
               
                   
                   
                 TPSHELSKSEADTSAIRNTDSTTLDQHLGIRSLGRTGDLTTVPITPLT 
               
               
                   
                   
                 TTWTSVIEHSTQAQDTLSATMSPTHVTQSLKDQTSIPASASPSHLTE 
               
               
                   
                   
                 VYPELGTQGRSSSEATTFWKPSTDTLSREIETGPTNIQSTPPMDNTTT 
               
               
                   
                   
                 GSSSSGVTLGIAHLPIGTSSPAETSTNMALERRSSTATVSMAGTMGL 
               
               
                   
                   
                 LVTSAPGRSISQSLGRVSSVLSESTTEGVTDSSKGSSPRLNTQGNTA 
               
               
                   
                   
                 LSSSLEPSYAEGSQMSTSIPLTSSPTTPDVEFIGGSTFWTKEVTTVMT 
               
               
                   
                   
                 SDISKSSARTESSSATLMSTALGSTENTGKEKLRTASMDLPSPTPSM 
               
               
                   
                   
                 EVTPWISLTLSNAPNTTDSLDLSHGVHTSSAGTLATDRSLNTGVTR 
               
               
                   
                   
                 ASRLENGSDTSSKSLSMGNSTHTSMTYTEKSEVSSSIHPRPETSAPG 
               
               
                   
                   
                 AETTLTSTPGNRAISLTLPFSSIPVEEVISTGITSGPDINSAPMTHSPITP 
               
               
                   
                   
                 PTIVWTSTGTIEQSTQPLHAVSSEKVSVQTQSTPYVNSVAVSASPTH 
               
               
                   
                   
                 ENSVSSGSSTSSPYSSASLESLDSTISRRNAITSWLWDLTTSLPTTTW 
               
               
                   
                   
                 PSTSLSEALSSGHSGVSNPSSTTTEFPLFSAASTSAAKQRNPETETHG 
               
               
                   
                   
                 PQNTAASTLNTDASSVTGLSETPVGASISSEVPLPMAITSRSDVSGLT 
               
               
                   
                   
                 SESTANPSLGTASSAGTKLTRTISLPTSESLVSFRMNKDPWTVSIPLG 
               
               
                   
                   
                 SHPTTNTETSIPVNSAGPPGLSTVASDVIDTPSDGAESIPTVSFSPSPD 
               
               
                   
                   
                 TEVTTISHFPEKTTHSERTISSLTHELTSRVTPIPGDWMSSAMSTKPT 
               
               
                   
                   
                 GASPSITLGERRTITSAAPTTSPIVLTASFTETSTVSLDNETTVKTSDI 
               
               
                   
                   
                 LDARKTNELPSDSSSSSDLINTSIASSTMDVTKTASISPTSISGMTASS 
               
               
                   
                   
                 SPSLFSSDRPQVPTSTTETNTATSPSVSSNTYSLDGGSNVGGTPSTLP 
               
               
                   
                   
                 PFTITHPVETSSALLAWSRPVRTFSTMVSTDTASGENPTSSNSVVTS 
               
               
                   
                   
                 VPAPGTWTSVGSTTDLPAMGFLKTSPAGEAHSLLASTIEPATAFTPH 
               
               
                   
                   
                 LSAAVVTGSSATSEASLLTTSESKAIHSSPQTPTTPTSGANWETSATP 
               
               
                   
                   
                 ESLLVVTETSDTTLTSKILVTDTILFSTVSTPPSKFPSTGTLSGASFPT 
               
               
                   
                   
                 LLPDTPAIPLTATEPTSSLATSFDSTPLVTIASDSLGTVPETTLTMSET 
               
               
                   
                   
                 SNGDALVLKTVSNPDRSIPGITIQGVTESPLHPSSTSPSKIVAPRNTTY 
               
               
                   
                   
                 EGSITVALSTLPAGTTGSLVFSQSSENSETTALVDSSAGLERASVMP 
               
               
                   
                   
                 LTTGSQGMASSGGIRSGSTHSTGTKTFSSLPLTMNPGEVTAMSEITT 
               
               
                   
                   
                 NRLTATQSTAPKGIPVKPTSAESGLLTPVSASSSPSKAFASLTTAPPT 
               
               
                   
                   
                 WGIPQSTLTFEFSEVPSLDTKSASLPTPGQSLNTIPDSDASTASSSLSK 
               
               
                   
                   
                 SPEKNPRARMMTSTKAISASSFQSTGFTETPEGSASPSMAGHEPRVP 
               
               
                   
                   
                 TSGTGDPRYASESMSYPDPSKASSAMTSTSLASKLTTLFSTGQAARS 
               
               
                   
                   
                 GSSSSPISLSTEKETSFLSPTASTSRKTSLFLGPSMARQPNILVHLQTS 
               
               
                   
                   
                 ALTLSPTSTLNMSQEEPPELTSSQTIAEEEGTTAETQTLTFTPSETPTS 
               
               
                   
                   
                 LLPVSSPTEPTARRKSSPETWASSISVPAKTSLVETTDGTLVTTIKMS 
               
               
                   
                   
                 SQAAQGNSTWPAPAEETGSSPAGTSPGSPEMSTTLKIMSSKEPSISPE 
               
               
                   
                   
                 IRSTVRNSPWKTPETTVPMETTVEPVTLQSTALGSGSTSISHLPTGTT 
               
               
                   
                   
                 SPTKSPTENMLATERVSLSPSPPEAWTNLYSGTPGGTRQSLATMSS 
               
               
                   
                   
                 VSLESPTARSITGTGQQSSPELVSKTTGMEFSMWHGSTGGTTGDTH 
               
               
                   
                   
                 VSLSTSSNILEDPVTSPNSVSSLTDKSKHKTETWVSTTAIPSTVLNNK 
               
               
                   
                   
                 IMAAEQQTSRSVDEAYSSTSSWSDQTSGSDITLGASPDVTNTLYITS 
               
               
                   
                   
                 TAQTTSLVSLPSGDQGITSLTNPSGGKTSSASSVTSPSIGLETLRANV 
               
               
                   
                   
                 SAVKSDIAPTAGHLSQTSSPAEVSILDVTTAPTPGISTTITTMGTNSIS 
               
               
                   
                   
                 TTTPNPEVGMSTMDSTPATERRTTSTEHPSTWSSTAASDSWTVTDM 
               
               
                   
                   
                 TSNLKVARSPGTISTMHTTSFLASSTELDSMSTPHGRITVIGTSLVTP 
               
               
                   
                   
                 SSDASAVKTETSTSERTLSPSDTTASTPISTFSRVQRMSISVPDILSTS 
               
               
                   
                   
                 WTPSSTEAEDVPVSMVSTDHASTKTDPNTPLSTFLFDSLSTLDWDT 
               
               
                   
                   
                 GRSLSSATATTSAPQGATTPQELTLETMISPATSQLPFSIGHITSAVTP 
               
               
                   
                   
                 AAMARSSGVTFSRPDPTSKKAEQTSTQLPTTTSAHPGQVPRSAATT 
               
               
                   
                   
                 LDVIPHTAKTPDATFQRQGQTALTTEARATSDSWNEKEKSTPSAPW 
               
               
                   
                   
                 ITEMMNSVSEDTIKEVTSSSSVLRTLNTLDINLESGTTSSPSWKSSPY 
               
               
                   
                   
                 ERIAPSESTTDKEAIHPSTNTVETTGWVTSSEHASHSTIPAHSASSKL 
               
               
                   
                   
                 TSPVVTTSTREQAIVSMSTTTWPESTRARTEPNSFLTIELRDVSPYM 
               
               
                   
                   
                 DTSSTTQTSIISSPGSTAITKGPRTEITSSKRISSSFLAQSMRSSDSPSE 
               
               
                   
                   
                 AITRLSNFPAMTESGGMILAMQTSPPGATSLSAPTLDTSATASWTGT 
               
               
                   
                   
                 PLATTQRFTYSEKTTLFSKGPEDTSQPSPPSVEETSSSSSLVPIHATTS 
               
               
                   
                   
                 PSNILLTSQGHSPSSTPPVTSVFLSETSGLGKTTDMSRISLEPGTSLPP 
               
               
                   
                   
                 NLSSTAGEALSTYEASRDTKAIHHSADTAVTNMEATSSEYSPIPGHT 
               
               
                   
                   
                 KPSKATSPLVTSHEVIGDITSSTSVFGSSETTEIETVSSVNQGLQERSTS 
               
               
                   
                   
                 QVASSATETSTVITHVSSGDATTHVTKTQATFSSGTSISSPHQFITST 
               
               
                   
                   
                 NTFTDVSTNPSTSLIMTESSGVTITTQTGPTGAATQGPYLLDTSTMP 
               
               
                   
                   
                 YLTETPLAVTPDFMQSEKTTLISKGPKDVSWTSPPSVAETSYPSSLT 
               
               
                   
                   
                 PFLVTTIPPATSTLQGQHTSSPVSATSVLTSGLVKTTDMLNTSMEPV 
               
               
                   
                   
                 TNSPQNLNNPSNEILATLAATTDIETIHPSINKAVTNMGTASSAHVL 
               
               
                   
                   
                 HSTLPVSSEPSTATSPMVPASSMGDALASISIPGSETTDIEGEPTSSLT 
               
               
                   
                   
                 AGRKENSTLQEMNSTTESNIILSNVSVGAITEATKMEVPSFDATFIPT 
               
               
                   
                   
                 PAQSTKFPDIFSVASSRLSNSPPMTISTHMTTTQTGSSGATSKIPLAL 
               
               
                   
                   
                 DTSTLETSAGTPSVVTEGFAHSKITTAMNNDVKDVSQTNPPFQDEA 
               
               
                   
                   
                 SSPSSQAPVLVTTLPSSVAFTPQWHSTSSPVSMSSVLTSSLVKTAGK 
               
               
                   
                   
                 VDTSLETVTSSPQSMSNTLDDISVTSAATTDIETTHPSINTVVTNVGT 
               
               
                   
                   
                 TGSAFESHSTVSAYPEPSKVTSPNVTTSTMEDTTISRSIPKSSKTTRT 
               
               
                   
                   
                 ETETTSSLTPKLRETSISQEITSSTETSTVPYKELTGATTEVSRTDVTS 
               
               
                   
                   
                 SSSTSFPGPDQSTVSLDISTETNTRLSTSPEVITESAEITITTQTGPHGAT 
               
               
                   
                   
                 SQDTFTMDPSNTTPQAGIHSAMTHGFSQLDVTTLMSRIPQDVSWTS 
               
               
                   
                   
                 PPSVDKTSSPSSFLSSPAMTTPSLISSTLPEDKLSSPMTSLLTSGLVKI 
               
               
                   
                   
                 TDILRTRLEPVTSSLPNFSSTSDKILATSKDSKDTKEIFPSINTEETNV 
               
               
                   
                   
                 KANNSGHESHSPALADSETPKATTQMVITTTVGDPAPSTSMPVHGS 
               
               
                   
                   
                 SETTNIKREPTYFLTPRLRETSTSQESSEPTDTSELLSKVPTGTITEVSS 
               
               
                   
                   
                 TGVNSSSKISTPDHDKSTVPPDTFTGEIPRVETSSIKTKSAEMTITTQA 
               
               
                   
                   
                 SPPESASHSTLPLDTSTTLSQGGTHSTVTQGFPYSEVTTLMGMGPGN 
               
               
                   
                   
                 VSWMTTPPVEETSSVSSLMSSPAMTSPSPVSSTSPQSIPSSPLPVTAL 
               
               
                   
                   
                 PTSVLVTTTDVLGTTSPESVTSSPPNLSSITHERPATYKDTAHTEAA 
               
               
                   
                   
                 MHHSTNTAVTNVGTSGSGHKSQSSVLADSETSKATPLMSTTSTLGD 
               
               
                   
                   
                 TSVSTSTPNISQTNQIQTEPTASLSPRLRESSTSEKTSSTTETNTAFSY 
               
               
                   
                   
                 VPTGAITQASRTEISSSRTSISDLDRPTIAPDISTGMITRLFTSPEVITKS 
               
               
                   
                   
                 AEMTVTTQTTTPGATSQGILPWDTSTTLFQGGTHSTVSQGFPHSEIT 
               
               
                   
                   
                 TLRSRTPGDVSWMTTPPVEETSSGFSLMSPSMTSPSPVSSTSPESIPSS 
               
               
                   
                   
                 PLPVTALLTSVLVTTTNVLGTTSPEPVTSSPPNLSSPTQERLTTYKDT 
               
               
                   
                   
                 AHTEAMHASMHTNTAVANVGTSISGHESQSSVPADSHTSKATSPM 
               
               
                   
                   
                 GITFAMGDTSVSTSTPAFFETRIQTESTSSLIPGLRDTRTSEEINTVTE 
               
               
                   
                   
                 TSTVLSEVPTTTTTEVSRTEVITSSRTTISGPDHSKMSPYISTETITRLS 
               
               
                   
                   
                 TFPFVTGSTEMAITNQTGPIGTISQATLTLDTSSTASWEGTHSPVTQR 
               
               
                   
                   
                 FPHSEETTTMSRSTKGVSWQSPPSVEETSSPSSPVPLPAITSHSSLYS 
               
               
                   
                   
                 AVSGSSPTSALPVTSLLTSGRRKTIDMLDTHSELVTSSLPSASSFSGEI 
               
               
                   
                   
                 LTSEASTNTETIHFSENTAETNMGTTNSMHKLHSSVSIHSQPSGHTP 
               
               
                   
                   
                 PKVTGSMMEDAIVSTSTPGSPETKNVDRDSTSPLTPELKEDSTALV 
               
               
                   
                   
                 MNSTTESNTVFSSVSLDAATEVSRAEVTYYDPTFMPASAQSTKSPDI 
               
               
                   
                   
                 SPEASSSHSNSPPLTISTHKTIATQTGPSGVTSLGQLTLDTSTIATSAG 
               
               
                   
                   
                 TPSARTQDFVDSETTSVMNNDLNDVLKTSPFSAEEANSLSSQAPLL 
               
               
                   
                   
                 VTTSPSPVTSTLQEHSTSSLVSVTSVPTPTLAKITDMDTNLEPVTRSP 
               
               
                   
                   
                 QNLRNTLATSEATTDTHTMHPSINTAVANVGTTSSPNEFYFTVSPDS 
               
               
                   
                   
                 DPYKATSAVVITSTSGDSIVSTSMPRSSAMKKIESETTFSLIFRLRETS 
               
               
                   
                   
                 TSQKIGSSSDTSTVFDKAFTAATTEVSRTELTSSSRTSIQGTEKPTMS 
               
               
                   
                   
                 PDTSTRSVTMLSTFAGLTKSEERTIATQTGPHRATSQGTLTWDTSIT 
               
               
                   
                   
                 TSQAGTHSAMTHGFSQLDLSTLTSRVPEYISGTSPPSVEKTSSSSSLL 
               
               
                   
                   
                 SLPAITSPSPVPTTLPESRPSSPVHLTSLPTSGLVKTTDMLASVASLPP 
               
               
                   
                   
                 NLGSTSHKIPTTSEDIKDTEKMYPSTNIAVTNVGTTTSEKESYSSVPA 
               
               
                   
                   
                 YSEPPKVTSPMVTSFNIRDTIVSTSMPGSSEITRIEMESTFSLAHGLK 
               
               
                   
                   
                 GTSTSQDPIVSTEKSAVLHKLTTGATETSRTEVASSRRTSIPGPDHST 
               
               
                   
                   
                 ESPDISTEVIPSLPISLGITESSNMTIITRTGPPLGSTSQGTFTLDTPTTS 
               
               
                   
                   
                 SRAGTHSMATQEFPHSEMTTVMNKDPEILSWTIPPSIEKTSFSSSLM 
               
               
                   
                   
                 PSPAMTSPPVSSTLPKTIHTTPSPMTSLLTPSLVMTTDTLGTSPEPTTS 
               
               
                   
                   
                 SPPNLSSTSHEILTTDEDTTAIEAMHPSTSTAATNVETTSSGHGSQSS 
               
               
                   
                   
                 VLADSEKTKATAPMDTTSTMGHTTVSTSMSVSSETTKIKRESTYSL 
               
               
                   
                   
                 TPGLRETSISQNASFSTDTSIVLSEVPTGTTAEVSRTEVTSSGRTSIPG 
               
               
                   
                   
                 PSQSTVLPEISTRTMTRLFASPTMTESAEMTIPTQTGPSGSTSQDTLT 
               
               
                   
                   
                 LDTSTTKSQAKTHSTLTQRFPHSEMTTLMSRGPGDMSWQSSPSLEN 
               
               
                   
                   
                 PSSLPSLLSLPATTSPPPISSTLPVTISSSPLPVTSLLTSSPVTTTDMLHT 
               
               
                   
                   
                 SPELVTSSPPKLSHTSDERLTTGKDTTNTEAVHPSTNTAASNVEIPSS 
               
               
                   
                   
                 GHESPSSALADSETSKATSPMFITSTQEDTTVAISTPHFLETSRIQKES 
               
               
                   
                   
                 ISSLSPKLRETGSSVETSSAIETSAVLSEVSIGATTEISRTEVTSSSRTSI 
               
               
                   
                   
                 SGSAESTMLPEISTTRKIIKEPTSPILAESSEMTIKTQTSPPGSTSESTFT 
               
               
                   
                   
                 LDTSTTPSLVITHSTMTQRLPHSEITTLVSRGAGDVPRPSSLPVEETS 
               
               
                   
                   
                 PPSSQLSLSAMISPSPVSSTLPASSHSSSASVTSLLTPGQVKTTEVLD 
               
               
                   
                   
                 ASAEPETSSPPSLSSTSVEILATSEVTTDTEKIHPFSNTAVTKVGTSSS 
               
               
                   
                   
                 GHESPSSVLPDSETTKATSAMGTISIMGDTSVSTLTPALSNTRKIQSE 
               
               
                   
                   
                 PASSLTTRLRETSTSEETSLATEANTVLSKVSTGATTEVSRTEAISFS 
               
               
                   
                   
                 RTSMSGPEQSTMSQDISIGTIPRISASSVLTESAKMTITTQTGPSESTL 
               
               
                   
                   
                 ESTLNLNTATTPSWVETHSIVIQGFPHPEMTTSMGRGPGGVSWPSPP 
               
               
                   
                   
                 FVKETSPPSSPLSLPAVTSPHPVSTTFLAHIPPSPLPVTSLLTSGPATTT 
               
               
                   
                   
                 DILGTSTEPGTSSSSSLSTTSHERLTTYKDTAHTEAVHPSTNTGGTN 
               
               
                   
                   
                 VATTSSGYKSQSSVLADSSPMCTTSTMGDTSVLTSTPAFLETRRIQT 
               
               
                   
                   
                 ELASSLTPGLRESSGSEGTSSGTKMSTVLSKVPTGATTEISKEDVTSI 
               
               
                   
                   
                 PGPAQSTISPDISTRTVSWFSTSPVMTESAEITMNTHTSPLGATTQGT 
               
               
                   
                   
                 STLDTSSTTSLTMTHSTISQGFSHSQMSTLMRRGPEDVSWMSPPLLE 
               
               
                   
                   
                 KTRPSFSLMSSPATTSPSPVSSTLPESISSSPLPVTSLLTSGLAKTTDM 
               
               
                   
                   
                 LHKSSEPVTNSPANLSSTSVEILATSEVTTDTEKTHPSSNRTVTDVG 
               
               
                   
                   
                 TSSSGHESTSFVLADSQTSKVTSPMVITSTMEDTSVSTSTPGFFETSR 
               
               
                   
                   
                 IQTEPTSSLTLGLRKTSSSEGTSLATEMSTVLSGVPTGATAEVSRTEV 
               
               
                   
                   
                 TSSSRTSISGFAQLTVSPETSTETITRLPTSSIMTESAEMMIKTQTDPP 
               
               
                   
                   
                 GSTPESTHTVDISTTPNWVETHSTVTQRFSHSEMTTLVSRSPGDML 
               
               
                   
                   
                 WPSQSSVEETSSASSLLSLPATTSPSPVSSTLVEDFPSASLPVTSLLNP 
               
               
                   
                   
                 GLVITTDRMGISREPGTSSTSNLSSTSHERLTTLEDTVDTEDMQPST 
               
               
                   
                   
                 HTAVTNVRTSISGHESQSSVLSDSETPKATSPMGTTYTMGETSVSIS 
               
               
                   
                   
                 TSDFFETSRIQIEPTSSLTSGLRETSSSERISSATEGSTVLSEVPSGATT 
               
               
                   
                   
                 EVSRTEVISSRGTSMSGPDQFTISPDISTEAITRLSTSPIMTESAESAITI 
               
               
                   
                   
                 ETGSPGATSEGTLTLDTSTTTFWSGTHSTASPGFSHSEMTTLMSRTP 
               
               
                   
                   
                 GDVPWPSLPSVEEASSVSSSLSSPAMTSTSFFSTLPESISSSPHPVTAL 
               
               
                   
                   
                 LTLGPVKTTDMLRTSSEPETSSPPNLSSTSAEILATSEVTKDREKIHP 
               
               
                   
                   
                 SSNTPVVNVGTVIYKHLSPSSVLADLVTTKPTSPMATTSTLGNTSVS 
               
               
                   
                   
                 TSTPAFPETMMTQPTSSLTSGLREISTSQETSSATERSASLSGMPTGA 
               
               
                   
                   
                 TTKVSRTEALSLGRTSTPGPAQSTISPEISTETITRISTPLTTTGSAEMT 
               
               
                   
                   
                 ITPKTGHSGASSQGTFTLDTSSRASWPGTHSAATHRSPHSGMTTPM 
               
               
                   
                   
                 SRGPEDVSWPSRPSVEKTSPPSSLVSLSAVTSPSPLYSTPSESSHSSPL 
               
               
                   
                   
                 RVTSLFTPVMMKTTDMLDTSLEPVTTSPPSMNITSDESLATSKATM 
               
               
                   
                   
                 ETEAIQLSENTAVTQMGTISARQEFYSSYPGLPEPSKVTSPVVTSSTI 
               
               
                   
                   
                 KDIVSTTIPASSEITRIEMESTSTLTPTPRETSTSQEIHSATKPSTVPYK 
               
               
                   
                   
                 ALTSATIEDSMTQVMSSSRGPSPDQSTMSQDISTEVITRLSTSPIKTES 
               
               
                   
                   
                 TEMTITTQTGSPGATSRGTLTLDTSTTFMSGTHSTASQGFSHSQMTA 
               
               
                   
                   
                 LMSRTPGDVPWLSHPSVEEASSASFSLSSPVMTSSSPVSSTLPDSIES 
               
               
                   
                   
                 SSLPVTSLLTSGLVKTTELLGTSSEPETSSPPNLSSTSAEILAITEVTTD 
               
               
                   
                   
                 TEKLEMTNVVTSGYTHESPSSVLADSVTTKATSSMGITYPTGDTNV 
               
               
                   
                   
                 LTSTPAFSDTSRIQTKSKLSLTPGLMETSISEETSSATEKSTVLSSVPT 
               
               
                   
                   
                 GATTEVSRTEAISSSRTSIPGPAQSTMSSDTSMETITRISTPLTRKEST 
               
               
                   
                   
                 DMAITPKTGPSGATSQGTFTLDSSSTASWPGTHSATTQRFPQSVVTT 
               
               
                   
                   
                 PMSRGPEDVSWPSPLSVEKNSPPSSLVSSSSVTSPSPLYSTPSGSSHSS 
               
               
                   
                   
                 PVPVTSLFTSINIMKATDMLDASLEPETTSAPNMNITSDESLAASKAT 
               
               
                   
                   
                 TETEAIHVFENTAASHVETTSATEELYSSSPGFSEPTKVISPVVTSSSI 
               
               
                   
                   
                 RDNMVSTTMPGSSGITRIEIESMSSLTPGLRETRTSQDITSSTETSTVL 
               
               
                   
                   
                 YKMPSGATPEVSRTEVMPSSRTSIPGPAQSTMSLDISDEVVTRLSTS 
               
               
                   
                   
                 PIMTESAEITITTQTGYSLATSQVTLPLGTSMTELSGTHSTMSQGLSH 
               
               
                   
                   
                 SEMTNLMSRGPESLSWTSPRFVETTRSSSSLTSLPLTTSLSPVSSTLL 
               
               
                   
                   
                 DSSPSSPLPVTSLILPGLVKTTEVLDTSSEPKTSSSPNLSSTSVEIPATS 
               
               
                   
                   
                 EEVITDTEKIHPSSNTAVAKVRTSSSVHESHSSVLADSETTITIPSMGIT 
               
               
                   
                   
                 SAVDDTTVFTSNPAFSETRRIPTEPTESLTPGFRETSTSEETTSITETSA 
               
               
                   
                   
                 VLYGVPTSATTEVSMTEIMSSNRIHIPDSDQSTMSPDIITEVITRLSSS 
               
               
                   
                   
                 SMMSESTQMTITTQKSSPGATAQSTLTLATTTAPLARTHSTVPPRFL 
               
               
                   
                   
                 HSEMTTLMSRSPENPSWKSSLFVEKTSSSSSLLSLPVTTSPSVSSTLP 
               
               
                   
                   
                 QSIPSSSFSVTSLLTPGMVKTTDTSTEPGTSLSPNLSGTSVEILAASEV 
               
               
                   
                   
                 TTDTEKIHPSSSMAVTNVGTTSSGHELYSSVSIHSEPSKATYPVGTPS 
               
               
                   
                   
                 SMAETSISTSMPANFETTGFEAEPFSHLTSGERKTNMSLDTSSVTPT 
               
               
                   
                   
                 NTPSSPGSTHLLQSSKTDFTSSAKTSSPDWPPASQYTEIPVDIITPFNA 
               
               
                   
                   
                 SPSITESTGITSFPESRFTMSVTESTHHLSTDLLPSAETISTGTVMPSLS 
               
               
                   
                   
                 EAMTSFATTGVPRAISGSGSPFSRTESGPGDATLSTIAESLPSSTPVPF 
               
               
                   
                   
                 SSSTFTTTDSSTIPALHEITSSSATPYRVDTSLGTESSTTEGRLVMVST 
               
               
                   
                   
                 LDTSSQPGRTSSSPILDTRMTESVELGTVTSAYQVPSLSTRLTRTDGI 
               
               
                   
                   
                 MEHITKIPNEAAHRGTIRPVKGPQTSTSPASPKGLHTGGTKRMETTT 
               
               
                   
                   
                 TALKTTTTALKTTSRATLTTSVYTPTLGTLTPLNASMQMASTIPTEM 
               
               
                   
                   
                 MITTPYVFPDVPETTSSLATSLGAETSTALPRTTPSVFNRESETTASL 
               
               
                   
                   
                 VSRSGAERSPVIQTLDVSSSEPDTTASWVIHPAETIPTVSKTTPNFFH 
               
               
                   
                   
                 SELDTVSSTATSHGADVSSAIPTNISPSELDALTPLVTISGTDTSTTFP 
               
               
                   
                   
                 TLTKSPHETETRTTWLTHPAETSSTIPRTIPNFSHHESDATPSIATSPG 
               
               
                   
                   
                 AETSSAIPIMTVSPGAEDLVTSQVTSSGTDRNMTIPTLTLSPGEPKTI 
               
               
                   
                   
                 ASLVTHPEAQTSSAIPTSTISPAVSRLVTSMVTSLAAKTSTTNRALTN 
               
               
                   
                   
                 SPGEPATTVSLVTHPAQTSPTVPWTTSIFFHSKSDTTPSMTTSHGAES 
               
               
                   
                   
                 SSAVPTPTVSTEVPGVVTPLVTSSRAVISTTIPILTLSPGEPETTPSMA 
               
               
                   
                   
                 TSHGEEASSAIPTPTVSPGVPGVVTSLVTSSRAVTSTTIPILTFSLGEP 
               
               
                   
                   
                 ETTPSMATSHGTEAGSAVPTVLPEVPGMVTSLVASSRAVTSTTLPT 
               
               
                   
                   
                 LTLSPGEPETTPSMATSHGAEASSTVPTVSPEVPGVVTSLVTSSSGV 
               
               
                   
                   
                 NSTSIPTLILSPGELETTPSMATSHGAEASSAVPTPTVSPGVSGVVTP 
               
               
                   
                   
                 LVTSSRAVTSTTIPILTLSSSEPETTPSMATSHGVEASSAVLTVSPEVP 
               
               
                   
                   
                 GMVTSLVTSSRAVTSTTIPTLTISSDEPETTTSLVTHSEAKMISAIPTL 
               
               
                   
                   
                 AVSPTVQGLVTSLVTSSGSETSAFSNLTVASSQPETIDSWVAHPGTE 
               
               
                   
                   
                 ASSVVPTLTVSTGEPFTNISLVTHPAESSSTLPRTTSRFSHSELDTMPS 
               
               
                   
                   
                 TVTSPEAESSSAISTTISPGIPGVLTSLVTSSGRDISATEPTVPESPHES 
               
               
                   
                   
                 EATASWVTHPAVTSTTVPRTTPNYSHSEPDTTPSIATSPGAEATSDF 
               
               
                   
                   
                 PTITVSPDVPDMVTSQVTSSGTDTSITIPTLTLSSGEPETTTSFITYSET 
               
               
                   
                   
                 HTSSAIPTLPVSPGASKMLTSLVISSGTDSTTTFPTLTETPYEPETTAI 
               
               
                   
                   
                 QLIHPAETNTMVPRTTPKESHSKSDTTLPVAITSPGPEASSAVSTTTIS 
               
               
                   
                   
                 PDMSDLVTSLVPSSGTDTSTTFPTLSETPYEPETTATWLTHPAETSTT 
               
               
                   
                   
                 VSGTIPNFSHRGSDTAPSMVTSPGVDTRSGVPTTTIPPSIPGVVTSQV 
               
               
                   
                   
                 TSSATDTSTAIPTLTPSPGEPETTASSATHPGTQTGFTVPIRTVPSSEP 
               
               
                   
                   
                 DTMASWVTHPPQTSTPVSRTTSSFSHSSPDATPVMATSPRTEASSAV 
               
               
                   
                   
                 LTTISPGAPEMVTSQITSSGAATSTTVPTLTHSPGMPETTALLSTHPR 
               
               
                   
                   
                 TETSKTFPASTVFPQVSETTASLTIRPGAETSTALPTQTTSSLFTLLVT 
               
               
                   
                   
                 GTSRVDLSPTASPGVSAKTAPLSTHPGTETSTMIPTSTLSLGLLETTG 
               
               
                   
                   
                 LLATSSSAETSTSTLTLTVSPAVSGLSSASITTDKPQTVTSWNTETSP 
               
               
                   
                   
                 SVTSVGPPEFSRTVTGTTMTLIPSEMPTPPKTSHGEGVSPTTILRTTM 
               
               
                   
                   
                 VEATNLATTGSSPTVAKTTTTFNTLAGSLFTPLTTPGMSTLASESVT 
               
               
                   
                   
                 SRTSYNHRSWISTTSSYNRRYWTPATSTPVTSTFSPGISTSSIPSSTAA 
               
               
                   
                   
                 TVPFMVPFTLNFTITNLQYEEDMRHPGSRKFNATERELQGLLKPLF 
               
               
                   
                   
                 RNSSLEYLYSGCRLASLRPEKDSSATAVDAICTHRPDPEDLGLDRER 
               
               
                   
                   
                 LYWELSNLTNGIQELGPYTLDRNSLYVNGFTHRSSMPTTSTPGTST 
               
               
                   
                   
                 VDVGTSGTPSSSPSPTTAGPLLMPFTLNFTITNLQYEEDMRRTGSRK 
               
               
                   
                   
                 FNTMESVLQGLLKPLFKNTSVGPLYSGCRLTLLRPEKDGAATGVD 
               
               
                   
                   
                 AICTHRLDPKSPGLNREQLYWELSKLTNDIEELGPYTLDRNSLYVN 
               
               
                   
                   
                 GFTHQSSVSTTSTPGTSTVDLRTSGTPSSLSSPTIMAAGPLLVPFTLN 
               
               
                   
                   
                 FTITNLQYGEDMGHPGSRKFNTTERVLQGLLGPIFKNTSVGPLYSG 
               
               
                   
                   
                 CRLTSLRSEKDGAATGVDAICIHEILDPKSPGLNRERLYWELSQLTN 
               
               
                   
                   
                 GIKELGPYTLDRNSLYVNGFTHRTSVPTSSTPGTSTVDLGTSGTPFS 
               
               
                   
                   
                 LPSPATAGPLLVLFTLNFTITNLKYEEDMHRPGSRKFNTTERVLQTL 
               
               
                   
                   
                 LGPMFKNTSVGLLYSGCRLTLLRSEKDGAATGVDAICTHRLDPKSP 
               
               
                   
                   
                 GVDREQLYWELSQLTNGIKELGPYTLDRNSLYVNGFTHWIPVPTSS 
               
               
                   
                   
                 TPGTSTVDLGSGTPSSLPSPTTAGPLLVPFTLNFTITNLKYEEDMHCP 
               
               
                   
                   
                 GSRKFNTTERVLQSLLGPMFKNTSVGPLYSGCRLTLLRSEKDGAAT 
               
               
                   
                   
                 GVDAICTHRLDPKSPGVDREQLYWELSQLTNGIKELGPYTLDRNSL 
               
               
                   
                   
                 YVNGFTHQTSAPNTSTPGTSTVDLGTSGTPSSLPSPTSAGPLLVPFTL 
               
               
                   
                   
                 NFTITNLQYEEDMHHPGSRKFNTTERVLQGLLGPMFKNTSVGLLYS 
               
               
                   
                   
                 GCRLTLLRPEKNGAATGMDAICSHRLDPKSPGLNREQLYWELSQL 
               
               
                   
                   
                 THGIKELGPYTLDRNSLYVNGFTHRSSVAPTSTPGTSTVDLGTSGTP 
               
               
                   
                   
                 SSLPSPTTAVPLLVPFTLNFTITNLQYGEDMRHPGSRKFNTTERVLQ 
               
               
                   
                   
                 GLLGPLFKNSSVGPLYSGCRLISLRSEKDGAATGVDAICTHHLNPQS 
               
               
                   
                   
                 PGLDREQLYWQLSQMTNGIKELGPYTLDRNSLYVNGFTHRSSGLT 
               
               
                   
                   
                 TSTPWTSTVDLGTSGTPSPVPSPTTTGPLLVPFTLNFTITNLQYEENM 
               
               
                   
                   
                 GHPGSRKFNITESVLQGLLKPLFKSTSVGPLYSGCRLTLLRPEKDGV 
               
               
                   
                   
                 ATRVDAICTHRPDPKIPGLDRQQLYWELSQLTHSITELGPYTLDRDS 
               
               
                   
                   
                 LYVNGFTQRSSVPTTSTPGTFTVQPETSETPSSLPGPTATGPVLLPFT 
               
               
                   
                   
                 LNFTITNLQYEEDMRRPGSRKFNTTERVLQGLLMPLFKNTSVSSLY 
               
               
                   
                   
                 SGCRLTLLRPEKDGAATRVDAVCTHRPDPKSPGLDRERLYWKLSQ 
               
               
                   
                   
                 LTHGITELGPYTLDRHSLYVNGFTHQSSMTTTRTPDTSTMHLATSR 
               
               
                   
                   
                 TPASLSGPMTASPLLVLFTINFTITNLRYEENMHHPGSRKFNTTERV 
               
               
                   
                   
                 LQGLLRPVFKNTSVGPLYSGCRLTLLRPKKDGAATKVDAICTYRPD 
               
               
                   
                   
                 PKSPGLDREQLYWELSQLTHSITELGPYTLDRDSLYVNGFTQRSSVP 
               
               
                   
                   
                 TTSIPGTPTVDLGTSGTPVSKPGPSAASPLLVLFTLNFTITNLRYEEN 
               
               
                   
                   
                 MQHPGSRKFNTTERVLQGLLRSLFKSTSVGPLYSGCRLTLLRPEKD 
               
               
                   
                   
                 GTATGVDAICTHHPDPKSPRLDREQLYWELSQLTHNITELGPYALD 
               
               
                   
                   
                 NDSLFVNGFTHRSSVSTTSTPGTPTVYLGASKTPASIFGPSAASHLLI 
               
               
                   
                   
                 LFTLNFTITNLRYEENMWPGSRKFNTTERVLQGLLRPLFKNTSVGP 
               
               
                   
                   
                 LYSGCRLTLLRPEKDGEATGVDAICTHRPDPTGPGLDREQLYLELS 
               
               
                   
                   
                 QLTHSITELGPYTLDRDSLYVNGFTHRSSVPTTSTGVVSEEPFTLNFT 
               
               
                   
                   
                 INNLRYMADMGQPGSLKFNITDNVMQHLLSPLFQRSSLGARYTGC 
               
               
                   
                   
                 RVIALRSVKNGAETRVDLLCTYLQPLSGPGLPIKQVFHELSQQTHGI 
               
               
                   
                   
                 TRLGPYSLDKDSLYLNGYNEPGPDEPPTTPKPATTFLPPLSEATTAM 
               
               
                   
                   
                 GYHLKTLTLNFTISNLQYSPDMGKGSATFNSTEGVLQHLLRPLFQK 
               
               
                   
                   
                 SSMGPFYLGCQLISLRPEKDGAATGVDTTCTYHPDPVGPGLDIQQL 
               
               
                   
                   
                 YWELSQLTHGVTQLGFYVLDRDSLFINGYAPQNLSIRGEYQINFHIV 
               
               
                   
                   
                 NWNLSNPDPTSSEYITLLRDIQDKVTTLYKGSQLHDTFRFCLVTNLT 
               
               
                   
                   
                 MDSVLVTVKALFSSNLDPSLVEQVFLDKTLNASFHWLGSTYQLVDI 
               
               
                   
                   
                 HVTEMESSVYQPTSSSSTQHFYLNFTITNLPYSQDKAQPGTTNYQR 
               
               
                   
                   
                 NKRNIEDALNQLFRNSSIKSYFSDCQVSTFRSVPNRHHTGVDSLCNF 
               
               
                   
                   
                 SPLARRVDRVAIYEEFLRMTRNGTQLQNFTLDRSSVLVDGYSPNRN 
               
               
                   
                   
                 EPLTGNSDLPFWAVILIGLAGLLGVITCLICGVLVTTRRRKKEGEYN 
               
               
                   
                   
                 VQQQCPGYYQSHLDLEDLQ 
               
               
                   
               
               
                 52 
                 MUC16 
                 TLDRSSVLVDGYSPNRNE 
               
               
                   
                 peptide-2 
                   
               
               
                   
               
               
                 53 
                 4H11 L1H1- 
                 DIELTQSPSSLAVSAGERVTMNCKSSQSLLNSRTRKNQLAWYQQKP 
               
               
                   
                 scFv 
                 GQSPELLIYWASTRQSGVPDRFSGSGSGTDFTLTISSVQAEDVAVYY 
               
               
                   
                   
                 CQQSYNLLTFGPGTKLEIKRGGGGSGGGGSGGGGSEVKLQESGGG 
               
               
                   
                   
                 FVKPGGSLRVSCAASGFTFSSYAMSWVRLAPEMRLEWVATISSAG 
               
               
                   
                   
                 GYIFYSDSVQGRFTISRDNAKNSLHLQMGSLRSGDTAMYYCARQG 
               
               
                   
                   
                 FGNYGDYYAMDYWGQGTTVTVSS 
               
               
                   
               
               
                 54 
                 4H11 L2H1- 
                 DIVLTQSPDSLAVSLGERVTMNCKSSQSLLNSRTRKNQLAWYQQK 
               
               
                   
                 scFv 
                 PGQSPELLIYWASTRQSGVPDRFSGSGSGTDFTLTISSVQAEDVAVY 
               
               
                   
                   
                 YCQQSYNLLTFGQGTKLEIKRGGGGSGGGGSGGGGSEVKLQESGG 
               
               
                   
                   
                 GFVKPGGSLRVSCAASGFTFSSYAMSWVRLAPEMRLEWVATISSA 
               
               
                   
                   
                 GGYIFYSDSVQGRFTISRDNAKNSLHLQMGSLRSGDTAMYYCARQ 
               
               
                   
                   
                 GFGNYGDYYAMDYWGQGTTVTVSS 
               
               
                   
               
               
                 55 
                 4H11 L1H2- 
                 DIELTQSPSSLAVSAGERVTMNCKSSQSLLNSRTRKNQLAWYQQKP 
               
               
                   
                 scFv 
                 GQSPELLIYWASTRQSGVPDRFSGSGSGTDFTLTISSVQAEDVAVYY 
               
               
                   
                   
                 CQQSYNLLTFGPGTKLEIKRGGGGSGGGGSGGGGSEVQLVESGGG 
               
               
                   
                   
                 LVKPGGSLRVSCAASGFTFSSYAMSWVRLAPGKGLEWVATISSAG 
               
               
                   
                   
                 GYIFYSDSVQGRFTISRDNAKNSLYLQMNSLRAEDTAMYYCARQG 
               
               
                   
                   
                 FGNYGDYYAMDYWGQGTLVTVSS 
               
               
                   
               
               
                 56 
                 4H11 L2H2- 
                 DIVLTQSPDSLAVSLGERVTMNCKSSQSLLNSRTRKNQLAWYQQK 
               
               
                   
                 scFv 
                 PGQSPELLIYWASTRQSGVPDRFSGSGSGTDFTLTISSVQAEDVAVY 
               
               
                   
                   
                 YCQQSYNLLTFGQGTKLEIKRGGGGSGGGGSGGGGSEVQLVESGG 
               
               
                   
                   
                 GLVKPGGSLRVSCAASGFTFSSYAMSWVRLAPGKGLEWVATISSA 
               
               
                   
                   
                 GGYIFYSDSVQGRFTISRDNAKNSLYLQMNSLRAEDTAMYYCARQ 
               
               
                   
                   
                 GFGNYGDYYAMDYWGQGTLVTVSS 
               
               
                   
               
               
                 57 
                 18C6 
                 DIVMTQSAPSVPVTPGESVSISCRSSKSLLHSNGNTYLYWFLQKPGQ 
               
               
                   
                 L1H1-scFv 
                 SPQRLIYYMSNLASGVPDRFSGRGSGTDFTLKISRVEAEDVGVYYC 
               
               
                   
                   
                 MQSLEYPLTFGGGTKLEIKRGGGGSGGGGSGGGGSQVTLKESGPGI 
               
               
                   
                   
                 LQPTQTLTLTCTFSGFSLSTVGMGVGWSRQPSGKGLEWLAHIWWD 
               
               
                   
                   
                 DEDKYYNPALKSRLTITKDTSKNQVFLKITNVDTADTATYYCTRIG 
               
               
                   
                   
                 TAQATDALDYWGQGTLVTVSS 
               
               
                   
               
               
                 58 
                 18C6 
                 DIVMTQSALSLPVTPGEPVSISCRSSKSLLHSNGNTYLYWFLQKPGQ 
               
               
                   
                 L2H1-scFv 
                 SPQRLIYYMSNLASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYC 
               
               
                   
                   
                 MQSLEYPLTFGGGTKLEIKRGGGGSGGGGSGGGGSQVTLKESGPGI 
               
               
                   
                   
                 LQPTQTLTLTCTFSGFSLSTVGMGVGWSRQPSGKGLEWLAHIWWD 
               
               
                   
                   
                 DEDKYYNPALKSRLTITKDTSKNQVFLKITNVDTADTATYYCTRIG 
               
               
                   
                   
                 TAQATDALDYWGQGTLVTVSS 
               
               
                   
               
               
                 59 
                 18C6 
                 DIVMTQSAPSVPVTPGESVSISCRSSKSLLHSNGNTYLYWFLQKPGQ 
               
               
                   
                 L1H2-scFv 
                 SPQRLIYYMSNLASGVPDRFSGRGSGTDFTLKISRVEAEDVGVYYC 
               
               
                   
                   
                 MQSLEYPLTFGGGTKLEIKRGGGGSGGGGSGGGGSQVTLKESGPTL 
               
               
                   
                   
                 VKPTQTLTLTCTFSGFSLSTVGMGVGWSRQPSGKGLEWLAHIWWD 
               
               
                   
                   
                 DEDKYYNPALKSRLTITKDTSKNQVVLTITNVDPVDTATYYCTRIG 
               
               
                   
                   
                 TAQATDALDYWGQGTLVTVSS 
               
               
                   
               
               
                 60 
                 18C6 
                 DIVMTQSALSLPVTPGEPVSISCRSSKSLLHSNGNTYLYWFLQKPGQ 
               
               
                   
                 L2H2-scFv 
                 SPQRLIYYMSNLASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYC 
               
               
                   
                   
                 MQSLEYPLTFGGGTKLEIKRGGGGSGGGGSGGGGSQVTLKESGPTL 
               
               
                   
                   
                 VKPTQTLTLTCTFSGFSLSTVGMGVGWSRQPSGKGLEWLAHIWWD 
               
               
                   
                   
                 DEDKYYNPALKSRLTITKDTSKNQVVLTITNVDPVDTATYYCTRIG 
               
               
                   
                   
                 TAQATDALDYWGQGTLVTVSS 
               
               
                   
               
               
                 61 
                 4H11 H1L1- 
                 EVKLQESGGGFVKPGGSLRVSCAASGFTFSSYAMSWVRLAPEMRL 
               
               
                   
                 scFv 
                 EWVATISSAGGYIFYSDSVQGRFTISRDNAKNSLHLQMGSLRSGDT 
               
               
                   
                   
                 AMYYCARQGFGNYGDYYAMDYWGQGTTVTVSSGGGGSGGGGS 
               
               
                   
                   
                 GGGGSDIELTQSPSSLAVSAGERVTMNCKSSQSLLNSRTRKNQLAW 
               
               
                   
                   
                 YQQKPGQSPELLIYWASTRQSGVPDRFSGSGSGTDFTLTISSVQAED 
               
               
                   
                   
                 VAVYYCQQSYNLLTFGPGTKLEIKR 
               
               
                   
               
               
                 62 
                 4H11 H1L2- 
                 EVKLQESGGGFVKPGGSLRVSCAASGFTFSSYAMSWVRLAPEMRL 
               
               
                   
                 scFv 
                 EWVATISSAGGYIFYSDSVQGRFTISRDNAKNSLHLQMGSLRSGDT 
               
               
                   
                   
                 AMYYCARQGFGNYGDYYAMDYWGQGTTVTVSSGGGGSGGGGS 
               
               
                   
                   
                 GGGGSDIVLTQSPDSLAVSLGERVTMNCKSSQSLLNSRTRKNQLA 
               
               
                   
                   
                 WYQQKPGQSPELLIYWASTRQSGVPDRFSGSGSGTDFTLTISSVQA 
               
               
                   
                   
                 EDVAVYYCQQSYNLLTFGQGTKLEIKR 
               
               
                   
               
               
                 63 
                 4H11 H2L1- 
                 EVQLVESGGGLVKPGGSLRVSCAASGFTFSSYAMSWVRLAPGKGL 
               
               
                   
                 scFv 
                 EWVATISSAGGYIFYSDSVQGRFTISRDNAKNSLYLQMNSLRAEDT 
               
               
                   
                   
                 AMYYCARQGFGNYGDYYAMDYWGQGTLVTVSSGGGGSGGGGS 
               
               
                   
                   
                 GGGGSDIELTQSPSSLAVSAGERVTMNCKSSQSLLNSRTRKNQLAW 
               
               
                   
                   
                 YQQKPGQSPELLIYWASTRQSGVPDRFSGSGSGTDFTLTISSVQAED 
               
               
                   
                   
                 VAVYYCQQSYNLLTFGPGTKLEIKR 
               
               
                   
               
               
                 64 
                 4H11 H2L2- 
                 EVQLVESGGGLVKPGGSLRVSCAASGFTFSSYAMSWVRLAPGKGL 
               
               
                   
                 scFv 
                 EWVATISSAGGYIFYSDSVQGRFTISRDNAKNSLYLQMNSLRAEDT 
               
               
                   
                   
                 AMYYCARQGFGNYGDYYAMDYWGQGTLVTVSSGGGGSGGGGS 
               
               
                   
                   
                 GGGGSDIVLTQSPDSLAVSLGERVTMNCKSSQSLLNSRTRKNQLA 
               
               
                   
                   
                 WYQQKPGQSPELLIYWASTRQSGVPDRFSGSGSGTDFTLTISSVQA 
               
               
                   
                   
                 EDVAVYYCQQSYNLLTFGQGTKLEIKR 
               
               
                   
               
               
                 65 
                 18C6 
                 QVTLKESGPGILQPTQTLTLTCTFSGFSLSTVGMGVGWSRQPSGKG 
               
               
                   
                 H1L1-scFv 
                 LEWLAHIWWDDEDKYYNPALKSRLTITKDTSKNQVFLKITNVDTA 
               
               
                   
                   
                 DTATYYCTRIGTAQATDALDYWGQGTLVTVSSGGGGSGGGGSGG 
               
               
                   
                   
                 GGSDIVMTQSAPSVPVTPGESVSISCRSSKSLLHSNGNTYLYWFLQK 
               
               
                   
                   
                 PGQSPQRLIYYMSNLASGVPDRFSGRGSGTDFTLKISRVEAEDVGV 
               
               
                   
                   
                 YYCMQSLEYPLTFGGGTKLEIKR 
               
               
                   
               
               
                 66 
                 18C6 
                 QVTLKESGPGILQPTQTLTLTCTFSGFSLSTVGMGVGWSRQPSGKG 
               
               
                   
                 H1L2-scFv 
                 LEWLAHIWWDDEDKYYNPALKSRLTITKDTSKNQVFLKITNVDTA 
               
               
                   
                   
                 DTATYYCTRIGTAQATDALDYWGQGTLVTVSSGGGGSGGGGSGG 
               
               
                   
                   
                 GGSDIVMTQSALSLPVTPGEPVSISCRSSKSLLHSNGNTYLYWFLQK 
               
               
                   
                   
                 PGQSPQRLIYYMSNLASGVPDRFSGSGSGTDFTLKISRVEAEDVGV 
               
               
                   
                   
                 YYCMQSLEYPLTFGGGTKLEIKR 
               
               
                   
               
               
                 67 
                 18C6 
                 QVTLKESGPTLVKPTQTLTLTCTFSGFSLSTVGMGVGWSRQPSGKG 
               
               
                   
                 H2L1-scFv 
                 LEWLAHIWWDDEDKYYNPALKSRLTITKDTSKNQVVLTITNVDPV 
               
               
                   
                   
                 DTATYYCTRIGTAQATDALDYWGQGTLVTVSSGGGGSGGGGSGG 
               
               
                   
                   
                 GGSDIVMTQSAPSVPVTPGESVSISCRSSKSLLHSNGNTYLYWFLQK 
               
               
                   
                   
                 PGQSPQRLIYYMSNLASGVPDRFSGRGSGTDFTLKISRVEAEDVGV 
               
               
                   
                   
                 YYCMQSLEYPLTFGGGTKLEIKR 
               
               
                   
               
               
                 68 
                 18C6 
                 QVTLKESGPTLVKPTQTLTLTCTFSGFSLSTVGMGVGWSRQPSGKG 
               
               
                   
                 H2L2-scFv 
                 LEWLAHIWWDDEDKYYNPALKSRLTITKDTSKNQVVLTITNVDPV 
               
               
                   
                   
                 DTATYYCTRIGTAQATDALDYWGQGTLVTVSSGGGGSGGGGSGG 
               
               
                   
                   
                 GGSDIVMTQSALSLPVTPGEPVSISCRSSKSLLHSNGNTYLYWFLQK 
               
               
                   
                   
                 PGQSPQRLIYYMSNLASGVPDRFSGSGSGTDFTLKISRVEAEDVGV 
               
               
                   
                   
                 YYCMQSLEYPLTFGGGTKLEIKR 
               
               
                   
               
               
                 69 
                 4H11 L2H1- 
                 MGWSCIILFLVATATGKLDIVLTQSPDSLAVSLGERVTMNCKSSQS 
               
               
                   
                 BsAB 
                 LLNSRTRKNQLAWYQQKPGQSPELLIYWASTRQSGVPDRFSGSGS 
               
               
                   
                   
                 GTDFTLTISSVQAEDVAVYYCQQSYNLLTFGQGTKLEIKRGGGGSG 
               
               
                   
                   
                 GGGSGGGGSEVKLQESGGGFVKPGGSLRVSCAASGFTFSSYAMSW 
               
               
                   
                   
                 VRLAPEMRLEWVATISSAGGYIFYSDSVQGRFTISRDNAKNSLHLQ 
               
               
                   
                   
                 MGSLRSGDTAMYYCARQGFGNYGDYYAMDYWGQGTTVTVSSTS 
               
               
                   
                   
                 GGGGSDVQLVQSGAEVKKPGASVKVSCKASGYTFTRYTMHWVRQ 
               
               
                   
                   
                 APGQGLEWIGYINPSRGYTNYADSVKGRFTITTDKSTSTAYMELSS 
               
               
                   
                   
                 LRSEDTATYYCARYYDDHYCLDYWGQGTTVTVSSGEGTSTGSGGS 
               
               
                   
                   
                 GGSGGADDIVLTQSPATLSLSPGERATLSCRASQSVSYMNWYQQK 
               
               
                   
                   
                 PGKAPKRWIYDTSKVASGVPARFSGSGSGTDYSLTINSLEAEDAAT 
               
               
                   
                   
                 YYCQQWSSNPLTFGGGTKVEIKHHHHHH 
               
               
                   
               
               
                 70 
                 4H11 L1H2- 
                 MGWSCIILFLVATATGKLDIELTQSPSSLAVSAGERVTMNCKSSQSL 
               
               
                   
                 BsAB 
                 LNSRTRKNQLAWYQQKPGQSPELLIYWASTRQSGVPDRFSGSGSG 
               
               
                   
                   
                 TDFTLTISSVQAEDVAVYYCQQSYNLLTFGPGTKLEIKRGGGGSGG 
               
               
                   
                   
                 GGSGGGGSEVQLVESGGGLVKPGGSLRVSCAASGFTFSSYAMSWV 
               
               
                   
                   
                 RLAPGKGLEWVATISSAGGYIFYSDSVQGRFTISRDNAKNSLYLQM 
               
               
                   
                   
                 NSLRAEDTAMYYCARQGFGNYGDYYAMDYWGQGTLVTVSS 
               
               
                   
                   
                 TSGGGGSDVQLVQSGAEVKKPGASVKVSCKASGYTFTRYTMHWV 
               
               
                   
                   
                 RQAPGQGLEWIGYINPSRGYTNYADSVKGRFTITTDKSTSTAYMEL 
               
               
                   
                   
                 SSLRSEDTATYYCARYYDDHYCLDYWGQGTTVTVSSGEGTSTGSG 
               
               
                   
                   
                 GSGGSGGADDIVLTQSPATLSLSPGERATLSCRASQSVSYMNWYQ 
               
               
                   
                   
                 QKPGKAPKRWIYDTSKVASGVPARFSGSGSGTDYSLTINSLEAEDA 
               
               
                   
                   
                 ATYYCQQWSSNPLTFGGGTKVEIKHHHHHH 
               
               
                   
               
               
                 71 
                 4H11 L2H2- 
                 MGWSCIILFLVATATGKLDIVLTQSPDSLAVSLGERVTMNCKSSQS 
               
               
                   
                 BsAB 
                 LLNSRTRKNQLAWYQQKPGQSPELLIYWASTRQSGVPDRFSGSGS 
               
               
                   
                   
                 GTDFTLTISSVQAEDVAVYYCQQSYNLLTFGQGTKLEIKR 
               
               
                   
                   
                 GGGGSGGGGSGGGGSEVQLVESGGGLVKPGGSLRVSCAASGFTFS 
               
               
                   
                   
                 SYAMSWVRLAPGKGLEWVATISSAGGYIFYSDSVQGRFTISRDNAK 
               
               
                   
                   
                 NSLYLQMNSLRAEDTAMYYCARQGFGNYGDYYAMDYWGQGTL 
               
               
                   
                   
                 VTVSSTSGGGGSDVQLVQSGAEVKKPGASVKVSCKASGYTFTRYT 
               
               
                   
                   
                 MIHWVRQAPGQGLEWIGYINPSRGYTNYADSVKGRFTITTDKSTST 
               
               
                   
                   
                 AYMELSSLRSEDTATYYCARYYDDHYCLDYWGQGTTVTVSSGEG 
               
               
                   
                   
                 TSTGSGGSGGSGGADDIVLTQSPATLSLSPGERATLSCRASQSVSYM 
               
               
                   
                   
                 NWYQQKPGKAPKRWIYDTSKVASGVPARFSGSGSGTDYSLTINSLE 
               
               
                   
                   
                 AEDAATYYCQQWSSNPLTFGGGTKVEIKHHHHHH 
               
               
                   
               
               
                 72 
                 18C6 
                 MGWSCIILFLVATATGKLDIVMTQSAPSVPVTPGESVSISCRSSKSLL 
               
               
                   
                 L1H1-BsAB 
                 HSNGNTYLYWFLQKPGQSPQRLIYYMSNLASGVPDRFSGRGSGTD 
               
               
                   
                   
                 FTLKISRVEAEDVGVYYCMQSLEYPLTFGGGTKLEIKRGGGGSGGG 
               
               
                   
                   
                 GSGGGGSQVTLKESGPGILQPTQTLTLTCTFSGFSLSTVGMGVGWS 
               
               
                   
                   
                 RQPSGKGLEWLAHIWWDDEDKYYNPALKSRLTITKDTSKNQVFLK 
               
               
                   
                   
                 ITNVDTADTATYYCTRIGTAQATDALDYWGQGTLVTVSSTSGGGG 
               
               
                   
                   
                 SDVQLVQSGAEVKKPGASVKVSCKASGYTFTRYTMHWVRQAPGQ 
               
               
                   
                   
                 GLEWIGYINPSRGYTNYADSVKGRFTITTDKSTSTAYMELSSLRSED 
               
               
                   
                   
                 TATYYCARYYDDHYCLDYWGQGTTVTVSSGEGTSTGSGGSGGSG 
               
               
                   
                   
                 GADDIVLTQSPATLSLSPGERATLSCRASQSVSYMNWYQQKPGKA 
               
               
                   
                   
                 PKRWIYDTSKVASGVPARFSGSGSGTDYSLTINSLEAEDAATYYCQ 
               
               
                   
                   
                 QWSSNPLTFGGGTKVEIKHHHHHH 
               
               
                   
               
               
                 73 
                 18C6 
                 MGWSCIILFLVATATGKLDIVMTQSALSLPVTPGEPVSISCRSSKSLL 
               
               
                   
                 L2H1-BsAB 
                 HSNGNTYLYWFLQKPGQSPQRLIYYMSNLASGVPDRFSGSGSGTDF 
               
               
                   
                   
                 TLKISRVEAEDVGVYYCMQSLEYPLTFGGGTKLEIKRGGGGSGGG 
               
               
                   
                   
                 GSGGGGSQVTLKESGPGILQPTQTLTLTCTFSGFSLSTVGMGVGWS 
               
               
                   
                   
                 RQPSGKGLEWLAHIWWDDEDKYYNPALKSRLTITKDTSKNQVFLK 
               
               
                   
                   
                 ITNVDTADTATYYCTRIGTAQATDALDYWGQGTLVTVSSTSGGGG 
               
               
                   
                   
                 SDVQLVQSGAEVKKPGASVKVSCKASGYTFTRYTMHWVRQAPGQ 
               
               
                   
                   
                 GLEWIGYINPSRGYTNYADSVKGRFTITTDKSTSTAYMELSSLRSED 
               
               
                   
                   
                 TATYYCARYYDDHYCLDYWGQGTTVTVSSGEGTSTGSGGSGGSG 
               
               
                   
                   
                 GADDIVLTQSPATLSLSPGERATLSCRASQSVSYMNWYQQKPGKA 
               
               
                   
                   
                 PKRWIYDTSKVASGVPARFSGSGSGTDYSLTINSLEAEDAATYYCQ 
               
               
                   
                   
                 QWSSNPLTFGGGTKVEIKHHHHHH 
               
               
                   
               
               
                 74 
                 18C6 
                 MGWSCIILFLVATATGKLDIVMTQSAPSVPVTPGESVSISCRSSKSLL 
               
               
                   
                 L1H2-BsAB 
                 HSNGNTYLYWFLQKPGQSPQRLIYYMSNLASGVPDRFSGRGSGTD 
               
               
                   
                   
                 FTLKISRVEAEDVGVYYCMQSLEYPLTFGGGTKLEIKRGGGGSGGG 
               
               
                   
                   
                 GSGGGGSQVTLKESGPTLVKPTQTLTLTCTFSGFSLSTVGMGVGWS 
               
               
                   
                   
                 RQPSGKGLEWLAHIWWDDEDKYYNPALKSRLTITKDTSKNQVVLT 
               
               
                   
                   
                 ITNVDPVDTATYYCTRIGTAQATDALDYWGQGTLVTVSSTSGGGG 
               
               
                   
                   
                 SDVQLVQSGAEVKKPGASVKVSCKASGYTFTRYTMHWVRQAPGQ 
               
               
                   
                   
                 GLEWIGYINPSRGYTNYADSVKGRFTITTDKSTSTAYMELSSLRSED 
               
               
                   
                   
                 TATYYCARYYDDHYCLDYWGQGTTVTVSSGEGTSTGSGGSGGSG 
               
               
                   
                   
                 GADDIVLTQSPATLSLSPGERATLSCRASQSVSYMNWYQQKPGKA 
               
               
                   
                   
                 PKRWIYDTSKVASGVPARFSGSGSGTDYSLTINSLEAEDAATYYCQ 
               
               
                   
                   
                 QWSSNPLTFGGGTKVEIKHHHHHH 
               
               
                   
               
               
                 75 
                 18C6 
                 MGWSCIILFLVATATGKLDIVMTQSALSLPVTPGEPVSISCRSSKSLL 
               
               
                   
                 L2H2-BsAB 
                 HSNGNTYLYWFLQKPGQSPQRLIYYMSNLASGVPDRFSGSGSGTDF 
               
               
                   
                   
                 TLKISRVEAEDVGVYYCMQSLEYPLTFGGGTKLEIKRGGGGSGGG 
               
               
                   
                   
                 GSGGGGSQVTLKESGPTLVKPTQTLTLTCTFSGFSLSTVGMGVGWS 
               
               
                   
                   
                 RQPSGKGLEWLAHIWWDDEDKYYNPALKSRLTITKDTSKNQVVLT 
               
               
                   
                   
                 ITNVDPVDTATYYCTRIGTAQATDALDYWGQGTLVTVSSTSGGGG 
               
               
                   
                   
                 SDVQLVQSGAEVKKPGASVKVSCKASGYTFTRYTMHWVRQAPGQ 
               
               
                   
                   
                 GLEWIGYINPSRGYTNYADSVKGRFTITTDKSTSTAYMELSSLRSED 
               
               
                   
                   
                 TATYYCARYYDDHYCLDYWGQGTTVTVSSGEGTSTGSGGSGGSG 
               
               
                   
                   
                 GADDIVLTQSPATLSLSPGERATLSCRASQSVSYMNWYQQKPGKA 
               
               
                   
                   
                 PKRWIYDTSKVASGVPARFSGSGSGTDYSLTINSLEAEDAATYYCQ 
               
               
                   
                   
                 QWSSNPLTFGGGTKVEIKHHHHHH 
               
               
                   
               
               
                 76 
                 CD8 signal 
                 MALPVTALLLPLALLLHA 
               
               
                   
                 sequence 
                   
               
               
                   
               
               
                 77 
                 CD8 
                 PTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIY 
               
               
                   
                 transmembrane 
                 IWAPLAGTCGVLLLSLVITLYCN 
               
               
                   
                 sequence 
                   
               
               
                   
               
               
                 78 
                 41BB 
                 KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL 
               
               
                   
                 costimulatory 
                   
               
               
                   
                 domain 
                   
               
               
                   
               
               
                 79 
                 CD3 zeta 
                 RVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPE 
               
               
                   
                 chain 
                 MGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHD 
               
               
                   
                   
                 GLYQGLSTATKDTYDALHMQALPPR 
               
               
                   
               
               
                 80 
                 4H11 H1L1- 
                 MALPVTALLLPLALLLHADIELTQSPSSLAVSAGERVTMNCKSSQS 
               
               
                   
                 CAR 
                 LLNSRTRKNQLAWYQQKPGQSPELLIYWASTRQSGVPDRFSGSGS 
               
               
                   
                   
                 GTDFTLTISSVQAEDVAVYYCQQSYNLLTFGPGTKLEIKRGGGGSG 
               
               
                   
                   
                 GGGSGGGGSEVKLQESGGGFVKPGGSLRVSCAASGFTFSSYAMSW 
               
               
                   
                   
                 VRLAPEMRLEWVATISSAGGYIFYSDSVQGRFTISRDNAKNSLHLQ 
               
               
                   
                   
                 MGSLRSGDTAMYYCARQGFGNYGDYYAMDYWGQGTTVTVSSAA 
               
               
                   
                   
                 APTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDI 
               
               
                   
                   
                 YIWAPLAGTCGVLLLSLVITLYCNKRGRKKLLYIFKQPFMRPVQTT 
               
               
                   
                   
                 QEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELN 
               
               
                   
                   
                 LGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAE 
               
               
                   
                   
                 AYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 
               
               
                   
               
               
                 81 
                 4H11 H1L2- 
                 MALPVTALLLPLALLLHAEVKLQESGGGFVKPGGSLRVSCAASGFT 
               
               
                   
                 CAR 
                 FSSYAMSWVRLAPEMRLEWVATISSAGGYIFYSDSVQGRFTISRDN 
               
               
                   
                   
                 AKNSLHLQMGSLRSGDTAMYYCARQGFGNYGDYYAMDYWGQG 
               
               
                   
                   
                 TTVTVSSGGGGSGGGGSGGGGSDIVLTQSPDSLAVSLGERVTMNC 
               
               
                   
                   
                 KSSQSLLNSRTRKNQLAWYQQKPGQSPELLIYWASTRQSGVPDRFS 
               
               
                   
                   
                 GSGSGTDFTLTISSVQAEDVAVYYCQQSYNLLTFGQGTKLEIKRAA 
               
               
                   
                   
                 APTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDI 
               
               
                   
                   
                 YIWAPLAGTCGVLLLSLVITLYCNKRGRKKLLYIFKQPFMRPVQTT 
               
               
                   
                   
                 QEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELN 
               
               
                   
                   
                 LGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAE 
               
               
                   
                   
                 AYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 
               
               
                   
               
               
                 82 
                 4H11 H2L1- 
                 MALPVTALLLPLALLLHAEVQLVESGGGLVKPGGSLRVSCAASGFT 
               
               
                   
                 CAR 
                 FSSYAMSWVRLAPGKGLEWVATISSAGGYIFYSDSVQGRFTISRDN 
               
               
                   
                   
                 AKNSLYLQMNSLRAEDTAMYYCARQGFGNYGDYYAMDYWGQG 
               
               
                   
                   
                 TLVTVSSGGGGSGGGGSGGGGSDIELTQSPSSLAVSAGERVTMNCK 
               
               
                   
                   
                 SSQSLLNSRTRKNQLAWYQQKPGQSPELLIYWASTRQSGVPDRFSG 
               
               
                   
                   
                 SGSGTDFTLTISSVQAEDVAVYYCQQSYNLLTFGPGTKLEIKRAAA 
               
               
                   
                   
                 PTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIY 
               
               
                   
                   
                 IWAPLAGTCGVLLLSLVITLYCNKRGRKKLLYIFKQPFMRPVQTTQ 
               
               
                   
                   
                 EEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNL 
               
               
                   
                   
                 GRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEA 
               
               
                   
                   
                 YSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 
               
               
                   
               
               
                 83 
                 4H11 H2L2- 
                 MALPVTALLLPLALLLHAEVQLVESGGGLVKPGGSLRVSCAASGFT 
               
               
                   
                 CAR 
                 FSSYAMSWVRLAPGKGLEWVATISSAGGYIFYSDSVQGRFTISRDN 
               
               
                   
                   
                 AKNSLYLQMNSLRAEDTAMYYCARQGFGNYGDYYAMDYWGQG 
               
               
                   
                   
                 TLVTVSSGGGGSGGGGSGGGGSDIVLTQSPDSLAVSLGERVTMNC 
               
               
                   
                   
                 KSSQSLLNSRTRKNQLAWYQQKPGQSPELLIYWASTRQSGVPDRFS 
               
               
                   
                   
                 GSGSGTDFTLTISSVQAEDVAVYYCQQSYNLLTFGQGTKLEIKRAA 
               
               
                   
                   
                 APTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDI 
               
               
                   
                   
                 YIWAPLAGTCGVLLLSLVITLYCNKRGRKKLLYIFKQPFMRPVQTT 
               
               
                   
                   
                 QEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELN 
               
               
                   
                   
                 LGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAE 
               
               
                   
                   
                 AYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 
               
               
                   
               
               
                 84 
                 18C6 
                 MALPVTALLLPLALLLHAQVTLKESGPGILQPTQTLTLTCTFSGFSL 
               
               
                   
                 H1L1- 
                 STVGMGVGWSRQPSGKGLEWLAHIWWDDEDKYYNPALKSRLTIT 
               
               
                   
                 CAR 
                 KDTSKNQVFLKITNVDTADTATYYCTRIGTAQATDALDYWGQGTL 
               
               
                   
                   
                 VTVSSGGGGSGGGGSGGGGSDIVMTQSAPSVPVTPGESVSISCRSSK 
               
               
                   
                   
                 SLLHSNGNTYLYWFLQKPGQSPQRLIYYMSNLASGVPDRFSGRGSG 
               
               
                   
                   
                 TDFTLKISRVEAEDVGVYYCMQSLEYPLTFGGGTKLEIKRAAAPTT 
               
               
                   
                   
                 TPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIW 
               
               
                   
                   
                 APLAGTCGVLLLSLVITLYCNKRGRKKLLYIFKQPFMRPVQTTQEE 
               
               
                   
                   
                 DGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGR 
               
               
                   
                   
                 REEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYS 
               
               
                   
                   
                 EIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 
               
               
                   
               
               
                 85 
                 18C6 
                 MALPVTALLLPLALLLHAQVTLKESGPGILQPTQTLTLTCTFSGFSL 
               
               
                   
                 H1L2- 
                 STVGMGVGWSRQPSGKGLEWLAHIWWDDEDKYYNPALKSRLTIT 
               
               
                   
                 CAR 
                 KDTSKNQVFLKITNVDTADTATYYCTRIGTAQATDALDYWGQGTL 
               
               
                   
                   
                 VTVSSGGGGSGGGGSGGGGSDIVMTQSALSLPVTPGEPVSISCRSSK 
               
               
                   
                   
                 SLLHSNGNTYLYWFLQKPGQSPQRLIYYMSNLASGVPDRFSGSGSG 
               
               
                   
                   
                 TDFTLKISRVEAEDVGVYYCMQSLEYPLTFGGGTKLEIKRAAAPTT 
               
               
                   
                   
                 TPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIW 
               
               
                   
                   
                 APLAGTCGVLLLSLVITLYCNKRGRKKLLYIFKQPFMRPVQTTQEE 
               
               
                   
                   
                 DGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGR 
               
               
                   
                   
                 REEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYS 
               
               
                   
                   
                 EIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 
               
               
                   
               
               
                 86 
                 18C6 
                 MALPVTALLLPLALLLHAQVTLKESGPTLVKPTQTLTLTCTFSGFSL 
               
               
                   
                 H2L1- 
                 STVGMGVGWSRQPSGKGLEWLAHIWWDDEDKYYNPALKSRLTIT 
               
               
                   
                 CAR 
                 KDTSKNQVVLTITNVDPVDTATYYCTRIGTAQATDALDYWGQGTL 
               
               
                   
                   
                 VTVSSGGGGSGGGGSGGGGSDIVMTQSAPSVPVTPGESVSISCRSSK 
               
               
                   
                   
                 SLLHSNGNTYLYWFLQKPGQSPQRLIYYMSNLASGVPDRFSGRGSG 
               
               
                   
                   
                 TDFTLKISRVEAEDVGVYYCMQSLEYPLTFGGGTKLEIKRAAAPTT 
               
               
                   
                   
                 TPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIW 
               
               
                   
                   
                 APLAGTCGVLLLSLVITLYCNKRGRKKLLYIFKQPFMRPVQTTQEE 
               
               
                   
                   
                 DGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGR 
               
               
                   
                   
                 REEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYS 
               
               
                   
                   
                 EIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 
               
               
                   
               
               
                 87 
                 18C6 
                 MALPVTALLLPLALLLHAQVTLKESGPTLVKPTQTLTLTCTFSGFSL 
               
               
                   
                 H2L2- 
                 STVGMGVGWSRQPSGKGLEWLAHIWWDDEDKYYNPALKSRLTIT 
               
               
                   
                 CAR 
                 KDTSKNQVVLTITNVDPVDTATYYCTRIGTAQATDALDYWGQGTL 
               
               
                   
                   
                 VTVSSGGGGSGGGGSGGGGSDIVMTQSALSLPVTPGEPVSISCRSSK 
               
               
                   
                   
                 SLLHSNGNTYLYWFLQKPGQSPQRLIYYMSNLASGVPDRFSGSGSG 
               
               
                   
                   
                 TDFTLKISRVEAEDVGVYYCMQSLEYPLTFGGGTKLEIKRAAAPTT 
               
               
                   
                   
                 TPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIW 
               
               
                   
                   
                 APLAGTCGVLLLSLVITLYCNKRGRKKLLYIFKQPFMRPVQTTQEE 
               
               
                   
                   
                 DGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGR 
               
               
                   
                   
                 REEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYS 
               
               
                   
                   
                 EIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 
               
               
                   
               
               
                 88 
                 4H11 H1L1- 
                 MGWSCIILFLVATATGKLEVKLQESGGGFVKPGGSLRVSCAASGFT 
               
               
                   
                 BsAb 
                 FSSYAMSWVRLAPEMRLEWVATISSAGGYIFYSDSVQGRFTISRDN 
               
               
                   
                   
                 AKNSLHLQMGSLRSGDTAMYYCARQGFGNYGDYYAMDYWGQG 
               
               
                   
                   
                 TTVTVSSGGGGSGGGGSGGGGSDIELTQSPSSLAVSAGERVTMNCK 
               
               
                   
                   
                 SSQSLLNSRTRKNQLAWYQQKPGQSPELLIYWASTRQSGVPDRFSG 
               
               
                   
                   
                 SGSGTDFTLTISSVQAEDVAVYYCQQSYNLLTFGPGTKLEIKRTSGG 
               
               
                   
                   
                 GGSDVQLVQSGAEVKKPGASVKVSCKASGYTFTRYTMHWVRQAP 
               
               
                   
                   
                 GQGLEWIGYINPSRGYTNYADSVKGRFTITTDKSTSTAYMELSSLRS 
               
               
                   
                   
                 EDTATYYCARYYDDHYCLDYWGQGTTVTVSSGEGTSTGSGGSGG 
               
               
                   
                   
                 SGGADDIVLTQSPATLSLSPGERATLSCRASQSVSYMNWYQQKPG 
               
               
                   
                   
                 KAPKRWIYDTSKVASGVPARFSGSGSGTDYSLTINSLEAEDAATYY 
               
               
                   
                   
                 CQQWSSNPLTFGGGTKVEIKHHHHHH 
               
               
                   
               
               
                 89 
                 4H11 H1L2- 
                 MGWSCIILFLVATATGKLEVKLQESGGGFVKPGGSLRVSCAASGFT 
               
               
                   
                 BsAb 
                 FSSYAMSWVRLAPEMRLEWVATISSAGGYIFYSDSVQGRFTISRDN 
               
               
                   
                   
                 AKNSLHLQMGSLRSGDTAMYYCARQGFGNYGDYYAMDYWGQG 
               
               
                   
                   
                 TTVTVSSGGGGSGGGGSGGGGSDIVLTQSPDSLAVSLGERVTMNC 
               
               
                   
                   
                 KSSQSLLNSRTRKNQLAWYQQKPGQSPELLIYWASTRQSGVPDRFS 
               
               
                   
                   
                 GSGSGTDFTLTISSVQAEDVAVYYCQQSYNLLTFGQGTKLEIKRTS 
               
               
                   
                   
                 GGGGSDVQLVQSGAEVKKPGASVKVSCKASGYTFTRYTMHWVRQ 
               
               
                   
                   
                 APGQGLEWIGYINPSRGYTNYADSVKGRFTITTDKSTSTAYMELSS 
               
               
                   
                   
                 LRSEDTATYYCARYYDDHYCLDYWGQGTTVTVSSGEGTSTGSGGS 
               
               
                   
                   
                 GGSGGADDIVLTQSPATLSLSPGERATLSCRASQSVSYMNWYQQK 
               
               
                   
                   
                 PGKAPKRWIYDTSKVASGVPARFSGSGSGTDYSLTINSLEAEDAAT 
               
               
                   
                   
                 YYCQQWSSNPLTFGGGTKVEIKHHHHHH 
               
               
                   
               
               
                 90 
                 4H11 H2L1- 
                 MGWSCIILFLVATATGKLEVQLVESGGGLVKPGGSLRVSCAASGFT 
               
               
                   
                 BsAb 
                 FSSYAMSWVRLAPGKGLEWVATISSAGGYIFYSDSVQGRFTISRDN 
               
               
                   
                   
                 AKNSLYLQMNSLRAEDTAMYYCARQGFGNYGDYYAMDYWGQG 
               
               
                   
                   
                 TLVTVSSGGGGSGGGGSGGGGSDIELTQSPSSLAVSAGERVTMNCK 
               
               
                   
                   
                 SSQSLLNSRTRKNQLAWYQQKPGQSPELLIYWASTRQSGVPDRFSG 
               
               
                   
                   
                 SGSGTDFTLTISSVQAEDVAVYYCQQSYNLLTFGPGTKLEIKRTSGG 
               
               
                   
                   
                 GGSDVQLVQSGAEVKKPGASVKVSCKASGYTFTRYTMHWVRQAP 
               
               
                   
                   
                 GQGLEWIGYINPSRGYTNYADSVKGRFTITTDKSTSTAYMELSSLRS 
               
               
                   
                   
                 EDTATYYCARYYDDHYCLDYWGQGTTVTVSSGEGTSTGSGGSGG 
               
               
                   
                   
                 SGGADDIVLTQSPATLSLSPGERATLSCRASQSVSYMNWYQQKPG 
               
               
                   
                   
                 KAPKRWIYDTSKVASGVPARFSGSGSGTDYSLTINSLEAEDAATYY 
               
               
                   
                   
                 CQQWSSNPLTFGGGTKVEIKHHHHHH 
               
               
                   
               
               
                 91 
                 4H11 H2L2- 
                 MGWSCIILFLVATATGKLEVQLVESGGGLVKPGGSLRVSCAASGFT 
               
               
                   
                 BsAb 
                 FSSYAMSWVRLAPGKGLEWVATISSAGGYIFYSDSVQGRFTISRDN 
               
               
                   
                   
                 AKNSLYLQMNSLRAEDTAMYYCARQGFGNYGDYYAMDYWGQG 
               
               
                   
                   
                 TLVTVSSGGGGSGGGGSGGGGSDIVLTQSPDSLAVSLGERVTMNC 
               
               
                   
                   
                 KSSQSLLNSRTRKNQLAWYQQKPGQSPELLIYWASTRQSGVPDRFS 
               
               
                   
                   
                 GSGSGTDFTLTISSVQAEDVAVYYCQQSYNLLTFGQGTKLEIKRTS 
               
               
                   
                   
                 GGGGSDVQLVQSGAEVKKPGASVKVSCKASGYTFTRYTMHWVRQ 
               
               
                   
                   
                 APGQGLEWIGYINPSRGYTNYADSVKGRFTITTDKSTSTAYMELSS 
               
               
                   
                   
                 LRSEDTATYYCARYYDDHYCLDYWGQGTTVTVSSGEGTSTGSGGS 
               
               
                   
                   
                 GGSGGADDIVLTQSPATLSLSPGERATLSCRASQSVSYMNWYQQK 
               
               
                   
                   
                 PGKAPKRWIYDTSKVASGVPARFSGSGSGTDYSLTINSLEAEDAAT 
               
               
                   
                   
                 YYCQQWSSNPLTFGGGTKVEIKHHHHHH 
               
               
                   
               
               
                 92 
                 18C6 
                 MGWSCIILFLVATATGKLQVTLKESGPGILQPTQTLTLTCTFSGFSLS 
               
               
                   
                 H1L1- 
                 TVGMGVGWSRQPSGKGLEWLAHIWWDDEDKYYNPALKSRLTITK 
               
               
                   
                 BsAb 
                 DTSKNQVFLKITNVDTADTATYYCTRIGTAQATDALDYWGQGTLV 
               
               
                   
                   
                 TVSSGGGGSGGGGSGGGGSDIVMTQSAPSVPVTPGESVSISCRSSKS 
               
               
                   
                   
                 LLHSNGNTYLYWFLQKPGQSPQRLIYYMSNLASGVPDRFSGRGSG 
               
               
                   
                   
                 TDFTLKISRVEAEDVGVYYCMQSLEYPLTFGGGTKLEIKRTSGGGG 
               
               
                   
                   
                 SDVQLVQSGAEVKKPGASVKVSCKASGYTFTRYTMHWVRQAPGQ 
               
               
                   
                   
                 GLEWIGYINPSRGYTNYADSVKGRFTITTDKSTSTAYMELSSLRSED 
               
               
                   
                   
                 TATYYCARYYDDHYCLDYWGQGTTVTVSSGEGTSTGSGGSGGSG 
               
               
                   
                   
                 GADDIVLTQSPATLSLSPGERATLSCRASQSVSYMNWYQQKPGKA 
               
               
                   
                   
                 PKRWIYDTSKVASGVPARFSGSGSGTDYSLTINSLEAEDAATYYCQ 
               
               
                   
                   
                 QWSSNPLTFGGGTKVEIKHHHHHH 
               
               
                   
               
               
                 93 
                 18C6 
                 MGWSCIILFLVATATGKLQVTLKESGPGILQPTQTLTLTCTFSGFSLS 
               
               
                   
                 H1L2- 
                 TVGMGVGWSRQPSGKGLEWLAHIWWDDEDKYYNPALKSRLTITK 
               
               
                   
                 BsAb 
                 DTSKNQVFLKITNVDTADTATYYCTRIGTAQATDALDYWGQGTLV 
               
               
                   
                   
                 TVSSGGGGSGGGGSGGGGSDIVMTQSALSLPVTPGEPVSISCRSSKS 
               
               
                   
                   
                 LLHSNGNTYLYWFLQKPGQSPQRLIYYMSNLASGVPDRFSGSGSGT 
               
               
                   
                   
                 DFTLKISRVEAEDVGVYYCMQSLEYPLTFGGGTKLEIKRTSGGGGS 
               
               
                   
                   
                 DVQLVQSGAEVKKPGASVKVSCKASGYTFTRYTMHWVRQAPGQG 
               
               
                   
                   
                 LEWIGYINPSRGYTNYADSVKGRFTITTDKSTSTAYMELSSLRSEDT 
               
               
                   
                   
                 ATYYCARYYDDHYCLDYWGQGTTVTVSSGEGTSTGSGGSGGSGG 
               
               
                   
                   
                 ADDIVLTQSPATLSLSPGERATLSCRASQSVSYMNWYQQKPGKAP 
               
               
                   
                   
                 KRWIYDTSKVASGVPARFSGSGSGTDYSLTINSLEAEDAATYYCQQ 
               
               
                   
                   
                 WSSNPLTFGGGTKVEIKHHHHHH 
               
               
                   
               
               
                 94 
                 18C6 
                 MGWSCIILFLVATATGKLQVTLKESGPTLVKPTQTLTLTCTFSGFSL 
               
               
                   
                 H2L1- 
                 STVGMGVGWSRQPSGKGLEWLAHIWWDDEDKYYNPALKSRLTIT 
               
               
                   
                 BsAb 
                 KDTSKNQVVLTITNVDPVDTATYYCTRIGTAQATDALDYWGQGTL 
               
               
                   
                   
                 VTVSSGGGGSGGGGSGGGGSDIVMTQSAPSVPVTPGESVSISCRSSK 
               
               
                   
                   
                 SLLHSNGNTYLYWFLQKPGQSPQRLIYYMSNLASGVPDRFSGRGSG 
               
               
                   
                   
                 TDFTLKISRVEAEDVGVYYCMQSLEYPLTFGGGTKLEIKRTSGGGG 
               
               
                   
                   
                 SDVQLVQSGAEVKKPGASVKVSCKASGYTFTRYTMHWVRQAPGQ 
               
               
                   
                   
                 GLEWIGYINPSRGYTNYADSVKGRFTITTDKSTSTAYMELSSLRSED 
               
               
                   
                   
                 TATYYCARYYDDHYCLDYWGQGTTVTVSSGEGTSTGSGGSGGSG 
               
               
                   
                   
                 GADDIVLTQSPATLSLSPGERATLSCRASQSVSYMNWYQQKPGKA 
               
               
                   
                   
                 PKRWIYDTSKVASGVPARFSGSGSGTDYSLTINSLEAEDAATYYCQ 
               
               
                   
                   
                 QWSSNPLTFGGGTKVEIKHHHHHH 
               
               
                   
               
               
                 95 
                 18C6 
                 MGWSCIILFLVATATGKLQVTLKESGPTLVKPTQTLTLTCTFSGFSL 
               
               
                   
                 H2L2- 
                 STVGMGVGWSRQPSGKGLEWLAHIWWDDEDKYYNPALKSRLTIT 
               
               
                   
                 BsAb 
                 KDTSKNQVVLTITNVDPVDTATYYCTRIGTAQATDALDYWGQGTL 
               
               
                   
                   
                 VTVSSGGGGSGGGGSGGGGSDIVMTQSALSLPVTPGEPVSISCRSSK 
               
               
                   
                   
                 SLLHSNGNTYLYWFLQKPGQSPQRLIYYMSNLASGVPDRFSGSGSG 
               
               
                   
                   
                 TDFTLKISRVEAEDVGVYYCMQSLEYPLTFGGGTKLEIKRTSGGGG 
               
               
                   
                   
                 SDVQLVQSGAEVKKPGASVKVSCKASGYTFTRYTMHWVRQAPGQ 
               
               
                   
                   
                 GLEWIGYINPSRGYTNYADSVKGRFTITTDKSTSTAYMELSSLRSED 
               
               
                   
                   
                 TATYYCARYYDDHYCLDYWGQGTTVTVSSGEGTSTGSGGSGGSG 
               
               
                   
                   
                 GADDIVLTQSPATLSLSPGERATLSCRASQSVSYMNWYQQKPGKA 
               
               
                   
                   
                 PKRWIYDTSKVASGVPARFSGSGSGTDYSLTINSLEAEDAATYYCQ 
               
               
                   
                   
                 QWSSNPLTFGGGTKVEIKHHHHHH 
               
               
                   
               
               
                 96 
                 4H11 L1H1- 
                 MALPVTALLLPLALLLHADIELTQSPSSLAVSAGERVTMNCKSSQS 
               
               
                   
                 CAR 
                 LLNSRTRKNQLAWYQQKPGQSPELLIYWASTRQSGVPDRFSGSGS 
               
               
                   
                   
                 GTDFTLTISSVQAEDVAVYYCQQSYNLLTFGPGTKLEIKRGGGGSG 
               
               
                   
                   
                 GGGSGGGGSEVKLQESGGGFVKPGGSLRVSCAASGFTFSSYAMSW 
               
               
                   
                   
                 VRLAPEMRLEWVATISSAGGYIFYSDSVQGRFTISRDNAKNSLHLQ 
               
               
                   
                   
                 MGSLRSGDTAMYYCARQGFGNYGDYYAMDYWGQGTTVTVSSAA 
               
               
                   
                   
                 APTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDI 
               
               
                   
                   
                 YIWAPLAGTCGVLLLSLVITLYCNKRGRKKLLYIFKQPFMRPVQTT 
               
               
                   
                   
                 QEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELN 
               
               
                   
                   
                 LGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAE 
               
               
                   
                   
                 AYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 
               
               
                   
               
               
                 97 
                 4H11 L2H1- 
                 MALPVTALLLPLALLLHADIVLTQSPDSLAVSLGERVTMNCKSSQS 
               
               
                   
                 CAR 
                 LLNSRTRKNQLAWYQQKPGQSPELLIYWASTRQSGVPDRFSGSGS 
               
               
                   
                   
                 GTDFTLTISSVQAEDVAVYYCQQSYNLLTFGQGTKLEIKRGGGGSG 
               
               
                   
                   
                 GGGSGGGGSEVKLQESGGGFVKPGGSLRVSCAASGFTFSSYAMSW 
               
               
                   
                   
                 VRLAPEMRLEWVATISSAGGYIFYSDSVQGRFTISRDNAKNSLHLQ 
               
               
                   
                   
                 MGSLRSGDTAMYYCARQGFGNYGDYYAMDYWGQGTTVTVSSAA 
               
               
                   
                   
                 APTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDI 
               
               
                   
                   
                 YIWAPLAGTCGVLLLSLVITLYCNKRGRKKLLYIFKQPFMRPVQTT 
               
               
                   
                   
                 QEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELN 
               
               
                   
                   
                 LGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAE 
               
               
                   
                   
                 AYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 
               
               
                   
               
               
                 98 
                 4H11 L1H2- 
                 MALPVTALLLPLALLLHADIELTQSPSSLAVSAGERVTMNCKSSQS 
               
               
                   
                 CAR 
                 LLNSRTRKNQLAWYQQKPGQSPELLIYWASTRQSGVPDRFSGSGS 
               
               
                   
                   
                 GTDFTLTISSVQAEDVAVYYCQQSYNLLTFGPGTKLEIKRGGGGSG 
               
               
                   
                   
                 GGGSGGGGSEVQLVESGGGLVKPGGSLRVSCAASGFTFSSYAMSW 
               
               
                   
                   
                 VRLAPGKGLEWVATISSAGGYIFYSDSVQGRFTISRDNAKNSLYLQ 
               
               
                   
                   
                 MNSLRAEDTAMYYCARQGFGNYGDYYAMDYWGQGTLVTVSSAA 
               
               
                   
                   
                 APTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDI 
               
               
                   
                   
                 YIWAPLAGTCGVLLLSLVITLYCNKRGRKKLLYIFKQPFMRPVQTT 
               
               
                   
                   
                 QEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELN 
               
               
                   
                   
                 LGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAE 
               
               
                   
                   
                 AYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 
               
               
                   
               
               
                 99 
                 4H11 L2H2- 
                 MALPVTALLLPLALLLHADIVLTQSPDSLAVSLGERVTMNCKSSQS 
               
               
                   
                 CAR 
                 LLNSRTRKNQLAWYQQKPGQSPELLIYWASTRQSGVPDRFSGSGS 
               
               
                   
                   
                 GTDFTLTISSVQAEDVAVYYCQQSYNLLTFGQGTKLEIKRGGGGSG 
               
               
                   
                   
                 GGGSGGGGSEVQLVESGGGLVKPGGSLRVSCAASGFTFSSYAMSW 
               
               
                   
                   
                 VRLAPGKGLEWVATISSAGGYIFYSDSVQGRFTISRDNAKNSLYLQ 
               
               
                   
                   
                 MNSLRAEDTAMYYCARQGFGNYGDYYAMDYWGQGTLVTVSSAA 
               
               
                   
                   
                 APTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDI 
               
               
                   
                   
                 YIWAPLAGTCGVLLLSLVITLYCNKRGRKKLLYIFKQPFMRPVQTT 
               
               
                   
                   
                 QEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELN 
               
               
                   
                   
                 LGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAE 
               
               
                   
                   
                 AYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 
               
               
                   
               
               
                 100 
                 18C6 
                 MALPVTALLLPLALLLHADIVMTQSAPSVPVTPGESVSISCRSSKSL 
               
               
                   
                 L1H1- 
                 LHSNGNTYLYWFLQKPGQSPQRLIYYMSNLASGVPDRFSGRGSGT 
               
               
                   
                 CAR 
                 DFTLKISRVEAEDVGVYYCMQSLEYPLTFGGGTKLEIKRGGGGSGG 
               
               
                   
                   
                 GGSGGGGSQVTLKESGPGILQPTQTLTLTCTFSGFSLSTVGMGVGW 
               
               
                   
                   
                 SRQPSGKGLEWLAHIWWDDEDKYYNPALKSRLTITKDTSKNQVFL 
               
               
                   
                   
                 KITNVDTADTATYYCTRIGTAQATDALDYWGQGTLVTVSSAAAPT 
               
               
                   
                   
                 TTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYI 
               
               
                   
                   
                 WAPLAGTCGVLLLSLVITLYCNKRGRKKLLYIF&#39;KQPFMRPVQTTQE 
               
               
                   
                   
                 EDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLG 
               
               
                   
                   
                 RREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAY 
               
               
                   
                   
                 SEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 
               
               
                   
               
               
                 101 
                 18C6 
                 MALPVTALLLPLALLLHADIVMTQSALSLPVTPGEPVSISCRSSKSL 
               
               
                   
                 L2H1- 
                 LHSNGNTYLYWFLQKPGQSPQRLIYYMSNLASGVPDRFSGSGSGT 
               
               
                   
                 CAR 
                 DFTLKISRVEAEDVGVYYCMQSLEYPLTFGGGTKLEIKRGGGGSGG 
               
               
                   
                   
                 GGSGGGGSQVTLKESGPGILQPTQTLTLTCTFSGFSLSTVGMGVGW 
               
               
                   
                   
                 SRQPSGKGLEWLAHIWWDDEDKYYNPALKSRLTITKDTSKNQVFL 
               
               
                   
                   
                 KITNVDTADTATYYCTRIGTAQATDALDYWGQGTLVTVSSAAAPT 
               
               
                   
                   
                 TTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYI 
               
               
                   
                   
                 WAPLAGTCGVLLLSLVITLYCNKRGRKKLLYIFKQPFMRPVQTTQE 
               
               
                   
                   
                 EDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLG 
               
               
                   
                   
                 RREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAY 
               
               
                   
                   
                 SEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 
               
               
                   
               
               
                 102 
                 18C6 
                 MALPVTALLLPLALLLHADIVMTQSAPSVPVTPGESVSISCRSSKSL 
               
               
                   
                 L1H2- 
                 LHSNGNTYLYWFLQKPGQSPQRLIYYMSNLASGVPDRFSGRGSGT 
               
               
                   
                 CAR 
                 DFTLKISRVEAEDVGVYYCMQSLEYPLTFGGGTKLEIKRGGGGSGG 
               
               
                   
                   
                 GGSGGGGSQVTLKESGPTLVKPTQTLTLTCTFSGFSLSTVGMGVG 
               
               
                   
                   
                 WSRQPSGKGLEWLAHIWWDDEDKYYNPALKSRLTITKDTSKNQV 
               
               
                   
                   
                 VLTITNVDPVDTATYYCTRIGTAQATDALDYWGQGTLVTVSSAAA 
               
               
                   
                   
                 PTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIY 
               
               
                   
                   
                 IWAPLAGTCGVLLLSLVITLYCNKRGRKKLLYIFKQPFMRPVQTTQ 
               
               
                   
                   
                 EEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNL 
               
               
                   
                   
                 GRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEA 
               
               
                   
                   
                 YSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 
               
               
                   
               
               
                 103 
                 18C6 
                 MALPVTALLLPLALLLHADIVMTQSALSLPVTPGEPVSISCRSSKSL 
               
               
                   
                 L2H2- 
                 LHSNGNTYLYWFLQKPGQSPQRLIYYMSNLASGVPDRFSGSGSGT 
               
               
                   
                 CAR 
                 DFTLKISRVEAEDVGVYYCMQSLEYPLTFGGGTKLEIKRGGGGSGG 
               
               
                   
                   
                 GGSGGGGSQVTLKESGPTLVKPTQTLTLTCTFSGFSLSTVGMGVG 
               
               
                   
                   
                 WSRQPSGKGLEWLAHIWWDDEDKYYNPALKSRLTITKDTSKNQV 
               
               
                   
                   
                 VLTITNVDPVDTATYYCTRIGTAQATDALDYWGQGTLVTVSSAAA 
               
               
                   
                   
                 PTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIY 
               
               
                   
                   
                 IWAPLAGTCGVLLLSLVITLYCNKRGRKKLLYIFKQPFMRPVQTTQ 
               
               
                   
                   
                 EEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNL 
               
               
                   
                   
                 GRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEA 
               
               
                   
                   
                 YSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 
               
               
                   
               
               
                 104 
                 4H11 LFW1 
                 DIELTQSPSSLAVSAGEKVTMSC 
               
               
                   
                 mouse 
                   
               
               
                   
               
               
                 105 
                 4H11 LFW2 
                 WYQQKPGQSPELLIY 
               
               
                   
                 mouse 
                   
               
               
                   
               
               
                 106 
                 4H11 LFW3 
                 GVPDRFTGSGSGTDFTLTISSVQAEDLAVYYC 
               
               
                   
                 mouse 
                   
               
               
                   
               
               
                 107 
                 4H11 LFW4 
                 FGPGTKLEVKR 
               
               
                   
                 mouse 
                   
               
               
                   
               
               
                 108 
                 Human 
                 DIVMTQSPDSLAVSL ERATINC 
               
               
                   
                 IGKV4-1*01 
                   
               
               
                   
                 LFW1 
                   
               
               
                   
               
               
                 109 
                 Human 
                 WYQQKPGQPPKLLIY 
               
               
                   
                 IGKV4-1*01 
                   
               
               
                   
                 LFW2 
                   
               
               
                   
               
               
                 110 
                 Human 
                 GVPDRFSGSGSGTDFTLTISSLQAEDVAVYYC 
               
               
                   
                 IGKV4-1*01 
                   
               
               
                   
                 LFW3 
                   
               
               
                   
               
               
                 111 
                 Human 
                 FGQGTKLEIKR 
               
               
                   
                 IGKJ2*01 
                   
               
               
                   
                 LFW4 
                   
               
               
                   
               
               
                 112 
                 4H11 L1- 
                 DIELTQSPSSLAVSAGERVTMNC 
               
               
                   
                 FW1 
                   
               
               
                   
               
               
                 113 
                 4H11 L1- 
                 WYQQKPGQSPELLIY 
               
               
                   
                 FW2 
                   
               
               
                   
               
               
                 114 
                 4H11 L1- 
                 GVPDRFSGSGSGTDFTLTISSVQAEDVAVYYC 
               
               
                   
                 FW3 
                   
               
               
                   
               
               
                 115 
                 4H11 L1- 
                 FGPGTKLEIKR 
               
               
                   
                 FW4 
                   
               
               
                   
               
               
                 116 
                 4H11 L2- 
                 DIVLTQSPDSLAVSLGERVTMNC 
               
               
                   
                 FW1 
                   
               
               
                   
               
               
                 117 
                 4H11 L2- 
                 WYQQKPGQSPELLIY 
               
               
                   
                 FW2 
                   
               
               
                   
               
               
                 118 
                 4H11 L2- 
                 GVPDRFSGSGSGTDFTLTISSVQAEDVAVYYC 
               
               
                   
                 FW3 
                   
               
               
                   
               
               
                 119 
                 4H11 L2- 
                 FGQGTKLEIKR 
               
               
                   
                 FW4 
                   
               
               
                   
               
               
                 120 
                 4H11 LFW1 
                 DIXLTQSPXSLAVSXGEXVTMXC 
               
               
                   
                 consensus 
                   
               
               
                   
               
               
                 121 
                 4H11 LFW2 
                 WYQQKPGQSPELLIY 
               
               
                   
                 consensus 
                   
               
               
                   
               
               
                 122 
                 4H11 LFW3 
                 GVPDRFXGSGSGTDFTLTISSVQAEDXAVYYC 
               
               
                   
                 consensus 
                   
               
               
                   
               
               
                 123 
                 4H11 LFW4 
                 FGXGTKLEXKR 
               
               
                   
                 consensus 
                   
               
               
                   
               
               
                 124 
                 4H11 HFW1 
                 SVKLQESGGGFVKPGGSLKVSCAASGFTFS 
               
               
                   
                 mouse 
                   
               
               
                   
               
               
                 125 
                 4H11 HFW2 
                 WVRLSPEMRLEWVA 
               
               
                   
                 mouse 
                   
               
               
                   
               
               
                 126 
                 4H11 HFW3 
                 RFTISRDNAKNTLHLQMGSLRSGDTAMYYCAR 
               
               
                   
                 mouse 
                   
               
               
                   
               
               
                 127 
                 Human 
                 EVQLVESGGGLVKPGGSLRLSCAASGFTFS 
               
               
                   
                 IGHV3-21*01 
                   
               
               
                   
                 HFW1 
                   
               
               
                   
               
               
                 128 
                 Human 
                 WVRQAPGKGLEWVS 
               
               
                   
                 IGHV3- 
                   
               
               
                   
                 21*01 
                   
               
               
                   
                 HFW2 
                   
               
               
                   
               
               
                 129 
                 Human 
                 RFTISRDNAKNSLYLQMNSLRAEDTAVYYCAR 
               
               
                   
                 IGHV3-21*01 
                   
               
               
                   
                 HFW3 
                   
               
               
                   
               
               
                 130 
                 4H11 H1- 
                 EVKLQESGGGFVKPGGSLRVSCAASGFTFS 
               
               
                   
                 FW1 
                   
               
               
                   
               
               
                 131 
                 4H11 H1- 
                 WVRLAPEMRLEWVA 
               
               
                   
                 FW2 
                   
               
               
                   
               
               
                 132 
                 4H11 H1- 
                 RFTISRDNAKNSLHLQMGSLRSGDTAMYYCAR 
               
               
                   
                 FW3 
                   
               
               
                   
               
               
                 133 
                 4H11 H2- 
                 EVQLVESGGGLVKPGGSLRVSCAASGFTFS 
               
               
                   
                 FW1 
                   
               
               
                   
               
               
                 134 
                 4H11 H2- 
                 WVRLAPGKGLEWVA 
               
               
                   
                 FW2 
                   
               
               
                   
               
               
                 135 
                 4H11 H2- 
                 RFTISRDNAKNSLYLQMNSLRAEDTAMYYCAR 
               
               
                   
                 FW3 
                   
               
               
                   
               
               
                 136 
                 4H11 HFW1 
                 XVXLXESGGGXVKPGGSLXVSCAASGFTFS 
               
               
                   
                 consensus 
                   
               
               
                   
               
               
                 137 
                 4H11 HFW2 
                 WVRLXPXXXLEWVA 
               
               
                   
                 consensus 
                   
               
               
                   
               
               
                 138 
                 4H11 HFW3 
                 RFTISRDNAKNXLXLQMXSLRXXDTAMYYCAR 
               
               
                   
                 consensus 
                   
               
               
                   
               
               
                 139 
                 18C6 LFW1 
                 DIVMTQAAPSVPVTPGESVSISC 
               
               
                   
                 mouse 
                   
               
               
                   
               
               
                 140 
                 18C6 LFW2 
                 WFLQRPGQSPQRLIY 
               
               
                   
                 mouse 
                   
               
               
                   
               
               
                 141 
                 18C6 LFW3 
                 GVPDRFSGRGSGTDFTLRISRVEAEDVGVYYC 
               
               
                   
                 mouse 
                   
               
               
                   
               
               
                 142 
                 18C6 LFW4 
                 FGGGTKLEIK 
               
               
                   
                 mouse 
                   
               
               
                   
               
               
                 143 
                 Human 
                 DIVMTQSPLSLPVTPGEPASISC 
               
               
                   
                 KV2-28*01 
                   
               
               
                   
                 LFW1 
                   
               
               
                   
               
               
                 144 
                 Human 
                 WYLQKPGQSPQLLIY 
               
               
                   
                 KV2-28*01 
                   
               
               
                   
                 LFW2 
                   
               
               
                   
               
               
                 145 
                 Human 
                 GVPDRFSGSGSGTDFTLKISRVEAEDVGVYYC 
               
               
                   
                 KV2-28*01 
                   
               
               
                   
                 LFW3 
                   
               
               
                   
               
               
                 146 
                 Human 
                 FGGGTKVEIK 
               
               
                   
                 J4*01 
                   
               
               
                   
                 LFW4 
                   
               
               
                   
               
               
                 147 
                 18C6 
                 DIVMTQSAPSVPVTPGESVSISC 
               
               
                   
                 L1-FW1 
                   
               
               
                   
               
               
                 148 
                 18C6 
                 WFLQKPGQSPQRLIY 
               
               
                   
                 L1-FW2 
                   
               
               
                   
               
               
                 149 
                 18C6 
                 GVPDRFSGRGSGTDFTLKISRVEAEDVGVYYC 
               
               
                   
                 L1-FW3 
                   
               
               
                   
               
               
                 150 
                 18C6 
                 FGGGTKLEIK 
               
               
                   
                 L1-FW4 
                   
               
               
                   
               
               
                 151 
                 18C6 
                 DIVMTQSALSLPVTPGEPVSISC 
               
               
                   
                 L2-FW1 
                   
               
               
                   
               
               
                 152 
                 18C6 
                 WFLQKPGQSPQRLIY 
               
               
                   
                 L2-FW2 
                   
               
               
                   
               
               
                 153 
                 18C6 
                 GVPDRFSGSGSGTDFTLKISRVEAEDVGVYYC 
               
               
                   
                 L2-FW3 
                   
               
               
                   
               
               
                 154 
                 18C6 
                 FGGGTKLEIK 
               
               
                   
                 L2-FW4 
                   
               
               
                   
               
               
                 155 
                 18C6 LFW1 
                 DIVMTQXAXSXPVTPGEXVSISC 
               
               
                   
                 consensus 
                   
               
               
                   
               
               
                 156 
                 18C6 LFW2 
                 WFLQXPGQSPQRLIY 
               
               
                   
                 consensus 
                   
               
               
                   
               
               
                 157 
                 18C6 LFW3 
                 GVPDRFSGXGSGTDFTLXISRVEAEDVGVYYC 
               
               
                   
                 consensus 
                   
               
               
                   
               
               
                 158 
                 18C6 LFW4 
                 FGGGTKLEIK 
               
               
                   
                 consensus 
                   
               
               
                   
               
               
                 159 
                 18C6 HFW1 
                 QVTLKESGPGILQPSQTLSLTCSFSGFSLS 
               
               
                   
                 mouse 
                   
               
               
                   
               
               
                 160 
                 18C6 HFW2 
                 WSRQPSGKGLEWLA 
               
               
                   
                 mouse 
                   
               
               
                   
               
               
                 161 
                 18C6 HFW3 
                 RLTISKDTSKNQVFLKIANVDTADTATYYCTR 
               
               
                   
                 mouse 
                   
               
               
                   
               
               
                 162 
                 18C6 HFW4 
                 WGQGTSVTVSS 
               
               
                   
                 mouse 
                   
               
               
                   
               
               
                 163 
                 Human 
                 QVTLKESGPTLVKPTQTLTLTCTFSGFSLS 
               
               
                   
                 HV2-5*09 
                   
               
               
                   
                 HFW1 
                   
               
               
                   
               
               
                 164 
                 Human 
                 WIRQPPGKALEWLA 
               
               
                   
                 HV2-5*09 
                   
               
               
                   
                 HFW2 
                   
               
               
                   
               
               
                 165 
                 Human 
                 RLTITKDTSKNQVVLTMTNMDPVDTATYYCAH 
               
               
                   
                 HV2-5*09 
                   
               
               
                   
                 HFW3 
                   
               
               
                   
               
               
                 166 
                 Human 
                 WGQGTLVTVSS 
               
               
                   
                 J4*01 
                   
               
               
                   
                 HFW4 
                   
               
               
                   
               
               
                 167 
                 18C6 
                 QVTLKESGPGILQPTQTLTLTCTFSGFSLS 
               
               
                   
                 H1-FW1 
                   
               
               
                   
               
               
                 168 
                 18C6 
                 WSRQPSGKGLEWLA 
               
               
                   
                 H1-FW2 
                   
               
               
                   
               
               
                 169 
                 18C6 
                 RLTITKDTSKNQVFLKITNVDTADTATYYCTR 
               
               
                   
                 H1-FW3 
                   
               
               
                   
               
               
                 170 
                 18C6 
                 WGQGTLVTVSS 
               
               
                   
                 H1-FW4 
                   
               
               
                   
               
               
                 171 
                 18C6 
                 QVTLKESGPTLVKPTQTLTLTCTFSGFSLS 
               
               
                   
                 H2-FW1 
                   
               
               
                   
               
               
                 172 
                 18C6 
                 WSRQPSGKGLEWLA 
               
               
                   
                 H2-FW2 
                   
               
               
                   
               
               
                 173 
                 18C6 
                 RLTITKDTSKNQVVLTITNVDPVDTATYYCTR 
               
               
                   
                 H2-FW3 
                   
               
               
                 174 
                 18C6 
                 WGQGTLVTVSS 
               
               
                   
               
               
                   
                 H2-FW4 
                   
               
               
                   
               
               
                 175 
                 18C6 HFW1 
                 QVTLKESGPXXXXPXQTLXLTCXFSGFSLS 
               
               
                   
                 consensus 
                   
               
               
                   
               
               
                 176 
                 18C6 HFW2 
                 WSRQPSGKGLEWLA 
               
               
                   
                 consensus 
                   
               
               
                   
               
               
                 177 
                 18C6 HFW3 
                 RLTIXKDTSKNQVXLXIXNVDXXDTATYYCTR 
               
               
                   
                 consensus 
                   
               
               
                   
               
               
                 178 
                 18C6 HFW4 
                 WGQGTXVTVSS 
               
               
                   
                 consensus 
               
               
                   
               
            
           
         
       
     
     The present disclosure is not to be limited in terms of the particular embodiments described in this application, which are intended as single illustrations of individual aspects of the disclosure. All the various embodiments of the present disclosure will not be described herein. Many modifications and variations of the disclosure can be made without departing from its spirit and scope, as will be apparent to those skilled in the art. Functionally equivalent methods and apparatuses within the scope of the disclosure, in addition to those enumerated herein, will be apparent to those skilled in the art from the foregoing descriptions. Such modifications and variations are intended to fall within the scope of the appended claims. The present disclosure is to be limited only by the terms of the appended claims, along with the full scope of equivalents to which such claims are entitled. 
     It is to be understood that the present disclosure is not limited to particular uses, methods, reagents, compounds, compositions or biological systems, which can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting. 
     In addition, where features or aspects of the disclosure are described in terms of Markush groups, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group. 
     As will be understood by one skilled in the art, for any and all purposes, particularly in terms of providing a written description, all ranges disclosed herein also encompass any and all possible subranges and combinations of subranges thereof. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc. As will also be understood by one skilled in the art all language such as “up to,” “at least,” “greater than,” “less than,” and the like, include the number recited and refer to ranges which can be subsequently broken down into subranges as discussed above. Finally, as will be understood by one skilled in the art, a range includes each individual member. Thus, for example, a group having 1-3 cells refers to groups having 1, 2, or 3 cells. Similarly, a group having 1-5 cells refers to groups having 1, 2, 3, 4, or 5 cells, and so forth.