Monoclonal antibodies against PCDH7 for lung cancer therapy

Abstract

The present disclosure generally relates to antibodies or fragments thereof that bind to Protocadherin 7(PCDH7). The disclosure further provides amino acid sequences and nucleic acid sequences encoding the antibodies. Also provided are compositions and methods for use in treatment of cancer.

Description

Attorney Docket No.106546-796518-4139 TITLE MONOCLONAL ANTIBODIES AGAINST PCDH7 FOR LUNG CANCER THERAPY CROSS REFERENCE TO RELATED APPLICATION

[0001] This application claims priority to U.S. Provisional Patent Application Serial No. 63 / 515,000, filed July 21, 2023, and titled “MONOCLONAL ANTIBODIES AGAINST PCDH7 FOR LUNG CANCER THERAPY,” which is incorporated by reference herein in its entirety. ACKNOWLEDGEMENT OF GOVERNMENT SUPPORT

[0002] This invention was made with government support under grant no. CA207763 awarded by the National Institutes of Health. The government has certain rights in the invention. INCORPORATION OF SEQUENCE LISTING

[0003] The present application contains a Sequence Listing which has been submitted in .XML format via Patent Center and is hereby incorporated by reference in its entirety. Said WIPO Sequence Listing was created on July 08, 2024, XML copy is named 106546-796518- 4139_Sequence listing.xml, and is 406 kilobytes in size. BACKGROUND

[0004] 1. Field

[0005] The present invention relates to the field of cancer biology. More particularly, it concerns antibodies or fragments thereof which bind to Protocadherin 7(PCDH7), and composition and methods using the antibodies for treatment of cancer.

[0006] 2. Discussion of Related Art

[0007] Non-small cell lung cancer (NSCLC) is the leading cause of cancer-associated deaths worldwide. Lung adenocarcinoma (LUAD) accounts for 40% of NSCLC cases, and a significant fraction of driver mutations occur in MAPK pathway genes including EGFR and KRAS. Over the last 15 years, significant effort has focused on the development of inhibitors directed against receptor tyrosine kinases and proteins downstream of KRAS, including the RAF-MAPK and PI3K-AKT signaling cascades. Recently, there have been advances in directly targeting KRAS. While these targeted therapies can induce disease remission, the development of drug resistance and disease progression are inevitable. These findings underscore the critical need for the identification of new targets and therapeutic approaches to treat NSCLC.

[0008] There has been exciting progress in the development of monoclonal antibodies (mAbs) for cancer therapeutics because they recognize cell surface proteins with highAttorney Docket No.106546-796518-4139 specificity and engage the immune system to direct anti-tumor immune responses. Prominently featured among these are mAbs targeting immune checkpoint proteins. Clinical trials utilizing monoclonal antibodies that disrupt the PD-1 / PD-L1 immune checkpoint have yielded remarkable results, with PD-1 immunotherapy approved as a first-line therapy for human lung cancer patients. However, a significant proportion of NSCLC patients do not exhibit durable responses to these therapies. Another class of mAbs are directed against tumor associated antigens enriched on the surface of cancer cells and include epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2). mAbs targeting these molecules are highly effective in their ability to neutralize oncogenic activity as well as direct the antitumor immune response. However, they have similar disadvantages to small molecule inhibitors targeting these proteins including off-target toxicity, acquired resistance, and eventual relapse. Thus, there is an unmet need for development of new antibody-based therapies cancer. SUMMARY

[0009] In one aspect, provided herein is an isolated antibody or fragment thereof that binds to an extracellular domain of protocadherin 7(PCDH7) comprising any one or more of the amino acid sequences listed in Tables 3, 4, 7, or 8.

[0010] In further aspect, the disclosure encompasses an isolated antibody or fragment thereof that binds to an extracellular domain of protocadherin 7(PCDH7) comprising a variable heavy chain region (VH) complementary determining region 1 (CDR1) that comprises at least 90% identity to the amino acid sequence set forth in SEQ ID NO: 227, 236, 278, or 242, a VHCDR2 that comprises at least 90% identity to the amino acid sequence set forth in SEQ ID NO: 228, 237, 279, or 243, a VHCDR3 that comprises at least 90% identity to the amino acid sequence set forth in SEQ ID NO: 229, 238, 280, or 244, or any combination thereof, a variable light chain region (VL) CDR1 that comprises at least 90% identity to the amino acid sequence set forth in SEQ ID NO: 162, 168, 196, or 172, a VLCDR2 that comprises at least 90% identity to the amino acid sequence NVS, RAS, EVT, or QAS, and / or a VLCDR3 that comprises at least 90% identity to the amino acid sequence set forth in SEQ ID NO: 163, 169, 197, or 173, or any combination thereof.

[0011] In some aspects, the extracellular domain of PCDH7 is EC1. In some aspects, the antibody binds to PCDH7 with high affinity. In some aspects, the antibody or fragment thereof binds to PCDH7 with at least a dissociation equilibrium constant K (KD) of less than about 0.02 nM to about 20nM. In some aspects, the antibody is a scFv. The isolated antibody or fragment thereof disclosed herein, wherein the antibody comprises a VH comprising an amino acid sequence at least 90% identical to the sequence set forth in SEQ ID NO: 378, 381, 395, or 383 and / or a VLcomprising an amino acid sequence at least 90% identical to the sequenceAttorney Docket No.106546-796518-4139 set forth in SEQ ID NO: 410, 413, 427, or 415. In some aspects, the disclosed antibody is an IgG, IgM, IgA or an antigen binding fragment thereof. In some aspects, the isolated antibody or fragment thereof is a chimeric, CDR grafted, humanized, muranized or human antibody, or an immunoreactive fragment thereof. In some aspects, the disclosed antibody is a humanized antibody.

[0012] In some aspects, the antibody comprises a VH with the amino acid sequence of SEQ ID NO: 406. In some aspects, the antibody comprises a VLwith the amino acid sequence of SEQ ID NO: 438.

[0013] An isolated antibody or fragment thereof of any one of the preceding claims, wherein the isolated antibody or fragment thereof is a chimeric, CDR grafted, humanized, muranized, human antibody, or an immunoreactive fragment thereof. In some aspects, The the antibody is a humanized antibody or de-immunized antibody. The isolated antibody or fragment thereof of claim 11, wherein the antibody comprises a VH comprising a sequence at least 90% identical to the sequence set forth in SEQ ID NO: 406. The isolated antibody or fragment thereof of claim 11, wherein the antibody comprises a VL comprising a sequence at least 90% identical to the sequence set forth in SEQ ID NO: 438.

[0014] The disclosure further encompasses an isolated antibody or fragment thereof that binds to an extracellular domain of protocadherin 7(PCDH7) comprising a VH CDR1 that comprises at least 90% identity to the polynucleotide sequence set forth in SEQ ID NO: 72, 81, 87, or 123, a VH CDR2 that comprises at least 90% identity to the polynucleotide sequence set forth in SEQ ID NO: 73, 82, 88, or 124, a VH CDR3 that comprises at least 90% identity to the polynucleotide sequence set forth in SEQ ID NO: 74, 83, 89, or 125, or any combination thereof, a VL CDR1 that comprises at least 90% identity to the polynucleotide sequence set forth in SEQ ID NO: 7, 13, 17, or 41, a VL CDR2 that comprises at least 90% identity to the polynucleotide sequence aatgtatcg, agggcatcc, caggcatcc, or gaggtcact, and / or a VL CDR3 that comprises at least 90% identity to the polynucleotide sequence set forth in SEQ ID NO: 8, 14, 18, or 173, or any combination thereof. In further aspect, the isolated antibody or fragment thereof disclosed herein, wherein the antibody comprises a VH comprising a polynucleotide sequence at least 90% identical to the sequence set forth in SEQ ID NO: 314, 317, 319, 331, or 342; and / or a VL comprising a polynucleotide sequence at least 90% identical to the sequence set forth in SEQ ID NO: 346, 349, 351, 363, or 374. In one aspect, a vector comprising one or more polynucleotide sequence disclosed herein. Further a cell comprising the disclosed vector is further provided.

[0015] In further aspects, the disclosure encompasses a composition for treatment of cancer in a subject in need thereof, the composition comprising an antibody or fragment thereof, disclosed herein.Attorney Docket No.106546-796518-4139

[0016] In some aspects, a method for treatment of cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a composition comprising a disclosed antibody or fragment thereof, is provided.

[0017] In some aspects, the cancer comprises cancer cells with increased endogenous PCDH7 expression. In some aspects, the cancer is a lung cancer. In some aspects, the cancer is a non-small cell lung cancer. In some aspects, the cancer is an adenocarcinoma, squamous cell carcinoma, or large cell carcinoma.

[0018] In some aspects, the administration of the disclosed antibody or fragment thereof results in reduction of tumor volume by about 10% to about 50%. In certain aspects, the administration of the disclosed antibody or fragment thereof results in reduction of tumor growth by about 10% to about 50%. In some aspects, the administration of the disclosed antibody or fragment thereof results in reduction of expression of one or more genes listed in Tables 10 and / or 11.

[0019] In some aspects, the composition or method results in stable serum antibody or fragment thereof for at least 10 days after administration of the antibody or fragment thereof in the subject. In some aspects, the serum antibody or fragment thereof level is stable for at least 20 days after administration of the antibody or fragment thereof in the subject. In some aspects, the serum antibody or fragment thereof level is stable for at least 30 days after administration of the antibody in the subject. In some aspects, the administration of the antibody or fragment thereof results in limited treatment associated toxicity in the subject.

[0020] In some aspects, the administration of the antibody or fragment thereof results in increased Fc-mediated immune effector killing of cancer cells in the subject. In some aspects, the administration of the antibody or fragment thereof results in increased antibody dependent cellular cytotoxicity (ADCC) in the subject. In some aspects, the increased Fc-mediated immune effector killing or ADCC results in lysis of at least about 20% of the cancer cells. In some aspects, the administration results in about 50% granzyme B production in the subject. In some aspects, the administration of the antibody or fragment thereof results in reduction of expression of phosphorylated ERK (p-ERK) in the subject by at least 25%.

[0021] In some aspects, the administration of the antibody or fragment thereof results in sensitization of the cancer to MEK inhibitors. In some aspects, the antibody or fragment thereof is administered in combination with a MEK inhibitor. In some aspects, the MEK inhibitor is Trametinib, Binimetinib, Selumetinib, Cobimetinib, PD-325901, CI-1040, TAK-733, or any combination thereof.

[0022] In further aspects, the antibody or fragment thereof is administered in combination with an EGFR inhibitor. In some aspects, the EGFR inhibitor is Afatinib, Almonertinib, Brigatinib, Dacomitinib, Erlotinib, Gefitinib, Icotinib, Laptinib, Neratinib, Olmutinib, Osimertinib, Pyrotinib, Simotinib, Vandetanib, or any combination thereof.Attorney Docket No.106546-796518-4139

[0023] In certain aspects, the administration of the antibody or fragment thereof results in sensitization of the cancer cells to a KRAS inhibitor. In one aspect, the antibody or fragment thereof disclosed herein is administered in combination with a KRAS inhibitor. In some aspects, the KRAS inhibitor is Adagrasib, Sotorasib, AMG 510 , or any combination thereof.

[0024] The disclosure further encompasses a multispecific antibody comprising a first binding site that specifically binds to an extracellular domain of protocadherin 7(PCDH7) comprising any one or more of the amino acid sequences listed in Tables 3, 4, 7, or 8. In one aspect, the first binding site comprises a variable heavy chain region (VH) complementary determining region 1 (CDR1) with the amino acid sequence of SEQ ID NO: 227, 236, 278, or 242, a VHCDR2 with the amino acid sequence of SEQ ID NO: 228, 237, 279, or 243, a VHCDR3 with the amino acid sequence of SEQ ID NO: 229, 238, 280, or 244, or any combination thereof, a variable light chain region (VL) CDR1 with the amino acid sequence of SEQ ID NO: 162, 168, 196, or 172, a VLCDR2 with the amino acid sequence of NVS, RAS, EVT, or QAS, and / or a VLCDR3 with the amino acid sequence of SEQ ID NO: 163, 169, 197, or 173, or any combination thereof. In some aspects, the first binding site comprises a VH with an amino acid sequence of SEQ ID NO: 406, and / or a VLwith an amino acid sequence of SEQ ID NO: 438. In further aspects, the multispecific antibody disclosed herein, comprises a second binding site that specifically binds to a T cell engager, wherein the T cell engager binds to a T cell activating the T cell. The T cell engager, in one aspect is a CD3. In certain aspects, the second binding site of the disclosed multispecific antibody is a CD3 scFv. In some aspects, the antibody is bispecific.

[0025] Further provided herein is a composition for treatment of cancer in a subject in need thereof, the composition comprising the multispecific antibody or fragment thereof of the present disclosure. The disclosure further encompasses a method for treatment of cancer in a subject in need thereof, the method comprising administering to the subject a composition comprising the multispecific antibody or fragment thereof disclosed herein. In one aspect, the cancer is a lung cancer. In an alternative aspect, the cancer is a non-small cell lung cancer. In one aspect, the cancer is an adenocarcinoma, squamous cell carcinoma, or large cell carcinoma.

[0026] Other technical features may be readily apparent to one skilled in the art from the following figures, descriptions, and claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] FIGs.1A-1F show generation and functional characterization of PCDH7 targeting monoclonal antibodies (mAbs). FIG.1A shows overview of rabbit B cell antibody generation. FIG.1B shows overview of phage display antibody generation. FIG.1C shows LiCOR in-cell western analysis of phospho-ERK expression in cells treated with top 3 candidates from eachAttorney Docket No.106546-796518-4139 antibody panel. Phospho-ERK signal was normalized to CellTag 700 and reported relative to control antibody values. For control vs Rb-mAb7, p<0.0001; for control vs Rb-mAb12, p=0.0001; for control vs Rb-mAb17, p=0.0001; for control vs H5, p= 0.0031; for control vs H15, p=0.0034; for control vs H26, p=0.0100. FIG.1D shows MTT assay data showing cell viability in top three candidates from rabbit B cell and phage display antibody groups. MTT signal was reported relative to control antibody values. For control vs Rb-mAb7, p<0.0001; for control vs Rb-mAb12, p=0.0001; for control vs Rb-mAb17, p=0.0001; for control vs H5, p= 0.0031; for control vs H15, p=0.0034; for control vs H26, p=0.0100. For all in-cell western and MTT assays, cells were treated with 10ug / ml antibody for 96 hours and statistics for each antibody versus the control was determined by one-way ANOVA with Dunnett’s multiple comparison test. Error bars indicate standard deviation and n=3. Experiments were repeated twice for confirmation. FIGs. 1E-1G shows PCDH7 monoclonal antibody (mAb) binding affinity determination with antibody titration ELISA for top candidates.

[0028] FIGs. 1H-1I show PCDH7 monoclonal antibody kinetic binding measurements using bio-layer interferometry (BLI) based Octet detection for top 3 mAb candidates. Detection using protein A biosensors and PCDH7-ECD (6HIS tag) were used as analytes in different concentrations.

[0029] FIGs.2A-2F show generation of anti-PCDH7 mAbs. FIG.2A shows coomassie gel of purified PCDH7 protein (the extracellular domain was expressed in insect cells with a polyhistidine tag at the N-terminus). FIG.2B shows representative image of LiCOR in-cell western assay for phospho-ERK. KRAS mutant H1944 cells were probed overnight with anti- pERK primary antibody before labeling with IRDye-800CW-conjugated goat anti-rabbit secondary antibody and CellTag 700 Stain. FIG. 2C shows quantification of pERK values (IRDye-800) following 96h treatment with 10ug / ml purified monoclonal B cell antibodies normalized to CellTag 700 and reported relative to control antibody values. FIG.2D shows quantification of pERK values (IRDye-800) following 96h treatment with 10ug / ml phage display antibodies normalized to CellTag 700 and reported relative to control antibody values. Experiments were repeated twice for confirmation. FIG.2E shows quantification of MTT values following 96hr treatment with 10ug / ml purified monoclonal B cell antibodies reported relative to control antibody values. FIG. 2F shows quantification of MTT values following 96hr treatment with 10ug / ml purified phage display antibodies reported relative to control antibody values. Error bars indicate standard deviation and n=3. Experiments were repeated twice for confirmation.

[0030] FIG.3A-3J show PCDH7-neutralizing antibodies reduce tumor growth of KRAS mutant xenografts alone and in combination with the MEK inhibitor trametinib. FIG.3A shows tumor volumes of H1944 or H1944 PCDH7- / -cells treated weekly with 10 mg / kg of theAttorney Docket No.106546-796518-4139 designated antibodies in immunocompromised NSG mice (n=11 control, n=12 PCDH7- / -, n=12 Rb-mAb7, n=12 Rb-mAb12, n=12 H5) measured every 3 days until endpoint at day 38. Rab57.4, an antibody without affinity for PCDH7, was used as the control for antibody treatments. For control vs PCDH7- / -, p<0.001; for control vs Rb-mAb7, p<0.001; for control vs Rb-mAb12, p=0.0075; for control vs H5, p=0.0037. Statistics were generated by generalized linear mixed models (GLMM). FIG. 3B shows final tumor volumes for control antibody, PCDH7- / -, and Rb-mAb7-treated mice from FIG.3A. Error bars indicate standard deviation and statistics were generated by one-way ANOVA with Dunnett’s multiple comparison test. FIGs.3C-3E show IHC staining for phospho-ERK expression, Ki67 expression and TUNEL staining performed on tumor sections from control antibody-treated (Rab57.4), PCDH7- / -, and Rb-mAb7-treated mice from FIG.3A. FIG.3F shows quantitation of p-ERK, Ki67, and TUNEL staining shown in FIGs. 3C-3E. For phospho-ERK, n=3 independent sections with 10 fields / section were analyzed. For Ki67, n=2 independent sections with 5 fields / section were analyzed. For TUNEL, n=3 independent sections with 10 fields / section. Statistics were generated by one-way ANOVA with Dunnett’s multiple comparison test. FIG.3G shows GSEA enrichment plot for MEK_UP identified as downregulated in Rb-mAb7-treated samples following RNA-seq analysis (n=3 tumors / group). FIG.3H shows LiCOR in-cell western data showing phospho-ERK expression in cells treated with control + DMSO, control + trametinib, Rb-mAb7 + DMSO, and Rb-mAb7 + trametinib cells reported relative to control + DMSO values. Error bars indicate standard deviation and n=3. Experiments were repeated twice for confirmation. FIG. 3I shows tumor volumes of mice harboring H1944 xenografts treated weekly with 5 mg / kg Rb-mAb7 with or without daily dosing of 1 mg / kg trametinib measured every 3 days until endpoint at day 37 (n=11 control + vehicle, n=11 Rb-mAb7 + vehicle, n=10 control + trametinib, n=11 Rb-mAb7 + trametinib). Statistics were generated by GLMM. FIG. 3J shows final tumor volumes for mice from FIG.3I. Statistics were generated by one-way ANOVA with Dunnett’s test for multiple comparisons.

[0031] FIGs.4A-4F show RNA-seq, body weight, serum analyses, and dosage studies. FIG.4A shows Ingenuity pathway analysis (IPA) of Control vs Rb-mAb7 RNAseq data for molecular and cellular functions. Bars represent maximum -log10p values from analysis and p-values are depicted next to each biological function. FIG.4B shows body weights of tumor- bearing mice (tumor volumes in FIG.3A) treated with 10 mg / kg of the indicated antibodies measured every 3 days until endpoint at day 38. FIG.4C shows final body weights of mice from FIG. 4B. Statistics were generated by one-way ANOVA with Dunnett’s multiple comparisons. Error bars indicate standard deviation. FIG. 4D shows ELISA data showing concentration of indicated antibody in blood sera collected at day 20 and endpoint (day 38) from tumor-bearing mice (tumor volumes in FIG. 3A). Data are reported after subtractingAttorney Docket No.106546-796518-4139 background values determined from sera of untreated mice bearing H1944 PCDH7- / - tumors. FIG.4E shows tumor volumes of H1944 or H1944 PCDH7- / - cells treated weekly with 10 mg / kg control antibody or Rb-mAb7 at the indicated concentrations in immunocompromised NSG mice (n=11 for all groups) measured every 3 days until endpoint at day 41. FIG. 4F shows final tumor volumes from FIG.4E.

[0032] FIGs.5A-5E show binding specificity of Rb-mAb7. FIG.5A is a schematic depicting homology between PCDH7 and other δ-1 protocadherin family members. FIG. 5B shows evaluation of Rb-mAb12, Rb-mAb17, and H5 PCDH7 antibody cross-reactivity to δ-1 protocadherin family members by ELISA. FIGs.5C-5E show evaluation of PCDH7 antibody cross-reactivity to murine PCDH7.

[0033] FIGs.6A-6E show binding specificity of Rb-mAb7. FIG.6A shows evaluation of PCDH7 antibody cross-reactivity to δ1 protocadherin family members by ELISA. FIG.6B show schematic representation of PCDH7 with 7 extracellular cadherin repeats (EC 1-7) (left) and coomassie gel of purified PCDH7 EC domain peptides (right). FIG. 6C shows Rb-mAb7 binding affinity determination for PCDH7 EC domains 1-7 with antibody titration ELISA. FIG. 6D shows Western blot analysis of HBEC-shp53; KRASG12Vcells expressing empty vector, PCDH7-V5 FL or PCDH7-V5 ΔC1. Vinculin served as a loading control. Representative images from a single experiment are shown and representative of three independent experiments. FIG.6E shows LiCOR in-cell western data showing phospho-ERK expression in HBEC- shp53; KRASG12V; PCDH7-V5 and HBEC-shp53; KRASG12V; PCDH7ΔC1-V5 cells treated with control or Rb-mAb7. Error bars indicate standard deviation and n=3. Experiments were repeated twice for confirmation.

[0034] FIGs.7A-7M show humanization and functional characterization Hu-mAb7. FIG. 7A shows overview of rabbit mAb humanization. FIG.7B shows binding affinity of humanized mAb7 using antibody titration ELISA. FIG.7C shows Hu-mAb7 kinetic binding measurements using bio-layor interferometry (BLI) based Octet detection. Detection using protein A biosensors and PCDH7-ECD (6HIS tag) were used as analytes in different concentrations. FIG. 7D shows flow cytometry data representing the percentage of human (h)CD45+ and hCD3+ cells in the peripheral blood of humanized NSG mice 12 weeks after CD34+ cell engraftment. FIG.7E shows Representative bioluminescent imaging (BLI) of H1944 orthotopic lung tumors in humanized NSG mice at 4 weeks post-inoculation. Mice were treated weekly with 10 mg / kg control of Hu-mAb7 antibodies and imaged following luciferin injection (n=11 control-treated mice and n=9 Hu-mAb7-treated mice). FIG. 7F shows Quantification of orthotopic tumor BLI signal from FIG.7E. Photons / sec values were generated using Spectral Instruments Aura 4.0 software. Analysis was performed by t-test. FIGs.7G-7H show LiCOR in-cell western data showing phospho-ERK expression and MTT data showing cell viability inAttorney Docket No.106546-796518-4139 control-, Hu-mAb7-, or Hu-mAb7 LALAPG-treated cells, or PCDH7- / - cells. Error bars indicate standard deviation and n=3. Experiments were repeated twice for confirmation. FIG.7I shows Flow cytometry data representing the percentage of hCD45+ and hCD3+ cells in the peripheral blood of humanized NSG-SGM3 mice 12 weeks after CD34+ cell engraftment. FIG.7J shows tumor volumes of mice harboring H1944 xenografts treated with 10 mg / kg of the designated antibodies in humanized NSG-SGM3 mice (n=11 control, n=9 Hu-mAb7 LALAPG, n=11 Hu- mAb7) measured every 3 days over 57 days. Red arrows denote antibody treatments (once per week). Statistics were generated by generalized linear mixed models (GLMM). FIG.7K shows Antibody-dependent cellular cytotoxicity (ADCC) data representing the percentage of tumor cell lysis when co-culture with peripheral blood mononuclear cells (PBMCs) and treated with the indicated antibodies. The tumor lysis (%) of each treatment group was calculated using the following formula: (cell index of control group−cell index of treatment group) / (cell index of control group)×100. The Y-axis shows the average of three independent assays (n=3), and error bars indicate standard deviation. P values were calculated using an unpaired t-test, * = p<0.05, ** = p<0.01. FIG.7L shows Granzyme B ELISA assay for NK-92 MI cells co-cultured for 24 hours with H1944 cells treated with the indicated antibodies. Experiments were repeated twice for confirmation. FIG.7M shows Granzyme B ELISA data for activated Jurkat T cells (stimulated with CD4, CD28, and IL-2 functional antibodies) co-cultured for 24 hours with H1944 cells treated with the indicated antibodies. For FIG. 7L and FIG. 7M, statistics were generated by one-way ANOVA with Bonferroni corrections. Error bars indicate standard deviation and n=3. Experiments were repeated three times for confirmation.

[0035] FIG.8A-8E show testing the efficacy of humanized mAb7. FIG.8A shows binding affinity of humanized mAb7 clones with different heavy and light chains using antibody titration ELISA. Hu-mAb7 (H1K1) shown in FIG.7B. FIGs.8B-8C show quantification of phospho- ERK and MTT values following 96hr treatment of H1944s with 10ug / ml of the indicated antibody reported relative to control antibody values. Untreated PCDH7- / - cells were included as positive controls for each experiment. Experiments were repeated twice for confirmation. FIG.8D shows tumor volumes of H1944 cells treated weekly with 10 mg / kg of the indicated antibodies in immunocompromised NSG mice (n=9 control, n=10 Rb-mAb7, n=11 Hu-mAb7) measured every 3 days until endpoint at day 47. Statistics were generated by generalized linear mixed models (GLMM). FIG.8E shows final tumor volumes from FIG.8D.

[0036] FIG. 9A-9D show Hu-mAb7 reduces tumorigenicity of EGFR-mutant LUAD xenografts and sensitizes EGFR mutant cells to osimertinib. FIGs.9A-9B show quantification of phospho-ERK and MTT values following 96hr treatment of H1975s with 10µg / ml control or Hu-mAb7 antibodies reported relative to control antibody values. Untreated PCDH7- / -cells were included as positive controls for each experiment. Error bars indicate standard deviationAttorney Docket No.106546-796518-4139 and n=3. Experiments were repeated twice for confirmation. FIG.9C shows tumor volumes of H1975 or H1975 PCDH7- / -cells treated weekly with 10 mg / kg of the designated antibodies in immunocompromised NSG mice (n=12 control, n=12 Hu-mAb7, n=9 PCDH7- / -) measured every 3 days until endpoint at day 22. Statistics were generated by generalized linear mixed models (GLMM). FIG. 9D shows LiCOR in-cell western data showing phospho-ERK expression in cells treated with control + DMSO, control + osimertinib, Hu-mAb7 + DMSO, or Hu-mAb7 + osimertinib cells reported relative to control + DMSO values. Error bars indicate standard deviation and n=3. Experiments were repeated twice for confirmation.

[0037] FIG. 10 illustrates a model of PCDH7 mAb7-mediated tumor inhibition. Anti- PCDH7 mAb7 inhibits KRAS and EGFR driven lung tumorigenesis by inhibiting PCDH7- mediated downstream MAPK pathway activation and by triggering antibody-dependent cellular cytotoxicity (ADCC).

[0038] FIG.11A-11C show generation of a murinized mAb7 (mAb7HM). FIG.11A depicts design of the murinized mAb7 antibody. FIGs 11B-11C are bar graphs showing murinized mAb7 reduces proliferation and pERK signaling of syngeneic tumor cell lines derived from KrasLSL-G12D; Tp53fl / fl(KP) mice to same extent as the humanized (Hu-mAb7).

[0039] FIG. 12A-12G show generation and testing of a PCDH7 / CD3 bispecific (BsAb) antibody. FIG. 12A illustrate design of the Bispecific antibody (BsAb). Knob-into-hole mutations were introduced to promote heterodimerization. The αCD3-scFv (single chain variable fragment) was fused to the C-terminus of the CH3 of IgG heavy chain. Hv = heavy chain variable region; Lv = light chain variable region. FIG.12B is a schematic showing BsAb binds to PCDH7 and the activating T cell co-receptor CD3, enhancing anti-tumor toxicity. FIG. 12C is a schematic of overview of co-culture assay. Supernatants were used for Granzyme B ELISA, shown in FIGs.12D-12E. FIG.12F is a line graph of normalized cell index over time showing PCDH7 bispecific-CD3 (BsAb) kills tumor cells. Freshly isolated PBMCs and indicated antibodies were added to KRAS mutant H1944 cells (10:1 ratio, PBMCs: cancer cells). Cell index was monitored using an xCelligence instrument. Red arrow indicates when PBMCs and antibodies added. FIG.12G is a line graph of BsAb binding affinity determination with an antibody titration ELISA assay.

[0040] FIG.13A-13E show Hu-mAb7 sensitizes KRAS G12C mutant cells to Adagrasib and elevated PCDH7 expression in resistant cells. FIG.13A is a bar graph depicting MTT data showing cell viability of DFCI024 cells with control IgG+DMSO, controI IgG+Adagrasib, Hu- mAb7+DMSO, and Hu-mAb7+Adagrasib for 96 hours. MTT values reported relative to control+DMSO values. Error bars indicate standard deviation and n=3. FIG.13B is a line graph showing Hu-mAb7 treatment sensitizes KRAS G12C mutant DFCI1024 tumors to low doseAttorney Docket No.106546-796518-4139 Adagrasib treatment in nude mice. FIG.13C is a line graph showing Generation of Adagrasib resistant tumors in nude mice. FIG.13D shows Western blots showing PCDH7 expression in parental and adagrasib resistant cell lines (derived from tumors). All samples were run on the same gel, several lanes removed for clarity. FIG. 13E is a bar graph showing Hu-mAb7 reduces proliferation of Adagrasib-resistant DFCI1024 resistant cell lines.

[0041] The drawing figures do not limit the present disclosure to the specific embodiments disclosed and described herein. The drawings are not necessarily to scale, emphasis instead being placed on clearly illustrating principles of certain embodiments of the present disclosure. DETAILED DESCRIPTION

[0042] The following detailed description references the accompanying drawings that illustrate various aspects of the present disclosure. The drawings and description are intended to describe aspects of the present disclosure in sufficient detail to enable those skilled in the art to practice the present disclosure. Other components can be utilized, and changes can be made without departing from the scope of the present disclosure. The following description is, therefore, not to be taken in a limiting sense.

[0043] The present disclosure is partly based on the identification of monoclonal antibodies (mAbs) which bind with high affinity and neutralizes protocadherin 7(PCDH7). The antibodies identified and disclosed herein bind to the extracellular domain of PCDH7 and inhibit MAPK pathway activation and proliferation in both mutant KRAS- and mutant EGFR- driven cancer cells expressing high levels of PCDH7. The disclosed PCDH7 mAbs reduce tumor burden and sensitizes tumors to the MEK inhibitor trametinib. Provided herein are also composition and methods of use of PCDH7 mAbs for treatment or prevention of cancer. I. Terminology

[0044] For the purposes of promoting an understanding of the principles of the present disclosure, reference will now be made to preferred aspects and specific language will be used to describe the same. 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 invention belongs.

[0045] As used in the specification, articles “a” and “an” are used herein to refer to one or to more than one (i.e., at least one) of the grammatical object of the article. By way of example, “an element” means at least one element and can include more than one element.

[0046] “About” is used to provide flexibility to a numerical range endpoint by providing that a given value may be “slightly above” or “slightly below” the endpoint without affecting theAttorney Docket No.106546-796518-4139 desired result. The term “about” in association with a numerical value means that the numerical value can vary plus or minus by 5% or less of the numerical value.

[0047] Throughout this specification, unless the context requires otherwise, the word “comprise” and “include” and variations (e.g., “comprises,” “comprising,” “includes,” “including”) will be understood to imply the inclusion of a stated component, feature, element, or step or group of components, features, elements or steps but not the exclusion of any other integer or step or group of integers or steps.

[0048] As used herein, “and / or” refers to and encompasses any and all possible combinations of one or more of the associated listed items, as well as the lack of combinations where interpreted in the alternative (“or”).

[0049] As used herein, the transitional phrase “consisting essentially of” (and grammatical variants) is to be interpreted as encompassing the recited materials or steps “and those that do not materially affect the basic and novel characteristic(s)” of the claimed invention. Thus, the term “consisting essentially of” as used herein should not be interpreted as equivalent to “comprising.”

[0050] Moreover, the present disclosure also contemplates that in some embodiments, any feature or combination of features set forth herein can be excluded or omitted. To illustrate, if the specification states that a complex comprises components A, B and C, it is specifically intended that any of A, B or C, or a combination thereof, can be omitted and disclaimed singularly or in any combination.

[0051] Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise-Indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. For example, if a concentration range is stated as 1% to 50%, it is intended that values such as 2% to 40%, 10% to 30%, or 1% to 3%, etc., are expressly enumerated in this specification. These are only examples of what is specifically intended, and all possible combinations of numerical values between and including the lowest value and the highest value enumerated are to be considered to be expressly stated in this disclosure.

[0052] As used herein, “treatment,” “therapy” and / or “therapy regimen” refer to the clinical intervention made in response to a disease, disorder or physiological condition manifested by a patient or to which a patient may be susceptible. The aim of treatment includes the alleviation or prevention of symptoms, slowing or stopping the progression or worsening of a disease, disorder, or condition and / or the remission of the disease, disorder or condition.Attorney Docket No.106546-796518-4139

[0053] As used herein, “prevent” or “prevention” refers to eliminating or delaying the onset of a particular disease, disorder or physiological condition, or to the reduction of the degree of severity of a particular disease, disorder or physiological condition, relative to the time and / or degree of onset or severity in the absence of intervention.

[0054] The term “effective amount” or “therapeutically effective amount” refers to an amount sufficient to effect beneficial or desirable biological and / or clinical results.

[0055] As used herein, “individual”, “subject”, “host”, and “patient” can be used interchangeably herein and refer to any mammalian subject for whom diagnosis, treatment, prophylaxis or therapy is desired, for example, humans, pets, livestock, horses or other animals. As used herein, the term “subject” and “patient” are used interchangeably herein and refer to both human and nonhuman animals. The term “nonhuman animals” of the disclosure includes all vertebrates, e.g., mammals and non-mammals, such as nonhuman primates, sheep, dog, cat, horse, cow, chickens, amphibians, reptiles, and the like. In one aspect, the subject may be a rodent, e.g. a mouse, a rat, a guinea pig, etc. In another aspect, the subject may be a livestock animal. Non-limiting examples of suitable livestock animals may include pigs, cows, horses, goats, sheep, llamas and alpacas. In still another aspect, the subject may be a companion animal. Non-limiting examples of companion animals may include pets such as dogs, cats, rabbits, and birds. In yet another aspect, the subject may be a zoological animal. As used herein, a “zoological animal” refers to an animal that may be found in a zoo. Such animals may include non-human primates, large cats, wolves, and bears. In some aspects, the subject can be a human. In other aspects, the subject can be a human in need of treating a cancer.

[0056] As used herein “specifically binds,” means that a binding molecule, e.g., an antibody or antigen-binding fragment thereof binds to an epitope via its antigen binding domain, and that the binding entails some recognition between the antigen binding domain and the epitope. According to this definition, a binding molecule is said to “specifically bind” to an epitope when it binds to that epitope, via its antigen-binding domain binds more readily than it would bind to a random, unrelated epitope.

[0057] As used herein “antibody”, is used in the broadest sense and encompasses various antibody and antibody-like structures, including but not limited to full-length monoclonal, polyclonal, and multispecific (e.g., bispecific, trispecific, etc.) antibodies, as well as heavy chain antibodies and antibody fragments provided, they exhibit the desired antigen-binding activity. The domain(s) of an antibody that is involved in binding an antigen is referred to as a “variable region” or “variable domain,” and is described in further detail below. A single variable domain may be sufficient to confer antigen-binding specificity. Preferably, but not necessarily,Attorney Docket No.106546-796518-4139 antibodies useful in the discovery are produced recombinantly. Antibodies may or may not be glycosylated, though glycosylated antibodies may be preferred. An “isolated” antibody is one which has been separated from a component of its natural environment. In some aspects, an antibody is purified to greater than 95% or 99% purity as determined by methods known in the art.

[0058] The terms “full length antibody” and “intact antibody” may be used interchangeably, and refer to an antibody having a structure substantially similar to a native antibody structure or having heavy chains that contain an Fc region as defined herein. The basic structural unit of a native antibody comprises a tetramer. Each tetramer is composed of two identical pairs of polypeptide chains, each pair having one “light” chain (about 25 kDa) and one “heavy” chain (about 50-70 kDa). Light chains are classified as gamma, mu, alpha, and lambda. Heavy chains are classified as gamma, mu, alpha, delta, or epsilon, and define the antibody's isotype as IgG, IgM, IgA, IgD and IgE, respectively. The amino-terminal portion of each light and heavy chain includes a variable region of about 100 to 110 or more amino acid sequences primarily responsible for antigen recognition (VL and VH, respectively). The carboxy-terminal portion of each chain defines a constant region primarily responsible for effector function. Within light and heavy chains, the variable and constant regions are joined by a “J” region of about 12 or more amino acid sequences, with the heavy chain also including a “D” region of about 10 more amino acid sequences. Intact antibodies are properly cross-linked via disulfide bonds, as is known in the art.

[0059] The variable domains of the heavy chain and light chain of an antibody generally have similar structures, with each domain comprising four conserved framework regions (FRs) and three hypervariable regions (HVRs). (See, e.g., Kindt et al. Kuby Immunology, 6th ed., W.H. Freeman and Co., page 91 (2007).) A single VHor VLdomain may be sufficient to confer antigen-binding specificity. Furthermore, anti-bodies that bind a particular antigen may be isolated using a VHor VLdomain from an antibody that binds the antigen to screen a library of complementary VLor VHdomains, respectively. See, e.g., Portolano et al., J. Immunol. 150:880-887 (1993); Clarkson et al., Nature 352:624-628 (1991).

[0060] “Framework region” or “FR” refers to variable domain residues other than hypervariable region (HVR) residues. The FR of a variable domain generally consists of four FR domains: FR1, FR2, FR3, and FR4. Accordingly, the HVR and FR sequences generally appear in the following sequence: FR1-HVR1-FR2-HVR2-FR3-HVR3-FR4. The FR domains of a heavy chain and a light chain may differ, as is known in the art.

[0061] The term “hypervariable region” or “HVR” as used herein refers to each of the regions of a variable domain which are hypervariable in sequence (also commonly referred toAttorney Docket No.106546-796518-4139 as “complementarity determining regions” or “CDR”) and / or form structurally defined loops (“hypervariable loops”) and / or contain the antigen-contacting residues (“antigen contacts”). Generally, antibodies comprise six HVRs / CDRs: three in the VH(H1, H2, H3), and three in the VL(L1, L2, L3). As used herein, “an HVR derived from a variable region” refers to an HVR that has no more than two amino acid substitutions, as compared to the corresponding HVR from the original variable region. Exemplary HVRs herein include: (a) hypervariable loops occurring at amino acid residues 26-32 (L1), 50-52 (L2), 91-96 (L3), 26-32 (H1), 53-55 (H2), and 96-101 (H3) (Chothia and Lesk, J. Mol. Biol.196:901-917 (1987)); (b) CDRs occurring at amino acid residues 24-34 (L1), 50-56 (L2), 89-97 (L3), 31-35b (H1), 50-65 (H2), and 95-102 (H3) (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991)); (c) antigen contacts occurring at amino acid residues 27c-36 (L1), 46-55 (L2), 89-96 (L3), 30-35b (H1), 47-58 (H2), and 93-101 (H3) (MacCallum et al. J. Mol. Biol.262: 732-745 (1996)); (d) CDR1-IMGT (positions 27-38), CDR2- IMGT (positions 56-65), and CDR3-IMGT regions (positions 105-116 or 105-117), which are based on IMGT unique numbering (Lefranc, “The IMGT unique numbering for Immunoglobulins, T cell receptors and Ig-like domains,” The Immunologist, 1999, 7: 132-136; Lefranc et al., Nucleic Acids Research, 2009, 37(Database issue): D1006-D1012; Ehrenmann et al., “Chapter 2: Standardized Sequence and Structure Analysis of Antibody Using IMGT,” in Antibody Engineering Volume 2, Eds. Roland E. Kontermann and Stefan Dubel, 2010, Springer-Verlag Berlin Heidelberg, doi: 10.1007 / 978-3-642-01147-4; imgt.org / IMGTScientificChart / Nomenclature / IMGT-FRCDRdefinition), and (e) combinations of (a), (b), (c), and / or (d), as defined below for various antibodies of this disclosure. Unless otherwise indicated, HVR residues and other residues in the variable domain (e.g., FR residues) that are assigned sequence identification numbers are numbered based on IMGT unique numbering, supra.

[0062] The term “Fc region” herein is used to define a C-terminal region of an immunoglobulin heavy chain that contains at least a portion of the constant region. The term includes native sequence Fc regions and variant Fc regions. In one aspect, a human IgG heavy chain Fc region extends from Cys226, or from Pro230, to the carboxyl-terminus of the heavy chain. However, the C-terminal lysine (Lys447) of the Fc region may or may not be present. Unless otherwise specified herein, numbering of amino acid residues in the Fc region or constant region is according to the EU numbering system, also called the EU index, as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md., 1991.

[0063] A “variant Fc region” comprises an amino acid sequence that can differ from that of a native Fc region by virtue of one or more amino acid substitution(s) and / or by virtue of aAttorney Docket No.106546-796518-4139 modified glycosylation pattern, as compared to a native Fc region or to the Fc region of a parent polypeptide. In an example, a variant Fc region can have from about one to about ten amino acid substitutions, or from about one to about five amino acid substitutions in a native sequence Fc region or in the Fc region of the parent polypeptide. The variant Fc region herein may possess at least about 80% homology, at least about 90% homology, or at least about 95% homology with a native sequence Fc region and / or with an Fc region of a parent polypeptide.

[0064] An “antibody fragment” refers to a molecule other than an intact antibody that comprises a portion of an intact antibody that binds the antigen to which the intact antibody binds. Non-limiting examples of antibody fragments include but are not limited to Fv, Fab, Fab′, Fab′-SH, F(ab′)2; single-chain forms of antibodies and higher or-der variants thereof; single- domain antibodies, and multi-specific antibodies formed from antibody fragments.

[0065] Single-chain forms of antibodies, and their higher order forms, may include, but are not limited to, single-domain antibodies, single chain variant fragments (scFvs), divalent scFvs (di-scFvs), trivalent scFvs (tri-scFvs), tetravalent scFvs (tetra-scFvs), diabodies, and triabodies and tetrabodies. ScFv’s are comprised of heavy and light chain variable regions connected by a linker. In most instances, but not all, the linker may be a peptide. A linker peptide is preferably from about 5 to 30 amino acids in length, or from about 10 to 25 amino acids in length. Typically, the linker allows for stabilization of the variable domains without interfering with the proper folding and creation of an active binding site. In preferred aspects, a linker peptide is rich in glycine, as well as serine or threonine. ScFvs can be used to facilitate phage display or can be used for flow cytometry, immunohistochemistry, or as targeting domains. Methods of making and using scFvs are known in the art. ScFvs may also be conjugated to a human constant domain (e.g. a heavy constant domain is derived from an IgG domain, such as lgG1, lgG2, lgG3, or lgG4, or a heavy chain constant domain derived from IgA, IgM, or IgE). Diabodies, triabodies, and tetrabodies and higher order variants are typically created by varying the length of the linker peptide from zero to several amino acids. Alternatively, it is also well known in the art that multivalent binding antibody variants can be generated using self-assembling units linked to the variable domain.

[0066] A “single-domain antibody” refers to an antibody fragment consisting of a single, monomeric variable antibody domain.

[0067] Multi-specific antibodies include bi-specific antibodies, tri-specific, or anti-bodies of four or more specificities. Multi-specific antibodies may be created by combining the heavy and light chains of one antibody with the heavy and light chains of one or more other antibodies. These chains can be covalently linked.Attorney Docket No.106546-796518-4139

[0068] An antibody of the disclosure may be a Dual-affinity Re-targeting Antibody (DART). The DART format is based on the diabody format that separates cognate variable domains of heavy and light chains of the 2 antigen binding specificities on 2 separate polypeptide chains. Whereas the 2 polypeptide chains associate noncovalently in the diabody format, the DART format provides additional stabilization through a C-terminal disulfide bridge. DARTs can be produced in high quantity and quality and reveal exceptional stability in both formulation buffer and human serum.

[0069] “Monoclonal antibody” refers to an antibody that is derived from a single copy or clone, including e.g., any eukaryotic, prokaryotic, or phage clone. “Monoclonal antibody” is not limited to antibodies produced through hybridoma technology. Monoclonal antibodies can be produced using hybridoma techniques well known in the art, as well as recombinant technologies, phage display technologies, synthetic technologies or combinations of such technologies and other technologies readily known in the art. Furthermore, the monoclonal antibody may be labeled with a detectable label, immobilized on a solid phase and / or conjugated with a heterologous compound (e.g., an enzyme or toxin) according to methods known in the art.

[0070] A “heavy chain antibody” refers to an antibody that consists of two heavy chains. A heavy chain antibody may be an IgG-like antibody from camels, llamas, alpacas, sharks, etc., or an IgNAR from a cartiliaginous fish.

[0071] A “humanized antibody” refers to a non-human antibody that has been modified to reduce the risk of the non-human antibody eliciting an immune response in humans following administration but retains similar binding specificity and affinity as the starting non-human antibody. A humanized antibody binds to the same or similar epitope as the non-human antibody. The term “humanized antibody” includes an antibody that is composed partially or fully of amino acid sequences derived from a human antibody germline by altering the sequence of an antibody having non-human hypervariable regions (“HVR”). The simplest such alteration may consist simply of substituting the constant region of a human antibody for the murine constant region, thus resulting in a human / murine chimera which may have sufficiently low immunogenicity to be acceptable for pharmaceutical use. Preferably, the variable region of the antibody is also humanized by techniques that are by now well known in the art. For example, the framework regions of a variable region can be substituted by the corresponding human framework regions, while retaining one, several, or all six non-human HVRs. Some framework residues can be substituted with corresponding residues from a non-human VLdomain or VHdomain (e.g., the non-human antibody from which the HVR residues are derived), e.g., to restore or improve specificity or affinity of the humanized antibody. Substantially human framework regions have at least about 75% homology with a knownAttorney Docket No.106546-796518-4139 human framework sequence (i.e. at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 99% sequence identity). HVRs may also be randomly mutated such that binding activity and affinity for the antigen is maintained or enhanced in the context of fully human germline framework regions or framework regions that are substantially human. As mentioned above, it is sufficient for use in the methods of this discovery to employ an antibody fragment. Further, as used herein, the term “humanized antibody” refers to an antibody comprising a substantially human framework region, at least one HVR from a nonhuman antibody, and in which any constant region present is substantially human. Substantially human constant regions have at least about 90% with a known human constant sequence (i.e. about 90%, about 95%, or about 99% sequence identity). Hence, all parts of a humanized antibody, except possibly the HVRs, are substantially identical to corresponding pairs of one or more germline human immunoglobulin sequences.

[0072] If desired, the design of humanized immunoglobulins may be carried out as follows or using similar methods familiar to those with skill in the art (for example, see Almagro, et al. Front. Biosci.2008, 13(5):1619-33). A murine antibody variable region is aligned to the most similar human germline sequences (e.g. by using BLAST or similar algorithm). The CDR residues from the murine antibody sequence are grafted into the similar human “acceptor” germline. Subsequently, one or more positions near the CDRs or within the framework (e.g., Vernier positions) may be reverted to the original murine amino acid in order to achieve a humanized antibody with similar binding affinity to the original murine antibody. Typically, several versions of humanized antibodies with different re-version mutations are generated and empirically tested for activity. The humanized antibody variant with properties most similar to the parent murine antibody and the fewest murine framework reversions is selected as the final humanized antibody candidate.

[0073] The term “specifically binds,” as used herein with regards to epitope binding agents, means that an epitope binding agent does not cross react to a significant extent with other epitopes on the protein of interest (e.g., PCDH7), or on other proteins in general.

[0074] As used herein “PROTOCADHERIN 7” or “PCDH7” is a transmembrane receptor and member of the Cadherin superfamily. The PCDH7 protein comprises an extracellular domain containing 7 cadherin repeats and is an integral membrane protein that is thought to function in cell-cell recognition and adhesion. Alternative splicing yields isoforms with unique cytoplasmic tails. As described herein, PCDH7 can be from vertebrates, including bovine, ovine, porcine, chicken, and human PCDH7. The wild type sequences of PCDH7 are well known in the art and may be obtained from publicly available databases. For e.g., nucleotide sequence for human PCDH7 is available at NCBI database under accession number NM_001173523.2 and the protein sequence under accession number NP_001166994.1.Attorney Docket No.106546-796518-4139

[0075] In an exemplary aspect, a full length PCDH7 polypeptide comprises the amino acid sequence of SEQ ID NO: 439 (MLRMRTAGWARGWCLGCCLLLPLSLSLAAAKQLLRYRLAEEGPADVRIGNVASDLGIVTG SGEVTFSLESGSEYLKIDNLTGELSTSERRIDREKLPQCQMIFDENECFLDFEVSVIGPSQS WVDLFEGQVIVLDINDNTPTFPSPVLTLTVEENRPVGTLYLLPTATDRDFGRNGIERYELLQE PGGGGSGGESRRAGAADSAPYPGGGGNGASGGGSGGSKRRLDASEGGGGTNPGGRSS VFELQVADTPDGEKQPQLIVKGALDREQRDSYELTLRVRDGGDPPRSSQAILRVLITDVND NSPRFEKSVYEADLAENSAPGTPILQLRAADLDVGVNGQIEYVFGAATESVRRLLRLDETSG WLSVLHRIDREEVNQLRFTVMARDRGQPPKTDKATVVLNIKDENDNVPSIEIRKIGRIPLKDG VANVAEDVLVDTPIALVQVSDRDQGENGVVTCTVVGDVPFQLKPASDTEGDQNKKKYFLH TSTPLDYEATREFNVVIVAVDSGSPSLSSNNSLIVKVGDTNDNPPMFGQSVVEVYFPENNIP GERVATVLATDADSGKNAEIAYSLDSSVMGIFAIDPDSGDILVNTVLDREQTDRYEFKVNAK DKGIPVLQGSTTVIVQVADKNDNDPKFMQDVFTFYVKENLQPNSPVGMVTVMDADKGRNA EMSLYIEENNNIFSIENDTGTIYSTMSFDREHQTTYTFRVKAVDGGDPRSATATVSLFVMDE NDNAPTVTLPKNISYTLLPPSSNVRTVVATVLATDSDDGINADLNYSIVGGNPFKLFEIDPTS GVVSLVGKLTQKHYGLHRLVVQVNDSGQPSQSTTTLVHVFVNESVSNATAIDSQIARSLHIP LTQDIAGDPSYEISKQRLSIVIGVVAGIMTVILIILIVVMARYCRSKNKNGYEAGKKDHEDFFTP QQHDKSKKPKKDKKNKKSKQPLYSSIVTVEASKPNGQRYDSVNEKLSDSPSMGRYRSVNG GPGSPDLARHYKSSSPLPTVQLHPQSPTAGKKHQAVQDLPPANTFVGAGDNISIGSDHCSE YSCQTNNKYSKQPFRRVTFSVVSQPQDPHQGSLQSCYDSGLEESETPSSKSSSGPRLGAL PLPEDNYERTTPDGSVGEAEHMENDSRPLPDVALTGKCTRECDEYGHSDSCWMPVRTSP ERKKSQPKLSTFMPVDERGSQEKLANGEAAIMGDRNRNLLNKKLTSSYETFSAASFSKNEE ANPEDIPLTKTGEYKPSPVNTLTRREVYL).

[0076] As used herein “KRAS” or “K-Ras” or “Kirsten rat sarcoma virus” is a member of the small GTPase superfamily and is part of a RAS / MAPK pathway. The protein relays signals from outside the cell to the cell's nucleus. These signals instruct the cell to grow and divide (proliferate) or to mature and take on specialized functions (differentiate). The K-Ras protein converts GTP into GDP. The K-Ras protein acts like a switch that is turned on and off by the GTP and GDP molecules. To transmit signals, it must be turned on by attaching (binding) to a molecule of GTP. The K-Ras protein is turned off (inactivated) when it converts the GTP to GDP. When the protein is bound to GDP, it does not relay signals to the cell's nucleus. A single amino acid substitution in K-Ras is responsible for an activating mutation. The transforming protein that results is implicated in various malignancies, including lung adenocarcinoma, mucinous adenoma, ductal carcinoma of the pancreas and colorectal carcinoma. Alternative splicing leads to variants encoding two isoforms that differ in the C-terminal region.Attorney Docket No.106546-796518-4139

[0077] The KRAS gene belongs to a class of genes known as oncogenes. When mutated, oncogenes have the potential to cause normal cells to become cancerous. The KRAS gene is in the Ras family of oncogenes, which also includes two other genes: HRAS and NRAS. These proteins play important roles in cell division, cell differentiation, and the self-destruction of cells (apoptosis). The wild type sequences of KRAS are well known in the art and may be obtained from publicly available databases. For e.g., nucleotide sequence for human KRAS isoform a is available at NCBI database under accession number NM_001369786.1 and the protein sequence under accession number NP_001356715.1.

[0078] As used herein “Epidermal growth factor receptor” or “EGFR” or “ErbB-1” or “HER1” is a transmembrane protein that is a receptor for members of the epidermal growth factor family (EGF family) of extracellular protein ligands. The epidermal growth factor receptor is a member of the ErbB family of receptors, a subfamily of four closely related receptor tyrosine kinases: EGFR (ErbB-1), HER2 / neu (ErbB-2), Her 3 (ErbB-3) and Her 4 (ErbB-4). In many cancer types, mutations affecting EGFR expression or activity could result in cancer. The wild type sequences of EGFR are well known in the art and may be obtained from publicly available databases. For e.g., nucleotide sequence for human EGFR isoform e precursor is available at NCBI database under accession number NM_001346897.2 and the protein sequence under accession number NP_001333826.1.

[0079] As used herein “Extracellular signal-related kinase” or “ERK” or “ERK1 / 2” or “p42 / 44” is a kinase in the mitogen-activated protein kinase (MAPK) family and phosphorylation of ERK (p-ERK) can be used as a common end point measurement for the activation of many classes of G protein coupled receptors (GPCR).

[0080] As used herein “abundance” refers to the amount of a particular analyte present in the sample. The amount may be a number, proportion, or a percentage of the analyte compared to the control sample. The amount may be an absolute amount or a relative amount.

[0081] As used herein “expression” or “level” or “level of expression” refers to amount of a particular protein present in the sample. The amount may be a number, proportion, or a percentage of the analyte compared to the control sample. The amount may be an absolute amount or a relative amount.

[0082] As used herein “cancer” may be one or more neoplasm or cancer. The neoplasm may be malignant or benign, the cancer may be primary or metastatic; the neoplasm or cancer may be early stage or late stage. Non-limiting examples of neoplasms or cancers include acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, AIDS- related cancers, AIDS-related lymphoma, anal cancer, appendix cancer, astrocytoma (childhood cerebellar or cerebral), basal cell carcinoma, bile duct cancer, bladder cancer, boneAttorney Docket No.106546-796518-4139 cancer, brainstem glioma, brain tumors (cerebellar astrocytoma, cerebral astrocytoma / malignant glioma, ependymoma, medulloblastoma, supratentorial primitive neuroectodermal tumors, visual pathway and hypothalamic gliomas), breast cancer, bronchial adenomas / carcinoids, Burkitt lymphoma, carcinoid tumors (childhood, gastrointestinal), carcinoma of unknown primary, central nervous system lymphoma (primary), cerebellar astrocytoma, cerebral astrocytoma / malignant glioma, cervical cancer, childhood cancers, chronic lymphocytic leukemia, chronic myelogenous leukemia, chronic myeloproliferative disorders, colon cancer, cutaneous T-cell lymphoma, desmoplastic small round cell tumor, endometrial cancer, ependymoma, esophageal cancer, Ewing's sarcoma in the Ewing family of tumors, extracranial germ cell tumor (childhood), extragonadal germ cell tumor, extrahepatic bile duct cancer, eye cancers (intraocular melanoma, retinoblastoma), gallbladder cancer, gastric (stomach) cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor, germ cell tumors (childhood extracranial, extragonadal, ovarian), gestational trophoblastic tumor, gliomas (adult, childhood brain stem, childhood cerebral astrocytoma, childhood visual pathway and hypothalamic), gastric carcinoid, hairy cell leukemia, head and neck cancer, hepatocellular (liver) cancer, Hodgkin lymphoma, hypopharyngeal cancer, hypothalamic and visual pathway glioma (childhood), intraocular melanoma, islet cell carcinoma, Kaposi sarcoma, kidney cancer (renal cell cancer), laryngeal cancer, leukemias (acute lymphoblastic, acute myeloid, chronic lymphocytic, chronic myelogenous, hairy cell), lip and oral cavity cancer, liver cancer (primary), lung cancers (non-small cell, small cell), lymphomas (AIDS-related, Burkitt, cutaneous T-cell, Hodgkin, non-Hodgkin, primary central nervous system), macroglobulinemia (Waldenström), malignant fibrous histiocytoma of bone / osteosarcoma, medulloblastoma (childhood), melanoma, intraocular melanoma, Merkel cell carcinoma, mesotheliomas (adult malignant, childhood), metastatic squamous neck cancer with occult primary, mouth cancer, multiple endocrine neoplasia syndrome (childhood), multiple myeloma / plasma cell neoplasm, mycosis fungoides, myelodysplastic syndromes, myelodysplastic / myeloproliferative diseases, myelogenous leukemia (chronic), myeloid leukemias (adult acute, childhood acute), multiple myeloma, myeloproliferative disorders (chronic), nasal cavity and paranasal sinus cancer, nasopharyngeal carcinoma, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, oral cancer, oropharyngeal cancer, osteosarcoma / malignant fibrous histiocytoma of bone, ovarian cancer, ovarian epithelial cancer (surface epithelial-stromal tumor), ovarian germ cell tumor, ovarian low malignant potential tumor, pancreatic cancer, pancreatic cancer (islet cell), paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pineal astrocytoma, pineal germinoma, pineoblastoma and supratentorial primitive neuroectodermal tumors (childhood), pituitary adenoma, plasma cell neoplasia, pleuropulmonary blastoma, primary central nervous system lymphoma, prostateAttorney Docket No.106546-796518-4139 cancer, rectal cancer, renal cell carcinoma (kidney cancer), renal pelvis and ureter transitional cell cancer, retinoblastoma, rhabdomyosarcoma (childhood), salivary gland cancer, sarcoma (Ewing family of tumors, Kaposi, soft tissue, uterine), Sézary syndrome, skin cancers (nonmelanoma, melanoma), skin carcinoma (Merkel cell), small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, squamous neck cancer with occult primary (metastatic), stomach cancer, supratentorial primitive neuroectodermal tumor (childhood), T-Cell lymphoma (cutaneous), testicular cancer, throat cancer, thymoma (childhood), thymoma and thymic carcinoma, thyroid cancer, thyroid cancer (childhood), transitional cell cancer of the renal pelvis and ureter, trophoblastic tumor (gestational), unknown primary site (adult, childhood), ureter and renal pelvis transitional cell cancer, urethral cancer, uterine cancer (endometrial), uterine sarcoma, vaginal cancer, visual pathway and hypothalamic glioma (childhood), vulvar cancer, and Wilms tumor (childhood).

[0083] In some aspects, treatment of cancer can comprise increased inhibition of cancer progression and / or metastases, inhibition of an increase in tumor volume, a reduction in tumor volume and / or growth, a reduction in tumor growth rate, an eradication of a tumor and / or cancer cell, or any combination thereof. In some aspects, the treatment can also prolong the survival of a subject and / or improve the prognosis.

[0084] The biological sample may be of any biological tissue, fluid, or cell from the subject. The sample can be solid or fluid. The sample can be a heterogeneous cell population. Non- limiting examples of suitable biological samples include sputum, serum, blood, blood cells (e.g., white cells), a biopsy, urine, peritoneal fluid, pleural fluid, or cells derived therefrom. The biopsy can be a fine needle aspirate biopsy, a core needle biopsy, a vacuum assisted biopsy, an open surgical biopsy, a shave biopsy, a punch biopsy, an incisional biopsy, a curettage biopsy, or a deep shave biopsy. Biological samples may also include sections of tissues, such as frozen sections or formalin fixed sections taken for histological purposes. A sample can be a tumor tissue, tissue surrounding a tumor, or non-tumor tissue. Methods of collecting a biological sample from a subject are well known in the art.

[0085] Sample from the subject can be procured one or more times, before, during and / or after diagnosis. In some aspects, samples can be procured from the subject before, during, and / or after treatment of cancer. In some aspects, sample can be procured before, during and / or after administration of a cancer treatment. Additionally, samples can be procured repeatedly at multiple stages after initial sample procurement.

[0086] In some aspects, control sample can be procured from a healthy subject. In some aspects, the control sample can comprise of non-cancer cells. In some aspects, the non- cancer cells can be from the same tissue type as the cancer cells. For example, if the cancerAttorney Docket No.106546-796518-4139 cells are from breast cancer, then the non-cancer cells can be from healthy breast tissue. In some aspects, the control can comprise of an average levels of the biomarker profile in a sample from a subject before onset of cancer. In some aspects, control sample can be a sample from the subject prior to diagnosis or treatment. In certain aspects, the biomarker profile can be measured in a person or persons other than the subject with cancer. In some aspects, the control a person or persons with similar characteristics to the subject with cancer. In some aspects, the control can be an average of the combination of disclosed biomarker levels from different healthy sources (e.g., more than one healthy control subject). In some aspects, the control sample can be pooled sample.

[0087] The “percent identity” of two amino acid sequences can be determined using the algorithm of Karlin and Altschul Proc. Natl. Acad. Sci. USA 87:2264-68, 1990, modified as in Karlin and Altschul Proc. Natl. Acad. Sci. USA 90:5873-77, 1993. Such an algorithm is incorporated into the NBLAST and XBLAST programs (version 2.0) of Altschul, et al. J. Mol. Biol. 215:403-10, 1990. BLAST protein searches can be performed with the XBLAST program, score=50, wordlength=3 to obtain amino acid sequences homologous to the protein molecules of interest. Where gaps exist between two sequences, Gapped BLAST can be utilized as described in Altschul et al., Nucleic Acids Res. 25(17):3389-3402, 1997. When utilizing BLAST and Gapped BLAST programs, the default parameters of the respective programs (e.g., XBLAST and NBLAST) can be used.

[0088] As used herein ‘’nucleic acid’’, ‘’nucleic acid molecule’’, and ‘’polynucleotide’’ are used interchangeably herein. The terms “nucleic acid encoding . . .”, or “nucleic acid molecule encoding . . . “, should be understood as referring to the sequence of nucleotides which encodes a polypeptide.

[0089] A polynucleotide described herein may comprise one or more nucleic acids each encoding a polypeptide, all operably linked to (i.e., in a functional relationship with) one or more regulatory sequences, such as a promoter. Such a polynucleotide may alternatively be referred to herein as a ‘’nucleic acid construct’’ or ‘’construct’’.

[0090] As used herein “polypeptide” and “protein” are used interchangeably to refer to a polymer of amino acid residues.

[0091] Each amino acid sequence described herein by virtue of its identity or similarity percentage with a given amino acid sequence respectively has in a further preferred aspect an identity or a similarity of at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at leastAttorney Docket No.106546-796518-4139 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% with the given nucleotide or amino acid sequence, respectively. The terms “homology”, “sequence identity” and the like are used interchangeably herein. Sequence identity is described herein as a relationship between two or more amino acid (polypeptide or protein) sequences or two or more nucleic acid (polynucleotide) sequences, as determined by comparing the sequences. In a preferred aspect, sequence identity is calculated based on the full length (in amino acids or nucleotides) of two given SEQ ID NOS or based on a portion thereof. A portion of a full-length sequence may be referred to as a fragment, and preferably means at least 50%, 60%, 70%, 80%, 90%, or 100% of the length (in amino acids or nucleotides) of a reference sequence. “Identity” also refers to the degree of sequence relatedness between two amino acid sequences, or between two nucleic acid sequences, as the case may be, as determined by the match between strings of such sequences. The degree of sequence identity between two sequences can be determined, for example, by comparing the two sequences using computer programs commonly employed for this purpose, such as global or local alignment algorithms. Non-limiting examples include BLASTp, BLASTn, Clustal W, MAFFT, Clustal Omega, AlignMe, Praline, GAP, BESTFIT, or another suitable method or algorithm. A Needleman and Wunsch global alignment algorithm can be used to align two sequences over their entire length or part thereof (part thereof may mean at least 50%, 60%, 70%, 80%, 90% of the length of this sequence), maximizing the number of matches and minimizes the number of gaps. Default settings can be used and preferred program is Needle for pairwise alignment (in an aspect, EMBOSS Needle 6.6.0.0, gap open penalty 10, gap extent penalty: 0.5, end gap penalty: false, end gap open penalty: 10 , end gap extent penalty: 0.5 is used) and MAFFT for multiple sequence alignment ( in an aspect, MAFFT v7Default value is: BLOSUM62 [bl62], Gap Open: 1.53, Gap extension: 0.123, Order: aligned , Tree rebuilding number: 2, Guide tree output: ON [true], Max iterate: 2 , Perform FFTS: none is used).

[0092] “Similarity” between two amino acid sequences is determined, for example, by comparing the amino acid sequence and its conserved amino acid substitutes of one polypeptide to the sequence of a second polypeptide. Similar algorithms used for determination of sequence identity may be used for determination of sequence similarity. Optionally, in determining the degree of amino acid similarity, the skilled person may also take into account so-called conservative amino acid substitutions. As used herein, “conservative” amino acid substitutions refer to the interchangeability of residues having similar side chains. Examples of classes of amino acid residues for conservative substitutions are given in the Tables below:Attorney Docket No.106546-796518-4139Alternative conservative amino acid residue substitution classes :Alternative physical and functional classifications of amino acid residues:Attorney Docket No.106546-796518-4139

[0093] For example, a group of amino acids having aliphatic side chains is glycine, alanine, valine, leucine, and isoleucine; a group of amino acids having aliphatic-hydroxyl side chains is serine and threonine; a group of amino acids having amide-containing side chains is asparagine and glutamine; a group of amino acids having aromatic side chains is phenylalanine, tyrosine, and tryptophan; a group of amino acids having basic side chains is lysine, arginine, and histidine; and a group of amino acids having sulphur-containing side chains is cysteine and methionine. Preferred conservative amino acids substitution groups are: valine-leucine-isoleucine, phenylalanine-tyrosine, lysine-arginine, alanine-valine, and asparagine-glutamine. Substitutional variants of the amino acid sequence disclosed herein are those in which at least one residue in the disclosed sequences has been removed and a different residue inserted in its place. Preferably, the amino acid change is conservative. Preferred conservative substitutions for each of the naturally occurring amino acids are as follows: Ala to Ser; Arg to Lys; Asn to Gln or His; Asp to Glu; Cys to Ser or Ala; Gln to Asn; Glu to Asp; Gly to Pro; His to Asn or Gln; Ile to Leu or Val; Leu to Ile or Val; Lys to Arg; Gln or Glu; Met to Leu or Ile; Phe to Met, Leu or Tyr; Ser to Thr; Thr to Ser; Trp to Tyr; Tyr to Trp or Phe; and, Val to Ile or Leu.

[0094] As used herein “fragment” means a portion of a polypeptide that contains, preferably, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or more of the entire length of the reference polypeptide. In certain aspects, the fragment as the same or similar biological activity as the reference polypeptide.

[0095] As used herein “treatment associated toxicity” refers to adverse physiological effects at the cellular, organ and / or organism level resulting from administration of the drug, for e.g., monoclonal antibodies. Non-limiting examples of treatment associated toxicity include body weight loss, pain, swelling, soreness, redness, itchiness, rash, chills, fatigue, fever, muscle aches and pains, nausea, headache, rash, vomiting, diarrhea, mouth and skin sores that can lead to serious infections, high blood pressure or low blood pressure, congestive heart failure, heart attacks, rapid heartbeat, inflammatory lung disease, allergic reactions, trouble breathing, capillary leak syndrome, multiple organ failure, shock, death, or any combination thereof.Attorney Docket No.106546-796518-4139

[0096] As used herein, “effective amount” and “amount effective” can refer to an amount that is sufficient to achieve the desired result such as, for example, the treatment and / or prevention of a disease or disorder (e.g., cancer). As used herein, the terms “effective amount” and “amount effective” can refer to an amount that is sufficient to achieve the desired an effect on an undesired condition (e.g., cancer).

[0097] In an aspect, “therapeutically effective amount” means an amount of the disclosed composition that (i) treats a disease or disorder (for. e.g., cancer), (ii) attenuates, ameliorates, or eliminates one or more symptoms associated with a disease or disorder (for e.g., cancer), or (iii) delays the onset of one or more symptoms of a disease or disorder (for e.g., cancer). The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the type of cancer being treated; the disclosed compositions employed; the disclosed methods employed; the age, body weight, general health, sex and diet of the patient; the time of administration; the route of administration; the rate of excretion of the disclosed compositions employed; the duration of the treatment; drugs used in combination or coincidental with the disclosed compositions employed, and other like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of the disclosed compositions at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. If desired, then the effective daily dose can be divided into multiple doses for purposes of administration. Consequently, a single dose of the disclosed compositions, disclosed viral vectors, disclosed pharmaceutical formulations, disclosed therapeutic agents, or a combination thereof can contain such amounts or submultiples thereof to make up the daily dose. The dosage can be adjusted by the individual physician in the event of any contraindications. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days. Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products. In further various aspects, a preparation can be administered in a “prophylactically effective amount”; that is, an amount effective for prevention of a sign or symptom associated with a disease or disorder (for e.g., cancer). II. Antibodies

[0098] The present disclosure provides monoclonal antibodies (mAbs) which bind with high affinity and can inhibit PCDH7. The disclosed antibodies bind an extracellular domain of PCDH7. In some aspects, antibodies herein can be isolated antibodies that bind an extracellular domain of PCDH7. In some aspects, isolated antibodies herein may bind an extracellular domain 1 (EC1) of PCDH7. In some aspects, isolated antibodies herein may bind an extracellular domain 3 (EC3) of PCDH7. In some aspects, isolated antibodies herein mayAttorney Docket No.106546-796518-4139 bind an extracellular domain 6 (EC6) of PCDH7. In some aspects, isolated antibodies herein may bind an extracellular domain 7 (EC7) of PCDH7.

[0099] In certain aspects, antibodies described herein may have a suitable binding affinity for a target antigen PCDH7 or an epitope thereof. In some aspects, an antibody described herein may have a binding affinity (KD) of at least about 100 nM, at least about 10 nM, at least about 1 nM, at least about 0.1 nM, or lower for PCDH7. In some aspects, an antibody described herein may have a binding affinity (KD) between about 100 nM to about 0.1 nM (e.g., about 100 nM, about 75 nM, about 50 nM, about 25 nM, about 10 nM, about 5 nM, about 3 nM, about 2 nM, about 1 nM, about 0.7 nM, about 0.6 nM, about 0.5 nM, about 0.4 nM, about 0.3 nM, about 0.2 nM, about 0.1 nM) for PCDH7. In some aspects, an antibody described herein may have a binding affinity (KD) between about 0.1 nM to about 0.01 nM (e.g., about 0.1 nM, about 0.05 nM, about 0.03 nM, about 0.02 nM, about 0.01 nM) for PCDH7. In some aspects, an antibody described herein may have a binding affinity (KD) between about 1 nM to 0.02 nM for PCDH7. In some aspects, binding affinity (or binding specificity) can be determined by a variety of methods including equilibrium dialysis, equilibrium binding, gel filtration, ELISA, surface plasmon resonance, and / or spectroscopy (e.g., using a fluorescence assay).

[0100] In certain aspects, antibodies described herein can block, inhibit or decrease PCDH7 activity. In certain aspects, antibodies described herein may decrease PCDH7 activity compared to PCDH7 activity in the absence of an antibody herein. In certain aspects, antibodies described herein may decrease PCDH7 activity by about 5% to about 99% (e.g., about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99%) compared to PCDH7 activity in the absence of an antibody herein.

[0101] In certain aspects, antibodies described herein may have neutralizing activity against PCDH7. In some aspects, antibodies described herein may have neutralizing activity against PCDH7 with binding constant EC50 of less than about 50. In some aspects, antibodies described herein may have neutralizing activity against PCDH7 with EC50 ranging from about 0.01 to about 50 (e.g., about 0.01, about 0.02, about 0.03 ng / ml, about 0.04, about 0.05, about 0.07, about 0.1, about 0.5, about 0.75, about 1, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50).

[0102] In some aspects, antibodies described herein can reduce expression of phosphorylated ERK (p-ERK). In certain aspects, antibodies described herein may reduce p- ERK expression by about 5% to about 99% (e.g., about 5%, about 10%, about 15%, aboutAttorney Docket No.106546-796518-4139 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99%) compared to p-ERK expression in the absence of an antibody herein. In some aspects, p-ERK expression is reduced by at least 25% compared to p-ERK expression in the absence of an antibody herein. p-ERK expression can be quantified in the presence and absence of the antibodies using methods well known in the art, for e.g., using western quantification.

[0103] In some aspects, antibodies described herein can reduce cell viability. In certain aspects, antibodies described herein may reduce cell viability by about 5% to about 99% (e.g., about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99%) compared to cell viability in the absence of an antibody herein. In some aspects, cell viability is reduced by at least 15% compared to cell viability in the absence of an antibody herein. Cell viability can be quantified in the presence and absence of the antibodies using methods well known in the art, such as dye exclusion assays, colorimetric assays, fluorometric assays, luminometric assays, flow cytometric assays including for e.g., using MTT assay.

[0104] In certain aspects, antibodies described herein may have the same heavy chain CDRs, and / or light chain CDRs as any of the exemplary antibodies described herein. Two antibodies having the same heavy chain CDRs, and / or light chain CDRs means that their CDRs are identical when determined by the same approach (e.g., the Kabat approach, the Chothia approach, the AbM approach, the Contact approach, or the IMGT approach). In certain aspects, antibodies described herein may have the same heavy chain and / or light chain as any of the exemplary antibodies described herein. The antibodies disclosed herein may comprise one or more amino acid sequences provided in Table 3, 4, 7, or 8, or one or more polynucleotide sequences provided in Table 1, 2, 5, or 6. The present application expressly covers antibody with any combination of VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, VLCDR3, VHand VLselected from the amino acid sequences or polynucleotide sequences disclosed in the Tables 1-8. For example, the application covers but not limited to, VLCDR1 comprising the sequence of SEQ ID NO: 1, VLCDR2 comprising the sequence of ctggcatcc, VLCDR3 comprising the sequence of SEQ ID NO: 2 and so on. The antibody may further comprise VHCDR1 comprising the sequence of SEQ ID NO: 63, VHCDR2 comprising the sequence of SEQ ID NO: 64, VHCDR3 comprising the sequence of SEQ ID NO: 65, and so on. In another example the antibody may comprise VHCDR1 comprising the sequence of SEQ ID NO: 218, VHCDR2 comprising the sequence of SEQ ID NO: 222, VHCDR3 comprising the sequence of SEQ ID NO: 226 and so on. The antibody may further comprise a VLCDR1Attorney Docket No.106546-796518-4139 comprising the sequence of SEQ ID NO: 156, VLCDR2 comprising the sequence of EAS, VLCDR3 comprising the sequence of SEQ ID NO: 161 and so on. In yet another example, the antibody may comprise a VHcomprising the sequence of SEQ ID NO: 311, and a VLcomprising the sequence of SEQ ID NO: 342 and so on. The antibody could also comprise a VHcomprising the sequence of SEQ ID NO: 375 and a VLcomprising the sequence of SEQ ID NO: 376, and so on.

[0105] In some embodiments, antibodies herein may comprise heavy chains that are at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) sequence identity, individually or collectively, as compared with the heavy chain of an exemplary antibody described herein. In some embodiments, antibodies herein may comprise light chains that are at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) sequence identity, individually or collectively, as compared with the light chains of an exemplary antibody described herein. In some embodiments, antibodies herein may comprise heavy chain CDRs that are at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) sequence identity, individually or collectively, as compared with the heavy chain CDRs of an exemplary antibody described herein. In some embodiments, antibodies herein may comprise light chain CDRs that are at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) sequence identity, individually or collectively, as compared with the light chain CDRs of an exemplary antibody described herein.

[0106] The antibodies disclosed herein may comprise one or more amino acid sequences, or combination thereof, provided in Table 3, 4, 7, or 8. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a heavy chain variable region (VH) that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of any one of SEQ ID NOs: 378, 381, 383, 395, or 406. In some aspects, the VHcomprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 378. In some aspects, the VHcomprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 381. In some aspects, the VHcomprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 383. In some aspects, the VHcomprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 395. In some aspects, the VHcomprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 406.

[0107] In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a light chain variable region (VL) that comprises at least about 80%Attorney Docket No.106546-796518-4139 (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of any one of SEQ ID NOs: 410, 413, 415, 427, or 438. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VLthat comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 410. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VL that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 413. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VL that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 415. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VL that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 427. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VLthat comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 438.

[0108] In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VH that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of any one of SEQ ID NOs: 378, 381, 383, 395, or 406; and a VLthat comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of any one of SEQ ID NOs: 410, 413, 415, 427, or 438, or any combination thereof. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHthat comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 378; and a VLthat comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 410. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHthat comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 378; and a VLthat comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 413. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHthat comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 383; and a VLthat comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 415. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHthatAttorney Docket No.106546-796518-4139 comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 395; and a VLthat comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 427. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHthat comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 383; and a VL that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 415. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VH that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 406; and a VLthat comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 438.

[0109] In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHthat comprises the amino acid sequence of any one of SEQ ID NOs: 378, 381, 383, 395, or 406. In some aspects, the VH comprises the amino acid sequence of SEQ ID NO: 378. In some aspects, the VHcomprises the amino acid sequence of SEQ ID NO: 381. In some aspects, the VHcomprises the amino acid sequence of SEQ ID NO: 383. In some aspects, the VH comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 395. In some aspects, the VHcomprises the amino acid sequence of SEQ ID NO: 406.

[0110] In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VLthat comprises the amino acid sequence of any one of SEQ ID NOs: 410, 413, 415, 427, or 438. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VLthat comprises the amino acid sequence of SEQ ID NO: 410. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VLthat comprises the amino acid sequence of SEQ ID NO: 413. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VLthat comprises the amino acid sequence of SEQ ID NO: 415. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VLthat comprises the amino acid sequence of SEQ ID NO: 427. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VLthat comprises the amino acid sequence of SEQ ID NO: 438.

[0111] In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHthat comprises the amino acid sequence of any one of SEQ ID NOs: 378, 381, 4383, 395, or 406; and a VLthat comprises the amino acid sequence of any one of SEQ ID NOs: 410, 413, 415, 427, or 438, or any combination thereof. In some aspects,Attorney Docket No.106546-796518-4139 isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHthat comprises the amino acid sequence of SEQ ID NO: 378; and a VLthat comprises the amino acid sequence of SEQ ID NO: 410. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHthat comprises the amino acid sequence of SEQ ID NO: 381; and a VLthat comprises the amino acid sequence of SEQ ID NO: 413. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHthat comprises the amino acid sequence of SEQ ID NO: 383; and a VLthat comprises the amino acid sequence of SEQ ID NO: 415. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VH that comprises the amino acid sequence of SEQ ID NO: 395; and a VLthat comprises the amino acid sequence of SEQ ID NO: 427. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VH that comprises the amino acid sequence of SEQ ID NO: 383; and a VLthat comprises the amino acid sequence of SEQ ID NO: 415. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VH that comprises the amino acid sequence of SEQ ID NO: 406; and a VL that comprises the amino acid sequence of SEQ ID NO: 438.

[0112] In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a variable heavy chain complementary determining region 1 (VH CDR1) that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of any one of SEQ ID NOs: 227, 236, 242, or 278. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR1 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 227. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR1 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 236. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR1 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 242. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR1 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 278.

[0113] In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR1 that comprises the amino acid sequence of any one of SEQ ID NOs: 227, 236, 242, or 278. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR1 that comprises the amino acidAttorney Docket No.106546-796518-4139 sequence of SEQ ID NO: 227. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR1 that comprises the amino acid sequence of SEQ ID NO: 236. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR1 that comprises the amino acid sequence of SEQ ID NO: 242. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VH CDR1 that comprises the amino acid sequence of SEQ ID NO: 278.

[0114] In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a variable light chain complementary determining region 1 (VL CDR1) that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of any one of SEQ ID NOs: 162, 168, 172, or 196. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VLCDR1 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 162. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VL CDR1 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 168. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VL CDR1 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 172. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VLCDR1 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 196.

[0115] In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VLCDR1 that comprises the amino acid sequence of any one of SEQ ID NOs: 162, 168, 172, or 196. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VLCDR1 that comprises the amino acid sequence of SEQ ID NO: 162. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VLCDR1 that comprises the amino acid sequence of SEQ ID NO: 168. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VLCDR1 that comprises the amino acid sequence of SEQ ID NO: 172. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VLCDR1 that comprises the amino acid sequence of SEQ ID NO: 196.

[0116] In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR1 that comprises at least about 80% (e.g., about 85%, aboutAttorney Docket No.106546-796518-4139 90%, about 95%, about 98%) identity to the amino acid sequence of any one of SEQ ID NOs: 227, 236, 242, or 278 and a VLCDR1 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of any one of SEQ ID NOs: 162, 168, 172, or 196, or any combination thereof. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR1 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 227, and a VLCDR1 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 162. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR1 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 236, and a VL CDR1 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 168. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR1 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 242, and a VLCDR1 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 172. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR1 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 278, and a VLCDR1 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 196.

[0117] In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR1 that comprises the amino acid sequence of any one of SEQ ID NOs: 227, 236, 242, or 278 and a VLCDR1 that comprises the amino acid sequence of any one of SEQ ID NOs: 162, 168, 172, or 196, or any combination thereof. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR1 that comprises the amino acid sequence of SEQ ID NO: 227, and a VLCDR1 that comprises the amino acid sequence of SEQ ID NO: 162. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR1 that comprises the amino acid sequence of SEQ ID NO: 236, and a VLCDR1 that comprises the amino acid sequence of SEQ ID NO: 168. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR1 that comprises the amino acid sequence of SEQ ID NO: 242, and a VLCDR1 that comprises the amino acid sequence of SEQ ID NO: 172. In some aspects, isolated antibodies herein that bind an extracellular domainAttorney Docket No.106546-796518-4139 of PCDH7 may comprise a VHCDR1 that comprises the amino acid sequence of SEQ ID NO: 278, and a VLCDR1 that comprises the amino acid sequence of SEQ ID NO: 196.

[0118] In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a variable heavy chain complementary determining region 2 (VHCDR2) that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of any one of SEQ ID NOs: 228, 237, 243, or 279. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR2 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 228. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR2 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 237. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR2 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 243. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR2 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 279.

[0119] In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR2 that comprises the amino acid sequence of any one of SEQ ID NOs: 228, 237, 243, or 279. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR2 that comprises the amino acid sequence of SEQ ID NO: 228. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR2 that comprises the amino acid sequence of SEQ ID NO: 237. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR2 that comprises the amino acid sequence of SEQ ID NO: 243. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR2 that comprises the amino acid sequence of SEQ ID NO: 279.

[0120] In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a variable light chain complementary determining region 2 (VLCDR2) that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of any one of NVS, RAS, QAS, or EVT. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VLCDR2 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of NVS. In some aspects, isolated antibodies hereinAttorney Docket No.106546-796518-4139 that bind an extracellular domain of PCDH7 may comprise a VLCDR2 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of RAS. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VLCDR2 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of QAS. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VLCDR2 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of EVT.

[0121] In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VLCDR2 that comprises the amino acid sequence of any one of NVS, RAS, QAS, or EVT. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VL CDR2 that comprises the amino acid sequence NVS. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VLCDR2 that comprises the amino acid sequence RAS. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VL CDR2 that comprises the amino acid sequence QAS. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VLCDR2 that comprises the amino acid sequence EVT.

[0122] In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR2 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of any one of SEQ ID NOs: 228, 237, 243, or 279 and a VLCDR2 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of any one of NVS, RAS, QAS, or EVT, or any combination thereof. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR2 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 228 and a VLCDR2 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence NVS. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR2 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 237 and a VLCDR2 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence RAS. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR2 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 243 and a VLCDR2 that comprises at least about 80% (e.g., about 85%, about 90%, aboutAttorney Docket No.106546-796518-4139 95%, about 98%) identity to the amino acid sequence QAS. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR2 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 279 and a VLCDR2 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence EVT.

[0123] In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR2 that comprises the amino acid sequence of any one of SEQ ID NOs: 228, 237, 243, or 279 and a VL CDR2 that comprises the amino acid sequence of any one of NVS, RAS, QAS, or EVT, or any combination thereof. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR2 that comprises the amino acid sequence of SEQ ID NO: 228 and a VL CDR2 that comprises the amino acid sequence NVS. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR2 that comprises the amino acid sequence of SEQ ID NO: 237 and a VL CDR2 that comprises the amino acid sequence RAS. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR2 that comprises the amino acid sequence of SEQ ID NO: 243 and a VLCDR2 that comprises the amino acid sequence QAS. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR2 that comprises the amino acid sequence of SEQ ID NO: 279 and a VLCDR2 that comprises the amino acid sequence EVT.

[0124] In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a variable heavy chain complementary determining region 3 (VHCDR3) that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of any one of SEQ ID NOs: 229, 238, 244, or 280. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR3 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 229. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR3 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 238. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR3 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 244. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR3 that comprises at least about 80%Attorney Docket No.106546-796518-4139 (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 280.

[0125] In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a variable heavy chain complementary determining region 3 (VHCDR3) that comprises the amino acid sequence of any one of SEQ ID NOs: 229, 238, 244, or 280. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR3 that comprises the amino acid sequence of SEQ ID NO: 229. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VH CDR3 that comprises the amino acid sequence of SEQ ID NO: 238. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR3 that comprises the amino acid sequence of SEQ ID NO: 2446. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VH CDR3 that comprises the amino acid sequence of SEQ ID NO: 280.

[0126] In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a variable light chain complementary determining region 3 (VL CDR3) that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of any one of SEQ ID NOs: 163, 169, 173, or 197. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VLCDR3 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 163. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VLCDR3 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 169. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VLCDR3 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 173. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VLCDR3 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 197.

[0127] In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise VLCDR3 that comprises the amino acid sequence of any one of SEQ ID NOs: 163, 169, 173, or 197. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VLCDR3 that comprises the amino acid sequence of SEQ ID NO: 163. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VLCDR3 that comprises the amino acid sequence of SEQ ID NO: 169. In some aspects, isolated antibodies herein that bind anAttorney Docket No.106546-796518-4139 extracellular domain of PCDH7 may comprise a VLCDR3 that comprises the amino acid sequence of SEQ ID NO: 173. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VLCDR3 that comprises the amino acid sequence of SEQ ID NO: 197.

[0128] In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VH CDR3 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of any one of SEQ ID NOs: 229, 238, 244, or 280 and a VLCDR3 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of any one of SEQ ID NOs: 163, 169, 173, or 197, or any combination thereof. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR3 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 229 and a VLCDR3 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 163. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR3 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 238 and a VL CDR3 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 169. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR3 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 244 and a VLCDR3 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 173. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR3 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 280 and a VLCDR3 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 197.

[0129] In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR3 that comprises the amino acid sequence of any one of SEQ ID NOs: 229, 238, 244, or 280 and a VLCDR3 that comprises the amino acid sequence of any one of SEQ ID NOs: 163, 169, 173, or 197, or any combination thereof. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR3 that comprises the amino acid sequence of SEQ ID NO: 229 and a VLCDR3 that comprises the amino acid sequence of SEQ ID NO: 163. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR3 that comprisesAttorney Docket No.106546-796518-4139 the amino acid sequence of SEQ ID NO: 238 and a VLCDR3 that comprises the amino acid sequence of SEQ ID NO: 169. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR3 that comprises the amino acid sequence of SEQ ID NO: 244 and a VLCDR3 that comprises the amino acid sequence of SEQ ID NO: 173. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VH CDR3 that comprises the amino acid sequence of SEQ ID NO: 280 and a VLCDR3 that comprises the amino acid sequence of SEQ ID NO: 197.

[0130] In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VH CDR1 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of any one of SEQ ID NOs: 227, 236, 342, or 278; a VHCDR2 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of any one of SEQ ID NOs: 228, 237, 243, or 279; and a VHCDR3 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of any one of SEQ ID NOs: 229, 238, 244, or 280, or any combination thereof. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR1 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 227; a VH CDR2 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 228; and a VHCDR3 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 229. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR1 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 236; a VHCDR2 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 237; and a VHCDR3 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 238. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR1 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 242; a VHCDR2 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 243; and a VHCDR3 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 244. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR1 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence ofAttorney Docket No.106546-796518-4139 SEQ ID NO: 278; a VHCDR2 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 279; and a VHCDR3 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 282.

[0131] In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VH CDR1 that comprises the amino acid sequence of any one of SEQ ID NOs: 227, 236, 242, or 278; a VHCDR2 that comprises the amino acid sequence of any one of SEQ ID NOs: 228, 237, 243, or 279; and a VHCDR3 that comprises the amino acid sequence of any one of SEQ ID NOs: 229, 238, 244, or 280, or any combination thereof. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR1 that comprises the amino acid sequence of SEQ ID NO: 227; a VHCDR2 that comprises the amino acid sequence of SEQ ID NO: 228; and a VH CDR3 that comprises the amino acid sequence of SEQ ID NO: 229. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR1 that comprises the amino acid sequence of SEQ ID NO: 236; a VH CDR2 that comprises the amino acid sequence of SEQ ID NO: 237; and a VHCDR3 that comprises the amino acid sequence of SEQ ID NO: 238. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VH CDR1 that comprises the amino acid sequence of SEQ ID NO: 242; a VH CDR2 that comprises the amino acid sequence of SEQ ID NO: 243; and a VHCDR3 that comprises the amino acid sequence of SEQ ID NO: 244. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR1 that comprises the amino acid sequence of SEQ ID NO: 278; a VHCDR2 that comprises the amino acid sequence of SEQ ID NO: 2791; and a VHCDR3 that comprises the amino acid sequence of SEQ ID NO: 280.

[0132] In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VLCDR1 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of any one of SEQ ID NOs: 162, 168, 172, or 196; a VLCDR2 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of any one of NVS, RAS, QAS, or EVT; and a VLCDR3 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of any one of SEQ ID NOs: 163, 169, 173, or 197, or any combination thereof. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VLCDR1 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 162; a VLCDR2 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence NVS; and a VLCDR3 thatAttorney Docket No.106546-796518-4139 comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 163. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VLCDR1 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 168; a VLCDR2 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence RAS; and a VL CDR3 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 169. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VL CDR1 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 172; a VLCDR2 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence QAS; and a VL CDR3 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 173. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VL CDR1 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 196; a VLCDR2 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence EVT; and a VLCDR3 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 197.

[0133] In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VLCDR1 that comprises the amino acid sequence of any one of SEQ ID NOs: 162, 168, 172, or 196; a VLCDR2 that comprises the amino acid sequence of any one of NVS, RAS, QAS, or EVT; and a VLCDR3 that comprises the amino acid sequence of any one of SEQ ID NOs: 163, 169, 173, or 197, or any combination thereof. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VLCDR1 that comprises the amino acid sequence of SEQ ID NO: 162; a VLCDR2 that comprises the amino acid sequence NVS; and a VLCDR3 that comprises the amino acid sequence of SEQ ID NO: 163. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VLCDR1 that comprises the amino acid sequence of SEQ ID NO: 168; a VLCDR2 that comprises the amino acid sequence RAS; and a VLCDR3 that comprises the amino acid sequence of SEQ ID NO: 169. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VLCDR1 that comprises the amino acid sequence of SEQ ID NO: 172; a VLCDR2 that comprises the amino acid sequence of QAS; and a VLCDR3 that comprises the amino acid sequence of SEQ ID NO: 173. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may compriseAttorney Docket No.106546-796518-4139 a VLCDR1 that comprises the amino acid sequence of SEQ ID NO: 196; a VLCDR2 that comprises the amino acid sequence EVT; and a VLCDR3 that comprises the amino acid sequence of SEQ ID NO: 197.

[0134] In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR1 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of any one of SEQ ID NOs: 227, 236, 242, or 278; a VHCDR2 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of any one of SEQ ID NOs: 228, 237, 243, or 279; a VH CDR3 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of any one of SEQ ID NOs: 229, 238, 244, or 280; a VLCDR1 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of any one of SEQ ID NOs: 162, 168, 172, or 196; a VLCDR2 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of any one of NVS, RAS, QAS, or EVT; and a VL CDR3 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of any one of SEQ ID NOs: 163, 169, 173, or 197, or any combination thereof. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VH CDR1 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 227; a VHCDR2 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 228; a VHCDR3 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 229; a VLCDR1 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 162; a VLCDR2 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence NVS; and a VLCDR3 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 163. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR1 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 236; a VHCDR2 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 237; a VHCDR3 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 238; a VLCDR1 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 168; a VLCDR2 that comprises atAttorney Docket No.106546-796518-4139 least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence RAS; and a VLCDR3 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of any one of SEQ ID NO: 169. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR1 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 242; a VH CDR2 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 243; a VHCDR3 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 244; a VLCDR1 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence SEQ ID NO: 172; a VL CDR2 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence QAS; and a VLCDR3 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 173. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR1 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 278; a VH CDR2 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 279; a VHCDR3 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 280; a VLCDR1 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 196; a VLCDR2 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of EVT; and a VLCDR3 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 197.

[0135] In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR1 that comprises the amino acid sequence of any one of SEQ ID NOs: 227, 236, 242, or 278; a VHCDR2 that comprises the amino acid sequence of any one of SEQ ID NOs: 228, 237, 243, or 279; a VHCDR3 that comprises the amino acid sequence of any one of SEQ ID NOs: 229, 238, 244, or 280; a VLCDR1 that comprises the amino acid sequence of any one of SEQ ID NOs: 162, 168, 172, or 196; a VLCDR2 that comprises the amino acid sequence of any one of NVS, RAS, QAS, or EVT; and a VLCDR3 that comprises the amino acid sequence of any one of SEQ ID NOs: 163, 169, 173, or 197, or any combination thereof. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR1 that comprises the amino acid sequence of SEQAttorney Docket No.106546-796518-4139 ID NO: 227; a VHCDR2 that comprises the amino acid sequence of SEQ ID NO: 228; a VHCDR3 that comprises the amino acid sequence of SEQ ID NO: 291; a VLCDR1 that comprises the amino acid sequence of SEQ ID NO: 162; a VLCDR2 that comprises the amino acid sequence NVS; and a VLCDR3 that comprises the amino acid sequence of SEQ ID NO: 163. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VH CDR1 that comprises the amino acid sequence of SEQ ID NO: 236; a VH CDR2 that comprises the amino acid sequence of SEQ ID NO: 237; a VHCDR3 that comprises the amino acid sequence of SEQ ID NO: 238; a VLCDR1 that comprises the amino acid sequence of SEQ ID NO: 168; a VL CDR2 that comprises the amino acid sequence RAS; and a VL CDR3 that comprises the amino acid sequence of any one of SEQ ID NO: 169. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR1 that comprises the amino acid sequence of SEQ ID NO: 242; a VH CDR2 that comprises the amino acid sequence of SEQ ID NO: 243; a VHCDR3 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 244; a VL CDR1 that comprises the amino acid sequence SEQ ID NO: 172; a VL CDR2 that comprises the amino acid sequence QAS; and a VLCDR3 that comprises the amino acid sequence of SEQ ID NO: 173. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VH CDR1 that comprises the amino acid sequence of SEQ ID NO: 278; a VHCDR2 that comprises the amino acid sequence of SEQ ID NO: 279; a VHCDR3 that comprises the amino acid sequence of SEQ ID NO: 280; a VLCDR1 that comprises the amino acid sequence of SEQ ID NO: 196; a VLCDR2 that comprises the amino acid sequence of EVT; and a VLCDR3 that comprises the amino acid sequence of SEQ ID NO: 197.

[0136] In some aspects, the isolated antibodies herein that bind an extracellular domain of PCDH7 may be a chimeric, CDR grafted, humanized, muranized, or human antibody, or an immunoreactive fragment thereof of antibodies provided in Table 3, 4, 7, or 8. In some embodiments, isolated antibodies herein may be a human antibody or a humanized antibody. Humanized antibodies refer to forms of non-human (e.g., rabbit) antibodies that are specific chimeric immunoglobulins, immunoglobulin chains, or antigen-binding fragments thereof that contain minimal sequence derived from non-human immunoglobulin. In some aspects, the isolated antibody is a humanized antibody. In some aspects, the humanized antibody may comprise a VHhaving at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO. 406. In some aspects, the humanized antibody may comprise a VHhaving the amino acid sequence of SEQ ID NO.406. In some aspects, the humanized antibody may comprise a VLhaving at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQAttorney Docket No.106546-796518-4139 ID NO.438. In some aspects, the humanized antibody may comprise a VLhaving the amino acid sequence of SEQ ID NO.438. In some aspects, the humanized antibody may comprise a VHhaving at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO.406 and a VLhaving at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO.438. In some aspects, the humanized antibody may comprise a VH having the amino acid sequence of SEQ ID NO.406 and a VLhaving the amino acid sequence of SEQ ID NO. 438.

[0137] In certain aspects, the heavy chain of any of the antibodies disclosed herein may further comprise a heavy chain constant region (CH) or a portion thereof (e.g., CH1, CH2, CH3, or a combination thereof). In some aspects, a heavy chain constant region for use herein may be of any suitable origin, e.g., human, mouse, rat, or rabbit. In some aspects, alternatively or in addition, a light chain of any of the antibodies disclosed herein may further comprise a light chain constant region (CL), which can be any CL known in the art. In some aspects, a CL may be a kappa light chain. In some aspects, a CL may be a lambda light chain. Antibody heavy and light chain constant regions are well known in the art, e.g., those provided in the IMGT database (www.imgt.org) or at www.vbase2.org / vbstat.php., both of which are incorporated by reference herein.

[0138] In some aspects, isolated antibodies herein that bind a that bind an extracellular domain of PCDH7 may be a full-length antibody or an antigen-binding fragment thereof. In some aspects, isolated antibodies herein may be a full-length antibody, which is an IgG molecule. In some aspects, isolated antibodies herein may be a Fab, a (Fab’)2, and / or a single- chain antibody. In some embodiments, antibodies disclosed herein may be a single chain antibody (scFv). In some aspects, scFv antibody herein may comprise a VHfragment and a VLfragment, which may be linked via a linker. In accordance with these aspects, a linker incorporated between the two variable regions herein may be a flexible linker, a rigid linker, a cleavable linker, or any combination thereof. In some aspects, a linker incorporated between the two variable regions herein may be a flexible peptide linker, a rigid peptide linker, a cleavable peptide linker, or any combination thereof. In accordance with these aspects, a peptide linker incorporated between the two variable regions herein may be at least one amino acid. In some aspects, a peptide linker incorporated between the two variable regions herein may be about 1 amino acid to about 50 amino acids (e.g., about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 32, about 34, about 36, about 38, about 40, about 42, about 44, about 46, about 48, about 50). In someAttorney Docket No.106546-796518-4139 aspects, a scFv antibody herein may comprise a VHfragment and a VLfragment, which may be linked via a flexible peptide linker.

[0139] In some aspects, a scFv antibody herein may be in the VH-VL orientation (from N- terminus to C-terminus). In some aspects, a scFv antibody herein may be in the VL-VH orientation (from N-terminus to C-terminus).

[0140] Polynucleotides, vectors and host cells can be used to prepare any one of the antibodies disclosed herein (e.g., an antibody that binds an extracellular domain of PCDH7) using recombinant technology, as exemplified herein. In certain aspects, nucleic acids (i.e., polynucleotides) encoding the heavy and light chain of an antibody as described herein can be cloned into one expression vector, each nucleotide sequence being in operable linkage to a suitable promoter. In some aspects, each of the polynucleotide sequences encoding the heavy chain and light chain may be in operable linkage to a distinct promoter. In some aspects, polynucleotide sequences encoding the heavy chain and the light chain may be in operable linkage with a single promoter, such that both heavy and light chains are expressed from the same promoter. In some aspects, when necessary, an internal ribosomal entry site (IRES) can be inserted between the heavy chain and light chain encoding sequences.

[0141] In certain aspects, the polynucleotide sequences encoding the heavy chain and / or light chain of the antibodies described herein may comprise one or more polynucleotide sequences, or combinations thereof, provided in Table 1, 2, 5, or 6.

[0142] In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHthat comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of any one of SEQ ID NOs: 314, 317, 319, 331, or 342. In some aspects, the VHcomprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 314. In some aspects, the VHcomprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 317. In some aspects, the VHcomprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 319. In some aspects, the VHcomprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 331. In some aspects, the VHcomprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 342.

[0143] In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHthat comprises the polynucleotide sequence of any one of SEQ ID NOs: 314, 317, 319, 331, or 342. In some aspects, the VHcomprises the polynucleotideAttorney Docket No.106546-796518-4139 sequence of SEQ ID NO: 314. In some aspects, the VHcomprises the polynucleotide sequence of SEQ ID NO: 317. In some aspects, the VHcomprises the polynucleotide sequence of SEQ ID NO: 319. In some aspects, the VHcomprises the polynucleotide sequence of SEQ ID NO: 331. In some aspects, the VHcomprises the polynucleotide sequence of SEQ ID NO: 342.

[0144] In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VLthat comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of any one of SEQ ID NOs: 346, 349, 351, 363, or 374. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VLthat comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 346. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VLthat comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 349. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VLthat comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 351. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VL that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 363. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VLthat comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 374.

[0145] In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VLthat comprises the polynucleotide sequence of any one of SEQ ID NOs: 346, 349, 351, 363, or 374. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VLthat comprises the polynucleotide sequence of SEQ ID NO: 346. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VLthat comprises the polynucleotide sequence of SEQ ID NO: 349. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VLthat comprises the polynucleotide sequence of SEQ ID NO: 351. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VLthat comprises the polynucleotide sequence of SEQ ID NO: 363. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VLthat comprises the polynucleotide sequence of SEQ ID NO: 373.Attorney Docket No.106546-796518-4139

[0146] In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHthat comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of any one of SEQ ID NOs: 314, 317, 319, 331, or 342; and a VLthat comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of any one of SEQ ID NOs: 346, 349, 351, 363, or 374, or any combination thereof. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHthat comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 314; and a VL that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 346. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VH that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 317; and a VLthat comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 349. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHthat comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 319; and a VL that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 351. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHthat comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 331; and a VLthat comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 363. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHthat comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 342; and a VLthat comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 374.

[0147] In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHthat comprises the polynucleotide sequence of any one of SEQ ID NOs: 314, 317, 319, 331, or 342; and a VLthat comprises the polynucleotide sequence of any one of SEQ ID NOs: 346, 349, 351, 363, or 374, or any combination thereof. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHthat comprises the polynucleotide sequence of SEQ ID NO: 314; and a VLthat comprises the polynucleotide sequence of SEQ ID NO: 346. In some aspects, isolated antibodies hereinAttorney Docket No.106546-796518-4139 that bind an extracellular domain of PCDH7 may comprise a VHthat comprises the polynucleotide sequence of SEQ ID NO: 317; and a VLthat comprises the polynucleotide sequence of SEQ ID NO: 349. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHthat comprises the polynucleotide sequence of SEQ ID NO: 319; and a VLthat comprises the polynucleotide sequence of SEQ ID NO: 351. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHthat comprises the polynucleotide sequence of SEQ ID NO: 331; and a VLthat comprises the polynucleotide sequence of SEQ ID NO: 363. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VH that comprises the polynucleotide sequence of SEQ ID NO: 342; and a VLthat comprises the polynucleotide sequence of SEQ ID NO: 374.

[0148] In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR1 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of any one of SEQ ID NOs: 72, 81, 87, or 123. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR1 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 72. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR1 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 81. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR1 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 87. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR1 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 123.

[0149] In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR1 that comprises the polynucleotide sequence of any one of SEQ ID NOs: 72, 81, 87, or 123. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR1 that comprises the polynucleotide sequence of SEQ ID NO: 72. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR1 that comprises the polynucleotide sequence of SEQ ID NO: 81. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR1 that comprises the polynucleotide sequence of SEQ ID NO: 87. In some aspects, isolated antibodies herein that bind anAttorney Docket No.106546-796518-4139 extracellular domain of PCDH7 may comprise a VHCDR1 that comprises the polynucleotide sequence of SEQ ID NO: 123.

[0150] In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VLCDR1 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of any one of SEQ ID NOs: 7, 13, 17, or 41. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VLCDR1 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 7. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VLCDR1 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 13. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VLCDR1 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 17. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VL CDR1 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 41.

[0151] In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VLCDR1 that comprises the polynucleotide sequence of any one of SEQ ID NOs: 7, 13, 17, or 41. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VLCDR1 that comprises the polynucleotide sequence of SEQ ID NO: 7. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VLCDR1 that comprises the polynucleotide sequence of SEQ ID NO: 13. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VLCDR1 that comprises the polynucleotide sequence of SEQ ID NO: 17. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VLCDR1 that comprises the polynucleotide sequence of SEQ ID NO: 41.

[0152] In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR1 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of any one of SEQ ID NOs: 72, 81, 87, or 123and a VLCDR1 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of any one of SEQ ID NOs: 7, 13, 17, or 41, or any combination thereof. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR1 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to theAttorney Docket No.106546-796518-4139 polynucleotide sequence of SEQ ID NO: 72, and a VLCDR1 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 7. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR1 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 81, and a VL CDR1 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 13. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VH CDR1 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 87, and a VLCDR1 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 17. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR1 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 123, and a VL CDR1 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 41.

[0153] In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR1 that comprises the polynucleotide sequence of any one of SEQ ID NOs: 72, 81, 87, or 123 and a VLCDR1 that comprises the polynucleotide sequence of any one of SEQ ID NOs: 7, 13, 17, or 41, or any combination thereof. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR1 that comprises the polynucleotide sequence of SEQ ID NO: 72, and a VLCDR1 that comprises the polynucleotide sequence of SEQ ID NO: 7. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR1 that comprises the polynucleotide sequence of SEQ ID NO: 81, and a VLCDR1 that comprises the polynucleotide sequence of SEQ ID NO: 13. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR1 that comprises the polynucleotide sequence of SEQ ID NO: 87, and a VLCDR1 that comprises the polynucleotide sequence of SEQ ID NO: 17. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR1 that comprises the polynucleotide sequence of SEQ ID NO: 123, and a VLCDR1 that comprises the polynucleotide sequence of SEQ ID NO: 41.

[0154] In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR2 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of any one of SEQ IDAttorney Docket No.106546-796518-4139 NOs: 73, 82, 88, or 124. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR2 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 73. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR2 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 82. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR2 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 88. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR2 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 124.

[0155] In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR2 that comprises the polynucleotide sequence of any one of SEQ ID NOs: 73, 82, 88, or 124. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR2 that comprises the polynucleotide sequence of SEQ ID NO: 73. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VH CDR2 that comprises the polynucleotide sequence of SEQ ID NO: 82. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR2 that comprises the polynucleotide sequence of SEQ ID NO: 88. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR2 that comprises the polynucleotide sequence of SEQ ID NO: 124.

[0156] In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VLCDR2 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of any one of aatgtatcg, agggcatcc, caggcatcc, or gaggtcact. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VLCDR2 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence aatgtatcg. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VLCDR2 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence agggcatcc. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VLCDR2 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence caggcatcc. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VLCDR2 that comprisesAttorney Docket No.106546-796518-4139 at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence gaggtcact.

[0157] In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VLCDR2 that comprises the polynucleotide sequence of any one of aatgtatcg, agggcatcc, caggcatcc, or gaggtcact. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VL CDR2 that comprises the polynucleotide sequence aatgtatcg. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VLCDR2 that comprises the polynucleotide sequence agggcatcc. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VLCDR2 that comprises the polynucleotide sequence caggcatcc. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VL CDR2 that comprises the polynucleotide sequence gaggtcact.

[0158] In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR2 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of any one of SEQ ID NOs: 73, 82, 88, or 124and a VLCDR2 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of any one of SEQ ID NOs: aatgtatcg, agggcatcc, caggcatcc, or gaggtcact, or any combination thereof. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR2 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 73 and a VLCDR2 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of aatgtatcg. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR2 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 82 and a VLCDR2 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence agggcatcc. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR2 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 88 and a VLCDR2 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence caggcatcc. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR2 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 124 and a VLCDR2 that comprises at least aboutAttorney Docket No.106546-796518-4139 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence ofgaggtcact.

[0159] In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR2 that comprises the polynucleotide sequence of any one of SEQ ID NOs: 73, 82, 88, or 124and a VLCDR2 that comprises the polynucleotide sequence of any one of aatgtatcg, agggcatcc, caggcatcc, or gaggtcact, or any combination thereof. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR2 that comprises the polynucleotide sequence of SEQ ID NO: 73 and a VLCDR2 that comprises the amino acid sequence aatgtatcg. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR2 that comprises the polynucleotide sequence of SEQ ID NO: 82 and a VLCDR2 that comprises the polynucleotide sequence of SEQ ID NO: agggcatcc. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR2 that comprises the polynucleotide sequence of SEQ ID NO: 88 and a VLCDR2 that comprises the polynucleotide sequence caggcatcc. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR2 that comprises the polynucleotide sequence of SEQ ID NO: 124 and a VLCDR2 that comprises the polynucleotide sequence gaggtcact.

[0160] In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR3 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of any one of SEQ ID NOs: 74, 83, 89, or 125. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR3 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 74. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR3 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 83. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR3 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 89. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR3 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 125.

[0161] In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR3 that comprises the polynucleotide sequence of any one of SEQ ID NOs: 74, 83, 89, or 125. In some aspects, isolated antibodies herein that bind anAttorney Docket No.106546-796518-4139 extracellular domain of PCDH7 may comprise a VHCDR3 that comprises the polynucleotide sequence of SEQ ID NO: 74. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR3 that comprises the polynucleotide sequence of SEQ ID NO: 83. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR3 that comprises the polynucleotide sequence of SEQ ID NO: 89. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR3 that comprises the polynucleotide sequence of SEQ ID NO: 125.

[0162] In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VLCDR3 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of any one of SEQ ID NOs: 8, 14, 18, or 42. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VLCDR3 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 8. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VLCDR3 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 14. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VLCDR3 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 18. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VLCDR3 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 42.

[0163] In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VLCDR3 that comprises the polynucleotide sequence of any one of SEQ ID NOs: 8, 14, 18, or 42. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VLCDR3 that comprises the polynucleotide sequence of SEQ ID NO: 8. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VLCDR3 that comprises the polynucleotide sequence of SEQ ID NO: 14. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VLCDR3 that comprises the polynucleotide sequence of SEQ ID NO: 18. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VLCDR3 that comprises the polynucleotide sequence of SEQ ID NO: 42.

[0164] In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR3 that comprises at least about 80% (e.g., about 85%, aboutAttorney Docket No.106546-796518-4139 90%, about 95%, about 98%) identity to the polynucleotide sequence of any one of SEQ ID NOs: 74, 83, 89, or 125 and a VLCDR3 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of any one of SEQ ID NOs: 8, 14, 18, or 42, or any combination thereof. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR3 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 74 and a VLCDR3 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 8. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR3 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 83 and a VL CDR3 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 14. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR3 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 89 and a VLCDR3 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 18. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR3 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 125 and a VLCDR3 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 42.

[0165] In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR3 that comprises the polynucleotide sequence of any one of SEQ ID NOs: 74, 83, 89, or 125and a VLCDR3 that comprises the polynucleotide sequence of any one of SEQ ID NOs: 8, 14, 18, or 42, or any combination thereof. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR3 that comprises the polynucleotide sequence of SEQ ID NO: 74 and a VLCDR3 that comprises the polynucleotide sequence of SEQ ID NO: 8. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR3 that comprises the polynucleotide sequence of SEQ ID NO: 83 and a VLCDR3 that comprises the polynucleotide sequence of SEQ ID NO: 14. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR3 that comprises the polynucleotide sequence of SEQ ID NO: 89 and a VLCDR3 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO: 18. In some aspects, isolated antibodies herein that bind an extracellular domainAttorney Docket No.106546-796518-4139 of PCDH7 may comprise a VHCDR3 that comprises the polynucleotide sequence of SEQ ID NO: 125 and a VLCDR3 that comprises the polynucleotide sequence of SEQ ID NO: 42.

[0166] In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR1 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of any one of SEQ ID NOs: 72, 81, 87, or 123; a VH CDR2 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of any one of SEQ ID NOs: 73, 82, 88, or 124; and a VHCDR3 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of any one of SEQ ID NOs: 74, 83, 89, or 125, or any combination thereof. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR1 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 72; a VHCDR2 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 73; and a VH CDR3 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 74. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VH CDR1 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 81; a VHCDR2 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 82; and a VHCDR3 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 83. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR1 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 87; a VHCDR2 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 88; and a VHCDR3 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 89. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR1 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 123; a VHCDR2 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 124; and a VHCDR3 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 125.Attorney Docket No.106546-796518-4139

[0167] In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR1 that comprises the polynucleotide sequence of any one of SEQ ID NOs: 72, 81, 87, or 123; a VHCDR2 that comprises the polynucleotide sequence of any one of SEQ ID NOs: 73, 82, 88, or 124; and a VHCDR3 that comprises the polynucleotide sequence of any one of SEQ ID NOs: 74, 83, 89, or 125, or any combination thereof. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR1 that comprises the polynucleotide sequence of SEQ ID NO: 72; a VHCDR2 that comprises the polynucleotide sequence of SEQ ID NO: 73; and a VHCDR3 that comprises the polynucleotide sequence of SEQ ID NO: 74. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR1 that comprises the polynucleotide sequence of SEQ ID NO: 81; a VHCDR2 that comprises the polynucleotide sequence of SEQ ID NO: 82; and a VH CDR3 that comprises the polynucleotide sequence of SEQ ID NO: 83. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR1 that comprises the polynucleotide sequence of SEQ ID NO: 87; a VH CDR2 that comprises the polynucleotide sequence of SEQ ID NO: 88; and a VH CDR3 that comprises the polynucleotide sequence of SEQ ID NO: 89. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR1 that comprises the polynucleotide sequence of SEQ ID NO: 123; a VH CDR2 that comprises the polynucleotide sequence of SEQ ID NO: 124; and a VHCDR3 that comprises the polynucleotide sequence of SEQ ID NO: 125.

[0168] In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VLCDR1 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of any one of SEQ ID NOs: 7, 13, 17, or 41; a VLCDR2 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of any one of aatgtatcg, agggcatcc, caggcatcc, or gaggtcact; and a VLCDR3 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of any one of SEQ ID NOs: 8, 14, 18, or 42, or any combination thereof. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VLCDR1 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 7; a VLCDR2 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: aatgtatcg; and a VLCDR3 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 8. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VLCDR1 that comprises at least about 80% (e.g., about 85%,Attorney Docket No.106546-796518-4139 about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 13; a VLCDR2 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence agggcatcc ; and a VLCDR3 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 14. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VL CDR1 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 17; a VLCDR2 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence caggcatcc; and a VLCDR3 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 18. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VL CDR1 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 41; a VLCDR2 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence gaggtcact; and a VLCDR3 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 42.

[0169] In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VLCDR1 that comprises the polynucleotide sequence of any one of SEQ ID NOs: 7, 13, 17, or 41; a VLCDR2 that comprises the polynucleotide sequence of aatgtatcg, agggcatcc, caggcatcc, or gaggtcact; and a VLCDR3 that comprises the polynucleotide sequence of any one of SEQ ID NOs: 8, 14, 18, or 42, or any combination thereof. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VLCDR1 that comprises the polynucleotide sequence of SEQ ID NO: 7; a VLCDR2 that comprises the polynucleotide sequence of aatgtatcg; and a VLCDR3 that comprises the polynucleotide sequence of SEQ ID NO: 8. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VLCDR1 that comprises the polynucleotide sequence of SEQ ID NO: 13; a VLCDR2 that comprises the polynucleotide sequence agggcatcc; and a VLCDR3 that comprises the polynucleotide sequence of SEQ ID NO: 14. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VLCDR1 that comprises the polynucleotide sequence of SEQ ID NO: 17; a VLCDR2 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence caggcatcc; and a VLCDR3 that comprises the polynucleotide sequence of SEQ ID NO: 18. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VLCDR1 that comprises theAttorney Docket No.106546-796518-4139 polynucleotide sequence of SEQ ID NO: 41; a VLCDR2 that comprises the polynucleotide sequence gaggtcact; and a VLCDR3 that comprises the polynucleotide sequence of SEQ ID NO: 42.

[0170] In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR1 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of any one of SEQ ID NOs: 72, 81, 87, or 123; a VHCDR2 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of any one of SEQ ID NOs: 73, 82, 88, or 124; a VH CDR3 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of any one of SEQ ID NOs: 74, 83,89, or 125; a VLCDR1 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of any one of SEQ ID NOs: 7, 13, 17, or 41; a VLCDR2 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of any one of aatgtatcg, agggcatcc, caggcatcc, or gaggtcact; and a VL CDR3 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of any one of SEQ ID NOs: 8, 14, 18, or 42, or any combination thereof. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VH CDR1 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 72; a VHCDR2 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 73; a VHCDR3 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 74; a VLCDR1 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 7; a VLCDR2 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence aatgtatcg; and a VLCDR3 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 8. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR1 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 81; a VHCDR2 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 82; a VHCDR3 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 83; a VLCDR1 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotideAttorney Docket No.106546-796518-4139 sequence of SEQ ID NO: 13; a VLCDR2 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence agggcatcc; and a VLCDR3 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of any one of SEQ ID NO: 14. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR1 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 87; a VHCDR2 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 88; a VH CDR3 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 89; a VLCDR1 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence SEQ ID NO: 17; a VL CDR2 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence caggcatcc; and a VLCDR3 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 18. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR1 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 123; a VHCDR2 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 124; a VHCDR3 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 125; a VLCDR1 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NOs: 41; a VLCDR2 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence gaggtcact; and a VLCDR3 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 42.

[0171] In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR1 that comprises the polynucleotide sequence of any one of SEQ ID NOs: 72, 81, 87, or 123; a VHCDR2 that comprises the polynucleotide sequence of any one of SEQ ID NOs: 73, 82, 88, or 124; a VHCDR3 that comprises the polynucleotide sequence of any one of SEQ ID NOs: 74, 83,89, or 125; a VLCDR1 that comprises the polynucleotide sequence of any one of SEQ ID NOs: 7, 13, 17, or 41; a VLCDR2 that comprises the polynucleotide sequence of any one of aatgtatcg, agggcatcc, caggcatcc, or gaggtcact; and a VLCDR3 that comprises the polynucleotide sequence of any one of SEQ IDAttorney Docket No.106546-796518-4139 NOs: 8, 14, 18, or 42, or any combination thereof. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR1 that comprises the polynucleotide sequence of SEQ ID NO: 72; a VHCDR2 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 73; a VHCDR3 that comprises the polynucleotide sequence of SEQ ID NO: 74; a VL CDR1 that comprises the polynucleotide sequence of SEQ ID NO: 7; a VL CDR2 that comprises the polynucleotide sequence aatgtatcg; and a VLCDR3 that comprises the polynucleotide sequence of SEQ ID NO: 8. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VH CDR1 that comprises the polynucleotide sequence of SEQ ID NO: 81; a VHCDR2 that comprises the polynucleotide sequence of SEQ ID NO: 82; a VHCDR3 that comprises the polynucleotide sequence of SEQ ID NO: 83; a VL CDR1 that comprises the polynucleotide sequence of SEQ ID NO: 13; a VL CDR2 that comprises the polynucleotide sequence agggcatcc; and a VLCDR3 that comprises the polynucleotide sequence of any one of SEQ ID NO: 14. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VH CDR1 that comprises the polynucleotide sequence of SEQ ID NO: 87; a VHCDR2 that comprises at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the polynucleotide sequence of SEQ ID NO: 88; a VH CDR3 that comprises the polynucleotide sequence of SEQ ID NO: 89; a VLCDR1 that comprises the polynucleotide sequence SEQ ID NO: 17; a VLCDR2 that comprises the polynucleotide sequence caggcatcc; and a VLCDR3 that comprises the polynucleotide sequence of SEQ ID NO: 18. In some aspects, isolated antibodies herein that bind an extracellular domain of PCDH7 may comprise a VHCDR1 that comprises the polynucleotide sequence of SEQ ID NO: 123; a VHCDR2 that comprises the polynucleotide sequence of SEQ ID NO: 124; a VHCDR3 that comprises the polynucleotide sequence of SEQ ID NO: 125; a VLCDR1 that comprises the polynucleotide sequence of SEQ ID NOs: 41; a VLCDR2 that comprises the polynucleotide sequence gaggtcact; and a VLCDR3 that comprises the polynucleotide sequence of SEQ ID NO: 42.

[0172] In some aspects, the isolated antibodies herein that bind an extracellular domain of PCDH7 may be a chimeric, CDR grafted, humanized, muranized, or human antibody, or an immunoreactive fragment thereof of antibodies, or combinations thereof provided in Table 3, 4, 7, or 8. In some aspects, isolated antibodies herein may be a human antibody or a humanized antibody. Humanized antibodies refer to forms of non-human (e.g., rabbit) antibodies that are specific chimeric immunoglobulins, immunoglobulin chains, or antigen- binding fragments thereof that contain minimal sequence derived from non-human immunoglobulin. In some aspects, the isolated antibody is a humanized antibody. In some aspects, the humanized antibody may comprise a VHhaving at least about 80% (e.g., aboutAttorney Docket No.106546-796518-4139 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO. 406. In some aspects, the humanized antibody may comprise a VHhaving the amino acid sequence of SEQ ID NO.468. In some aspects, the humanized antibody may comprise a VLhaving at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO.500. In some aspects, the humanized antibody may comprise a VL having the amino acid sequence of SEQ ID NO.438. In some aspects, the humanized antibody may comprise a VHhaving at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO.406 and a VL having at least about 80% (e.g., about 85%, about 90%, about 95%, about 98%) identity to the amino acid sequence of SEQ ID NO.438. In some aspects, the humanized antibody may comprise a VHhaving the amino acid sequence of SEQ ID NO.406 and a VLhaving the amino acid sequence of SEQ ID NO.438.

[0173] In some aspects, the expression and / or production of the antibodies in the host cell can be promoted by expressing a leader peptide ahead of the variable region of the heavy or light chain of the antibody. In some embodiments, a leader peptide can be optimized for expression in a certain host cell (e.g., E. coli).

[0174] In some aspects, genetically engineered antibodies such as single-chain antibodies can be produced via, e.g., conventional recombinant technology or any methods known in the art. In some aspects, DNA encoding a monoclonal antibodies specific to a target antigen 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 the monoclonal antibodies). Once isolated, the DNA can be placed into one or more expression vectors, which are then transfected into host cells such as E. coli cells, 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 can then be modified, for example, by substituting the coding sequence for human heavy and light chain constant domains in place of the homologous murine sequences, or by covalently joining to the immunoglobulin coding sequence all or part of the coding sequence for a non-immunoglobulin polypeptide. In some aspects, genetically engineered antibodies, such as chimeric or hybrid antibodies; can be prepared that have the binding specificity of a target antigen.

[0175] In some aspects, a single-chain antibody herein can be prepared via recombinant technology by linking a nucleotide sequence coding for a heavy chain variable region and a nucleotide sequence coding for a light chain variable region. In some aspects, a linker may be incorporated between the two variable regions. In some aspects, techniques described for the production of single chain antibodies can be adapted to produce a phage or yeast scFvAttorney Docket No.106546-796518-4139 library and scFv clones specific to the extracellular domain of PCDH7 can be identified from the library following routine procedures. In some aspects, positive clones can be subjected to further screening to identify those that bind to the extracellular domain of PCDH7.

[0176] In some aspects, one or more vectors (e.g., expression vectors) having nucleic acids encoding any of the antibodies herein can be introduced into suitable host cells for producing the antibodies. In some embodiments, host cells can be cultured under suitable conditions for expression of the antibody or any polypeptide chain thereof. In some embodiments, antibodies or polypeptide chains thereof can be recovered by the cultured cells (e.g., from the cells or the culture supernatant) via a conventional method, e.g., affinity purification. In some embodiments, polypeptide chains of the antibody herein can be incubated under suitable conditions for a suitable period of time allowing for production of the antibody.

[0177] In some aspects, methods for preparing an antibody described herein can include a recombinant expression vector that encodes both the heavy chain and the light chain of an antibody that binds extracellular domain of PCDH7, as also described herein. In some aspects, a recombinant expression vector can be introduced into a suitable host cell by a conventional method, e.g., calcium phosphate-mediated transfection. In some aspects, positive transformant host cells can be selected and cultured under suitable conditions allowing for the expression of the two polypeptide chains that form the antibody, which can be recovered from the cells or from the culture medium. In some aspects, the two chains recovered from the host cells can be incubated under suitable conditions allowing for the formation of the antibody.

[0178] In certain aspects, two recombinant expression vectors can be provided, one encoding the heavy chain of a disclosed antibody and the other encoding the light chain of the disclosed antibody. In some embodiments, both of the two recombinant expression vectors can be introduced into a suitable host cell by a conventional method, e.g., calcium phosphate- mediated transfection. In some aspects, each of the expression vectors can be introduced into a suitable host cell. In some aspects, positive transformants can be selected and cultured under suitable conditions allowing for the expression of the polypeptide chains of the antibody. In some aspects, when the two expression vectors are introduced into the same host cells, the antibody produced therein can be recovered from the host cells or from the culture medium. In some aspects, the polypeptide chains can be recovered from the host cells or from the culture medium and then incubated under suitable conditions allowing for formation of the antibody. In some aspects, when the two expression vectors are introduced into different host cells, each of them can be recovered from the corresponding host cells or fromAttorney Docket No.106546-796518-4139 the corresponding culture media. In some aspects, two polypeptide chains can then be incubated under suitable conditions for formation of the antibody.

[0179] In certain aspects, standard molecular biology techniques can be used to prepare the recombinant expression vector, transfect the host cells, select for transformants, culture the host cells, and recover the antibodies from the culture medium. In some aspects, some antibodies can be isolated by affinity chromatography with a Protein A or Protein G coupled matrix.

[0180] In further aspects, the present disclosure encompasses a host cell engineered to express one or more polypeptides or polynucleotides disclosed herein. In an alternative aspect, the host cell comprises a vector comprising or encoding one or more polynucleotides disclosed herein. Non-limiting examples of a host cell include mammalian cell, a yeast cell, a bacterial cell, a ciliate cell, or an insect cell. In certain aspect, the host cell is a hybridoma cell. In another aspect, the host cell is a mammalian cell.

[0181] In an aspect, the polynucleotide encoding the disclosed polynucleotide sequences may be a vector, for example a plasmid vector, a viral vector, or a transposon. In some aspects the current disclosure also encompasses vectors that facilitate transfer of nucleic acids encoding the activators or inhibitors disclosed herein, such as, but not limited to, plasmids, transposons, cosmids, chromosomes, artificial chromosomes, viruses, virions, and the like. A vector may also be a chemical vector, such as a lipid complex or naked DNA. In some aspects the vector may be a viral vector. A viral vector may comprise an expression construct or the engineered nucleic acid as described herein.

[0182] As used herein, the term “viral vector” can refer to a nucleic acid vector construct that includes at least one element of viral origin and has the capacity to be packaged into a viral vector particle and encodes at least an exogenous polynucleotide. In certain aspects, the vector and / or particle can be utilized for the purpose of transferring any nucleic acids into cells either in vitro or in vivo. Numerous viral vectors are known in the art. The term virion can refer to a single infective viral particle. “Viral vector,” “viral vector particle,” and “viral particle” also refer to a complete virus particle with its DNA or RNA core and protein coat as it exists outside the cell. Non-limiting examples of viral vectors for use herein can include adenoviruses, adeno- associated viruses (AAV), herpesviruses, retroviruses, lentiviruses, integrase defective lentiviruses (IDLV), and the like. In some aspects, a viral vector disclosed herein can be a lentiviral vector. Examples of lentiviruses include, but are not limited to, human lentiviruses such as HIV (in particular HIV-1 or HIV-2), simian immunodeficiency virus (SIV), equine infectious anemia virus (EIAV), feline immunodeficiency virus (FIV), Caprine Arthritis Encephalitis Virus (CAEV), visna and progressive pneumonia viruses of sheep, baboonAttorney Docket No.106546-796518-4139 pseudotype viruses, bovine immunodeficiency virus (BIV), and the like. In some aspects, nucleic acid molecules and / or vectors described herein can be prepared by conventional recombinant technology known to one of skill in the art. In other aspects, polynucleotide sequences molecules and / or vectors described herein can be prepared by a gene editing method known in the art (e.g., by CRISPR).

[0183] In some aspects, cells, polypeptides, polynucleotides, vectors, viral particles, and the like as contemplated herein may be encapsulated into a suitable delivery system for delivery to a subject. Delivery systems may include but are not restricted to liposomes, a lipidoid, a lipoplex, a nanoparticle, a lipid nanoparticle, a polymeric compound, a peptide, a protein, a cell, a nanoparticle mimic, a nanotube, or a conjugate.

[0184] In additional aspects, antibodies herein can be characterized by identifying an epitope or more than one epitope to which the antigen binds, or “epitope mapping.” There are many methods known in the art for mapping and characterizing the location of epitopes on proteins, including, but not limited to, solving the crystal structure of an antibody-antigen complex, competition assays, gene fragment expression assays, and synthetic peptide-based assays. In some aspects, epitope mapping can be used to determine the sequence, to which an antibody binds. CAR-Immune effector cells

[0185] In some aspects, the present disclosure encompasses a chimeric antigen receptor (CAR) immune effector cell (CAR-immune effector cell) comprising an antibody that specifically binds to PCDH7 disclosed herein. In one aspect, CAR-immune effector cell comprising an antibody that specifically binds to PCDH7 comprising a polynucleotide or amino acid sequence listed in Table 1, 2, 3, 4, 5, 6, 7, and / or 8.

[0186] The hinge domain is a structure between the antigen recognition domain (e.g., antibody that binds PCDH7) and the cell plasma membrane; these sequences are generally derived from IgG subclasses (such as IgG1 and IgG4), IgD and CD8 domains, of which IgG1 has been the most extensively used for CAR construction. Currently, studies of the hinge domain mainly focus on the following four aspects: 1) reducing binding affinity to the Fcγ receptor, thereby eliminating off-target activation; 2) enhancing the single-chain variable fragment (scFv) flexibility, thereby relieving the spatial constraints between tumor antigens and CARs, and in turn promoting synapse formation between the CAR-immune effector cells and target cells; 3) reducing the distance between an scFv and the target epitope; and 4) facilitating the detection of CAR expression using anti-Fc reagents.

[0187] In one aspect, the hinge domain includes a hinge domain of a human protein selected from CD28, 4-1BB (CD137), OX-40 (CD134), CD3ζ, T cell receptor α or β chain,Attorney Docket No.106546-796518-4139 CD45, CD4, CD5, CD8, CD8α, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, ICOS, CD154, functional derivatives and / or combinations thereof.

[0188] Typically, the extracellular domain, i.e. an antigen recognition domain (e.g., antibody that binds PCDH7) or target element is linked to the intracellular domain, i.e., the co- stimulatory and signaling domain(s) of the chimeric antigen receptor by a transmembrane domain. A transmembrane domain traverses the cell membrane, anchors the CAR to the immune effector cell surface, and connects the extracellular domain to the intracellular domain, thus impacting expression of the CAR on the immune effector cell surface.

[0189] The transmembrane domain includes a hydrophobic polypeptide that spans the cellular membrane. In particular, the transmembrane domain spans from one side of a cell membrane (extracellular) through to the other side of the cell membrane (intracellular or cytoplasmic).

[0190] The transmembrane domain may be in the form of an alpha helix or a beta barrel, or combinations thereof. The transmembrane domain may include a polytopic protein, which has many transmembrane segments, each alpha-helical, beta sheets, or combinations thereof.

[0191] In one aspect, the transmembrane domain that is naturally associated with one of the domains in the CAR is used. In another aspect, the transmembrane domain is selected or modified by amino acid substitution to avoid binding of such domains to the transmembrane domains of the same or different surface membrane proteins to minimize interactions with other members of the receptor complex.

[0192] For example, the transmembrane domain is selected from a transmembrane domain of a T-cell receptor α or β chain, a CD3ζ chain, CD28, CD3s, CD45, CD4, CD5, CD7, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD68, OX-40 (CD134), 4-1BB (CD137), ICOS, CD41, CD154, functional derivatives and / or combinations thereof.

[0193] A chimeric antigen receptor of the present disclosure may comprise one or more costimulatory domain and / or one or more spacers. A costimulatory domain is derived from costimulatory proteins that enhance cytokine production, proliferation, cytotoxicity, and / or persistence in vivo.

[0194] In one aspect, the co-stimulatory domain is selected from OX-40 (CD134), CD27, CD28, CD30, CD40, PD-1, CD2, CD7, CD258, Natural killer Group 2 member C (NKG2C), Natural killer Group 2 member D (NKG2D), B7-H3, a ligand that binds to at least one of CD83, ICAM-1, LFA-1 (CD1 la / CD18), ICOS, and 4-1BB (CD137), CDS, ICAM-1, LFA-1Attorney Docket No.106546-796518-4139 (CDla / CD18), CD40, CD27, active fragments thereof, functional derivatives thereof, and combinations thereof.

[0195] A chimeric antigen receptor of the present disclosure also comprises a signaling domain that provides an intracellular signal to the immune effector cell upon antigen binding to the antigen recognition domain. The signaling domain of a chimeric antigen receptor of the present disclosure is responsible for activation of at least one of the effector functions of the immune effector cell in which the chimeric receptor is expressed. The term “effector function” refers to a specialized function of a differentiated cell. An effector function of an immune cell, for example, may be cytolytic activity or helper activity including the secretion of cytokines. An effector function in a naive, memory, or memory-type immune cell may also include antigen- dependent proliferation. Thus, the term “intracellular domain” refers to the intracellular portion of a CAR that transduces the effector function signal upon binding of an antigen to the extracellular domain and directs the immune cell to perform a specialized function. Non- limiting examples of suitable signaling domains include the zeta chain of the immune-cell receptor or any of its homologs (e.g., eta, delta, gamma, or epsilon), MB-1 chain, 829, FcRIII, FcRI, and combinations of signaling molecules, such as CD3ζ and CD28, CD27, 4-1BB (CD137), DNAX-activating protein 10 (DAP10), OX-40 (CD134), and combinations thereof, as well as other similar molecules and fragments. Signaling domains of other activating proteins may be used, such as FcγRIII and Fc€RI. While usually the entire signaling domain will be employed, in many cases it will not be necessary to use the entire intracellular polypeptide. To that extent, a truncated portion of the signaling domain may be used as long as it still transduces the effector function signal. The term intracellular domain is also meant to include any truncated portion of the intracellular domain sufficient to transduce the effector function signal. Alternatively, or in addition, CAR-immune effector cells encompassed by the present disclosure may further comprise one or more suicide genes. As used herein, “suicide gene” refers to a nucleic acid sequence introduced to a CAR-immune effector cell by standard methods known in the art that, when activated, results in the death of the CAR-immune effector cell. Suicide genes may facilitate effective tracking and elimination of the CAR-immune effector cells in vivo if required. Facilitated killing by activating the suicide gene may occur by methods known in the art. Suitable suicide gene therapy systems known in the art include, but are not limited to, various the herpes simplex virus thymidine kinase (HSVtk) / ganciclovir (GCV) suicide gene therapy systems or inducible caspase 9 protein. In an exemplary embodiment, a suicide gene is a CD34 / thymidine kinase chimeric suicide gene.

[0196] Methods for CAR design, delivery and expression in immune cells, and the manufacturing of clinical-grade CAR-immune effector cell populations are known in the art. See, for example, Lee et al., Clin. Cancer Res., 2012, 18(10): 2780-90, hereby incorporatedAttorney Docket No.106546-796518-4139 by reference in its entirety. For example, the engineered CARs may be introduced into immune effector cells using retroviruses, which efficiently and stably integrate a nucleic acid sequence encoding the chimeric antigen receptor into the target cell genome. An exemplary method for the viral vector production is described in the Methods to the Examples. Other methods known in the art include, but are not limited to, lentiviral transduction, transposon-based systems, direct RNA transfection, and CRISPR / Cas systems (e.g., type I, type II, or type III systems using a suitable Cas protein such Cas3, Cas4, Cas5, Cas5e (or CasD), Cas6, Cas6e, Cas6f, Cas7, Cas8a1 , Cas8a2, Cas8b, Cas8c, Cas9, Cas10, Casl Od, CasF, CasG, CasH, Csy1 , Csy2, Csy3, Cse1 (or CasA), Cse2 (or CasB), Cse3 (or CasE), Cse4 (or CasC), Csc1 , Csc2, Csa5, Csn2, Csm2, Csm3, Csm4, Csm5, Csm6, Cmr1 , Cmr3, Cmr4, Cmr5, Cmr6, Csb1 , Csb2, Csb3,Csx17, Csx14, Csx10, Csx16, CsaX, Csx3, Csz1 , Csx15, Csf1 , Csf2, Csf3, Csf4, and Cu1966, etc.).

[0197] In some aspects, an immune effector cell is selected from the group consisting of a T cell, a Natural Killer (NK) cell, a cytotoxic T lymphocyte (CTL), and a regulatory T cell.

[0198] In some aspects, the immune effector cells comprise any leukocyte involved in defending the body against infectious disease and foreign materials. For example, the immune effector cells can comprise lymphocytes, monocytes, macrophages, dendritic cells, mast cells, neutrophils, basophils, eosinophils, or any combinations thereof. In some aspects, the immune effector cells comprise T lymphocytes.

[0199] As disclosed herein, T cells can be T cell of any subset, non-limiting examples can include T helper cells (TH cells), Cytotoxic T cells (TC cells, or CTLs), Memory T cells, Regulatory T cells (Treg cells), or Natural killer T (NKT) cells.

[0200] T helper cells (TH cells) assist other white blood cells in immunologic processes, including maturation of B cells into plasma cells and memory B cells, and activation of cytotoxic T cells and macrophages. These cells are also known as CD4+ T cells because they express the CD4 glycoprotein on their surface. Helper T cells become activated when they are presented with peptide antigens by MHC class II molecules, which are expressed on the surface of antigen-presenting cells (APCs). Once activated, they divide rapidly and secrete small proteins called cytokines that regulate or assist in the active immune response. These cells can differentiate into one of several subtypes, including TH1, TH2, TH3, TH17, TH9, or TFH, which secrete different cytokines to facilitate a different type of immune response.

[0201] Cytotoxic T cells (TC cells, or CTLs) destroy virally infected cells and tumor cells, and are also implicated in transplant rejection. These cells are also known as CD8+ T cells since they express the CD8 glycoprotein at their surface. These cells recognize their targets by binding to antigen associated with MHC class I molecules, which are present on the surfaceAttorney Docket No.106546-796518-4139 of all nucleated cells. Through IL-10, adenosine and other molecules secreted by regulatory T cells, the CD8+ cells can be inactivated to an anergic state, which prevents autoimmune diseases.

[0202] Memory T cells are a subset of antigen-specific T cells that persist long-term after an infection has resolved. They quickly expand to large numbers of effector T cells upon re- exposure to their cognate antigen, thus providing the immune system with “memory” against past infections. Memory cells may be either CD4+ or CD8+. Memory T cells typically express the cell surface protein CD45RO.

[0203] Regulatory T cells (Treg cells), formerly known as suppressor T cells, are crucial for the maintenance of immunological tolerance. Their major role is to shut down T cell- mediated immunity toward the end of an immune reaction and to suppress auto-reactive T cells that escaped the process of negative selection in the thymus. Two major classes of CD4+ Treg cells have been described—naturally occurring Treg cells and adaptive Treg cells.

[0204] Natural killer T (NKT) cells, not to be confused with natural killer (NK) cells) bridge the adaptive immune system with the innate immune system. Unlike conventional T cells that recognize peptide antigens presented by major histocompatibility complex (MHC) molecules, NKT cells recognize glycolipid antigen presented by an MHC like I, CD1d. In some aspects, NKT cells are invariant natural killer T (iNKT) cells. iNKT cells recognize CD1d and are restricted by their T-cell Receptor (TCR) which in humans is Vα24Jα18 and typically paired with Vβ11. iNKT cells, further reduce graft-versus-host disease (GVHD).

[0205] In some aspects, the T cells comprise a mixture of CD4+ cells. In other aspects, the T cells are enriched for one or more subsets based on cell surface expression. For example, in some cases, the T comprise are cytotoxic CD8+ T lymphocytes. In some embodiments, the T cells comprise γδ T cells, which possess a distinct T-cell receptor (TCR) having one γ chain and one δ chain instead of α and β chains.

[0206] Natural-killer (NK) cells are CD56+CD3− large granular lymphocytes that can kill virally infected and transformed cells, and constitute a critical cellular subset of the innate immune system. Unlike cytotoxic CD8+ T lymphocytes, NK cells launch cytotoxicity against tumor cells without the requirement for prior sensitization, and can also eradicate MHC-I- negative cells.

[0207] In some aspects, immune effector cells can be obtained from the subject to be treated (i.e. are autologous) and can be administered after genetic modification to express CAR with the disclosed anti-PCDH7 antigen recognition domain (e.g., PCDH7 antibodies disclosed herein), as adoptive transfer. In such aspects, adoptive transfer comprises procuring subject’s immune effector cells, followed by genetically modifying the cells to express theAttorney Docket No.106546-796518-4139 disclosed CARs with anti-PCDH7 antigen recognition domain, and infusing the modified cells back into the subject. In some aspects, immune effector cell lines or donor effector cells (allogeneic) are used. The immune effector cells for allogeneic therapy may be collected from a single subject or multiple subjects. Immune effector cells can be obtained from a number of sources, including peripheral blood mononuclear cells, bone marrow, lymph node tissue, cord blood, thymus tissue, tissue from a site of infection, ascites, pleural effusion, spleen tissue, and tumors. Immune effector cells can be obtained from blood collected from a subject using any number of techniques known to the skilled artisan, such as Ficoll™ separation. For example, cells from the circulating blood of an individual may be obtained by apheresis. In some aspects, immune effector cells can be isolated from peripheral blood lymphocytes by lysing the red blood cells and depleting the monocytes, for example, by centrifugation through a PERCOLL™ gradient or by counterflow centrifugal elutriation. A specific subpopulation of immune effector cells can be further isolated by positive or negative selection techniques. For example, immune effector cells can be isolated using a combination of antibodies directed to surface markers unique to the positively selected cells, e.g., by incubation with antibody- conjugated beads for a time period sufficient for positive selection of the desired immune effector cells. Alternatively, enrichment of immune effector cells population can be accomplished by negative selection using a combination of antibodies directed to surface markers unique to the negatively selected cells.

[0208] In some aspects, the expression of nucleic acids encoding CARs can be achieved by operably linking a nucleic acid encoding the CAR polypeptide comprising the disclosed anti-PCDH7 antigen recognition domain, to a promoter, and incorporating the construct into an expression vector. Typical cloning vectors contain transcription and translation terminators, initiation sequences, and promoters useful for regulation of the expression of the desired nucleic acid sequence. In some aspects, immune effector cells are further comprises a modification of the endogenous T-cell Receptor Alpha Chain (TRAC) such that endogenous T cell receptor mediated signaling is blocked in the CAR-T cell.

[0209] In some aspects, the CAR comprising the disclosed anti-PCDH7 antigen recognition domain, can be cloned into a number of types of vectors. For example, the CAR comprising the disclosed anti-PCDH7 antigen recognition domain can be cloned into a vector including, but not limited to a plasmid, a phagemid, a phage derivative, an animal virus, and a cosmid. In some aspects, non-limiting examples of vectors include expression vectors, replication vectors, probe generation vectors, and sequencing vectors.

[0210] A number of viral based systems have been developed for gene transfer into mammalian cells. For example, the CAR comprising the disclosed anti-PCDH7 antigen recognition domain can be inserted into a vector and packaged in retroviral particles usingAttorney Docket No.106546-796518-4139 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. Bispecific, multi-specific antibody, or hybrid antibody

[0211] In some aspects, the present disclosure further encompasses a bispecific antibody, a multi-specific antibody, or a hybrid antibody having at least two distinct binding domains with different specificities, with at least one domain comprising a VH CDR1, VH CDR2, VH CDR3, VLCDR1, VLCDR2, VLCDR3, VHand / or VLdisclosed in Tables 1, 2, 3, 4, 5, 6, 7, and / or 8. In some aspects, a bispecific antibody, a multi-specific antibody, or a hybrid antibody comprises a PCDH7 VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, VL CDR3, VH and / or VL disclosed herein, and at least one of an immune cell engager (e.g., a T cell engager, an NK cell engager, an iNKT cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager). Such antibody constructs are recombinant protein constructs made from two flexibly linked antibody derived binding domains, with one binding domain specific for a selected tumor antigen on target tumor cells and the second binding domain that binds to and / or activates T cells, NK cells, iNKT cells, B cells, dendritic cells, or macrophage cells. In some aspects, the disclosed antibodies can transiently direct immune cells to the target tumor cells and / or activate the inherent cytolytic potential of immune cells against target tumor cells. In some aspects, a bispecific antibody, a multi-specific antibody, or a hybrid antibody comprises with at least one domain comprising a PCDH7 VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, VLCDR3, VHand / or VLdisclosed herein, and a second domain comprising a binding domain specific for an antigen expressed by B cell and / or plasma cell tumor cells. A bispecific antibody, a multi-specific antibody, or a hybrid antibody construct can be produced by a variety of methods, including fusion of hybridomas, linking of Fab' fragments, or any other known method in the art.

[0212] In some aspects, the bispecific antibody, the multi-specific antibody, or the hybrid antibody comprises a T-cell engager (e.g., bispecific T cell engager (BiTE)) comprising first antigen recognition domain comprising PCDH7 VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, VLCDR3, VHand / or VLdisclosed herein, and a second antigen recognition domain comprising an antibody or antigen-binding antibody fragment that bind to or activate T cells. In such aspects, a second antigen recognition domain comprising antibody or antigen-binding antibody fragment binds to one or more of CD2, CD3, CD4, CD5, CD6, CD8, CD25, CD27, CD28, CD30, CD40, CD40L, CD44, CD45, CD69, CD90, CRa, TCRp, TCRy, TCRC, ICOS, HVEM, LIGHT, 4-lBB, OX40, DR3, GITR, TIMl, SLAM, or CD226

[0213] In some aspects, the bispecific antibody, the multi-specific antibody, or the hybrid antibody has a binding domain that engages NK cells. In such aspects, the bispecific antibodyAttorney Docket No.106546-796518-4139 comprises a first antigen recognition domain comprising PCDH7 VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, VLCDR3, VHand / or VLdisclosed herein, and a second antigen recognition domain comprising an antibody or antigen-binding antibody fragments that bind to or activate NK cells. In such aspects, a second antigen recognition domain comprising an antibody or antigen-binding antibody fragment binds to one or more of CD16 (e.g., CD16a, CD16b, or both), NKp30, NKp40, NKp44, NKp46, NKG2D, DNAMl, DAP10, CRTAM, CD27, PSGL1, CD96, CD100 (SEMA4D), NKp80, CD244 (also known as SLAMF4 or 2B4), SLAMF6, SLAMF7, KIR2DS2, KIR2DS4, KIR3DS 1, KIR2DS3, KIR2DS5, KIR2DS 1, CD94, NKG2C, NKG2E, or CD160.

[0214] In some aspects, the bispecific antibody, the multi-specific antibody, or the hybrid antibody has a binding domain that engages iNKT cells. In such aspects, the bispecific antibody comprises a first antigen recognition domain comprising PCDH7 VH CDR1, VH CDR2, VHCDR3, VLCDR1, VLCDR2, VLCDR3, VHand / or VLdisclosed herein, and a second antigen recognition domain comprising an antibody or antigen-binding antibody fragments that bind to or activate iNKT cells. In such aspects, a second antigen recognition domain comprising an antibody or antigen-binding antibody fragment binds to CD3.

[0215] In some aspects, the bispecific antibody, the multi-specific antibody, or the hybrid antibody has a binding domain that engages B cells. In such aspects, the bispecific antibody comprises a first antigen recognition domain comprising PCDH7 VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, VLCDR3, VHand / or VLdisclosed herein, and a second antigen recognition domain comprising an antibody or antigen-binding antibody fragments that bind to or activate B cells. In such aspects, a second antigen recognition domain comprising an antibody or antigen-binding antibody fragment binds to one or more of OX40, CD40 or CD70.

[0216] In some aspects, the bispecific antibody, the multi-specific antibody, or the hybrid antibody has a binding domain that engages dendritic cells. In such aspects, the bispecific antibody comprises a first antigen recognition domain comprising PCDH7 VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, VLCDR3, VHand / or VLdisclosed herein, and a second antigen recognition domain comprising an antibody or antigen-binding antibody fragments that bind to or activate dendritic cells. In such aspects, a second antigen recognition domain comprising an antibody or antigen-binding antibody fragment binds to one or more of CD2, OX40, 4-IBB, TLR4, CD47, or STING.

[0217] In some aspects, the bispecific antibody, the multi-specific antibody, or the hybrid antibody has a binding domain that engages macrophage cell. In such aspects, the bispecific antibody comprises a first antigen recognition domain comprising PCDH7 VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, VLCDR3, VHand / or VLdisclosed herein, and a second antigenAttorney Docket No.106546-796518-4139 recognition domain comprising an antibody or antigen-binding antibody fragments that bind to or activate macrophage cells. In such aspects, a second antigen recognition domain comprising an antibody or antigen-binding antibody fragment binds to one or more of OX40, CD40, CD70, TLR4, TLR9, CD47 or STING agonist.

[0218] In some aspects, a bispecific antibody, a multi-specific antibody, or a hybrid antibody comprises a first antigen recognition domain comprising PCDH7 VH CDR1, VH CDR2, VHCDR3, VLCDR1, VLCDR2, VLCDR3, VHand / or VLdisclosed herein, and a second antigen recognition domain comprising an antibody or antigen-binding antibody fragments that bind to an antigen expressed by tumor cells. In some aspects, the antigen is an antigen expressed by lung cancer cells (for e.g., NSCLC). In such aspects, a second antigen recognition domain comprising an antibody or antigen-binding antibody fragment binds to one or more of EA, MAGE-A1, MAGE-A3, MAGE-A4, PRAME, hTERT, HER2, MUC1, Survivin, STEAP1, SOX2, EGFR, PD-L1, CD155 and NY-ESO-1.

[0219] In one aspect, the disclosure encompasses a multispecific antibody comprising: a first target binding site that specifically binds to an extracellular domain of protocadherin 7(PCDH7). The first target binding site may comprise any one or more of the amino acid sequences listed in Tables 3, 4, 7, or 8. The first binding site may comprise a variable heavy chain region (VH) complementary determining region 1 (CDR1) with the amino acid sequence selected from SEQ ID NO: 227, 236, 278, and 242, a VH CDR2 with the amino acid sequence selected from SEQ ID NO: 228, 237, 279, and 243, a VH CDR3 with the amino acid sequence selected from SEQ ID NO: 229, 238, 280, and 244, or any combination thereof, a variable light chain region (VL) CDR1 with the amino acid sequence selected from SEQ ID NO: 162, 168, 196, and 172, a VL CDR2 with the amino acid sequence selected from NVS, RAS, EVT, and QAS, and / or a VL CDR3 with the amino acid sequence selected SEQ ID NO: 163, 169, 197, or 173, or any combination thereof. In a specific aspect, the multispecific antibody comprises a VH CDR1 with amino acid sequence of SEQ ID NO: 227, a VH CDR2 with amino acid sequence of SEQ ID NO: 228, a VH CDR3 with amino acid sequence of SEQ ID NO: 229, a VL CDR1 with amino acid sequence of SEQ ID NO: 162, a VL CDR2 with amino acid sequence NVS7, and / or a VL CDR3 with amino acid sequence of SEQ ID NO: 163.

[0220] In certain aspects, the first binding site multispecific antibody comprises a VH with an amino acid sequence of SEQ ID NO: 406, and / or a VL with an amino acid sequence of SEQ ID NO: 438.

[0221] The second target binding site of the multispecific antibody specifically bind to a T cell engager. T cell engager, in one aspect is an antibody that binds to CD3. In specific aspects, the second binding site a CD3 scFv.Attorney Docket No.106546-796518-4139

[0222] In one aspect, the disclosure encompasses a bispecific antibody comprising a first binding site that specifically binds to an extracellular domain of protocadherin 7(PCDH7). The first binding site may comprise any one or more of the amino acid sequences listed in Tables 3, 4, 7, or 8. The first binding site may comprise a variable heavy chain region (VH) complementary determining region 1 (CDR1) with the amino acid sequence selected from SEQ ID NO: 227, 236, 270, and 242, a VH CDR2 with the amino acid sequence selected from SEQ ID NO: 228, 237, 279, and 243, a VH CDR3 with the amino acid sequence selected from SEQ ID NO: 229, 238, 280, and 244, or any combination thereof, a variable light chain region (VL) CDR1 with the amino acid sequence selected from SEQ ID NO: 162, 168, 196, and 172, a VL CDR2 with the amino acid sequence selected from NVS, RAS, EVT, and QAS, and / or a VL CDR3 with the amino acid sequence selected SEQ ID NO: 163, 169, 197, or 173, or any combination thereof. In a specific aspect, the bispecific antibody comprises a VH CDR1 with amino acid sequence of SEQ ID NO: 227, a VH CDR2 with amino acid sequence of SEQ ID NO: 228, a VH CDR3 with amino acid sequence of SEQ ID NO: 229, a VL CDR1 with amino acid sequence of SEQ ID NO: 162, a VL CDR2 with amino acid sequence NVS, and / or a VL CDR3 with amino acid sequence of SEQ ID NO: 163.

[0223] In certain aspects, the first binding site bispecific antibody comprises a VH with an amino acid sequence of SEQ ID NO: 406, and / or a VL with an amino acid sequence of SEQ ID NO: 438.

[0224] The second binding site of the bispecific antibody specifically bind to a T cell engager. T cell engager, in one aspect is an antibody that binds to CD3. In specific aspects, the second binding site a CD3 scFv. III. Compositions

[0225] In some aspects, provided herein are compositions comprising one or more of the antibodies disclosed herein, or fragments thereof. In one aspect, composition disclosed herein may comprise one or more of the PCDH7 antibodies disclosed herein, or fragments thereof and at least one pharmaceutically acceptable carrier and / or excipient. In another aspect, the composition may comprise a multispecific or a bispecific PCDH7 antibody. In an alternate aspect, the composition comprises a bispecific antibody comprising a first binding site that specifically binds to an extracellular domain of protocadherin 7(PCDH7) and a second binding site which binds to a T cell engager, for e.g., CD3. Composition of the present disclosure may further comprise a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers or excipients suitable for the compositions described herein are well known to one of skill in the art of use for preserving and delivering antibodies or antibody fragments to any mammalian subject including humans and other mammals.Attorney Docket No.106546-796518-4139

[0226] In some aspects, compositions described herein may be administered to a subject in need thereof. In some aspects, the subject is a human. In some aspects, the subject is a human subject having, suspected of having, or at risk for a cancer. In some aspects, the cancer is a cancer comprising cells with increased endogenous PCDH7 expression. In some aspects, the cancer is a lung cancer. In some aspects, the cancer is a non-small cell lung cancer. In some aspects, cancer is an adenocarcinoma, squamous cell carcinoma, or large cell carcinoma.

[0227] In some aspects, the composition described herein results in stable serum antibody or fragment thereof level for at least 10-60 days after administration of the antibody or fragment thereof in the subject. In some aspects, the serum antibody or fragment thereof level is stable for at least 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 49 days, 50 days, 51 days, 52 days 53 days, 54 days, 55 days, or 60 days. In some aspects, the serum antibody or fragment thereof level is stable for at least 10 days after administration of the antibody or fragment thereof in the subject. In some aspects, the serum antibody or fragment thereof level is stable for at least 20 days after administration of the antibody or fragment thereof in the subject. In some aspects, the serum antibody or fragment thereof level is stable for at least 30 days after administration of the antibody in the subject.

[0228] The compositions comprising PCDH7 antibodies disclosed herein, or fragments thereof, or multispecific or bispecific PCDH7 antibodies, or fragments thereof may be formulated for administration, in any convenient manner, including by compositions for injection, transfusion, or implantation. The compositions described herein may be formulated for subcutaneous, intradermal, intratumoral, intranodal, intramedullar, intramuscular, intravenous (i.v.), or intraperitoneal, injection or administration. In some aspects, the disclosed compositions are formulated to be administered by intradermal or subcutaneous injection. In some aspects, the disclosed compositions are formulated to be administered by i.v. injection. The compositions may also be formulated, to be injected directly into a tumor, lymph node, or site of infection. In some aspects, the compositions disclosed herein are formulated for intravenous administration. In some aspects, the compositions disclosed herein are formulated for intraperitoneal injection.

[0229] In certain aspects, the pharmaceutical compositions can further include a non- specific innate immune response stimulator mixture or composition or other immunomodulatory agent for enhancing an immune response. In accordance with theseAttorney Docket No.106546-796518-4139 embodiments, the non-specific innate immune response stimulator can elicit both a cell- mediated immune response and a humoral immune response.

[0230] In certain aspects, the pharmaceutical compositions to be used in the present methods can include pharmaceutically acceptable carriers, excipients, and / or stabilizers in the form of lyophilized formulations or aqueous solutions. In some embodiments, acceptable carriers, excipients, and / or stabilizers are nontoxic to recipients at the dosages and concentrations used, and can 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 propyl paraben; 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 polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrans; 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).

[0231] In some aspects, the pharmaceutical composition described herein can have liposomes containing the antibodies, fragments thereof, or the polynucleotides encoding the antibodies. In some aspects, liposomes for use herein can be generated by the reverse phase evaporation method with a lipid composition having phosphatidylcholine, cholesterol and PEG-derivatized phosphatidylethanolamine (PEG-PE). In some aspects, liposomes for use herein can be extruded through filters of defined pore size to yield liposomes with the desired diameter.

[0232] In some aspects, antibodies, fragments thereof, or the encoding polynucleotide(s) herein, can 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.

[0233] In some aspects, the pharmaceutical compositions described herein can be formulated in sustained-release format. In some aspects, pharmaceutical compositions herein to be used for in vivo administration may be sterile. In some embodiments, this can be readily accomplished by, for example, filtration through sterile filtration membranes. In some aspects,Attorney Docket No.106546-796518-4139 therapeutic antibody compositions herein can be placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle.

[0234] In certain aspects, pharmaceutical compositions described herein can be in unit dosage forms such as tablets, pills, capsules, powders, granules, solutions or suspensions, or suppositories, for oral, parenteral or rectal administration, or administration by inhalation or insufflation.

[0235] In some aspects, emulsion compositions herein can be those prepared by mixing an antibody with IntralipidTM or the components thereof (soybean oil, egg phospholipids, glycerol and water).

[0236] Suitable emulsions may be prepared using commercially available fat emulsions, such as IntralipidTM, LiposynTM, InfonutrolTM, LipofundinTM and LipiphysanTM. The active ingredient may be either dissolved in a pre-mixed emulsion composition or alternatively it may be dissolved in an oil (e.g., soybean oil, safflower oil, cottonseed oil, sesame oil, corn oil or almond oil) and an emulsion formed upon mixing with a phospholipid (e.g. egg phospholipids, soybean phospholipids or soybean lecithin) and water. It will be appreciated that other ingredients may be added, for example glycerol or glucose, to adjust the tonicity of the emulsion. Suitable emulsions will typically contain up to about 20% oil, for example, between about 5% and about 20%. The fat emulsion can comprise fat droplets between about 0.1 µm and about 1.0 µm, particularly about 0.1 µm and 0.5 µm, and have a pH in the range of about 5.5 to about 8.0.

[0237] In some aspects, pharmaceutical compositions herein for inhalation or intranasal administration may include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. In some aspects, liquid or solid compositions herein can contain suitable pharmaceutically acceptable excipients as set out above. In other aspects, the compositions can be administered by the oral or nasal respiratory route for local or systemic effect.

[0238] In some aspects, compositions can be in sterile pharmaceutically acceptable solvents can be nebulized by use of gases. In some aspects, nebulized solutions herein can be breathed directly from the nebulizing device or the nebulizing device can be attached to a face mask, tent or intermittent positive pressure breathing machine. In some embodiments, solution, suspension or powder compositions herein can be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.

[0239] In certain aspects, pharmaceutical compositions disclosed herein may comprise a buffer system. As used herein, a “buffer system” is a composition comprised of one or moreAttorney Docket No.106546-796518-4139 buffering agents wherein “buffering agents” are compounds used to resist change in pH upon dilution or addition of acid or alkali. Buffering agents include, by way of example and without limitation, potassium metaphosphate, potassium phosphate, monobasic sodium acetate and sodium citrate anhydrous and dihydrate and other materials known to one of ordinary skill in the art. In some aspects, any pharmaceutically acceptable organic or inorganic buffer can be used. In some aspects, pharmaceutical compositions disclosed herein may comprise at least 5%, at least 10%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50% total amount of one or more buffering agents by total weight of the composition. In some aspects, pharmaceutical compositions disclosed herein may comprise about 5% to about 99%, about 10%, about 95%, or about 15% to about 90% total amount of one or more buffering agents by total weight of the composition.

[0240] In some aspects, the amount of one or more buffering agents may depend on the desired pH level of a composition. In some aspects, pharmaceutical compositions disclosed herein may have a pH of about 6 to about 9. In some aspects, pharmaceutical compositions disclosed herein may have a pH greater than about 8, greater than about 7.5, greater than about 7, greater than about 6.5, or greater than about 6.

[0241] In certain aspects, pharmaceutical compositions disclosed herein may comprise one or more preservatives. As used herein, “preservatives” refers to agents or combination of agents that inhibits, reduces or eliminates bacterial growth in a pharmaceutical dosage form. Non-limiting examples of preservatives include Nipagin, Nipasol, isopropyl alcohol and a combination thereof. In some aspects, any pharmaceutically acceptable preservative can be used. In some aspects, pharmaceutical compositions disclosed herein may comprise at least 5%, at least 10%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50% total amount of one or more preservatives by total weight of the composition. In some aspects, pharmaceutical compositions disclosed herein may comprise about 5% to about 99%, about 10%, about 95%, or about 15% to about 90% total amount of one or more preservatives by total weight of the composition.

[0242] In certain aspects, pharmaceutical compositions disclosed herein may comprise one or more surface-acting reagents or detergents. In some aspects, surface-acting reagents or detergents may be synthetic, natural, or semi-synthetic. In some aspects, compositions disclosed herein may comprise anionic detergents, cationic detergents, zwitterionic detergents, ampholytic detergents, amphoteric detergents, nonionic detergents having a steroid skeleton, or a combination thereof. In some aspects, pharmaceutical compositions disclosed herein may comprise at least 5%, at least 10%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50% total amount of one or more surface-acting reagents or detergents by total weight of the composition. In some aspects,Attorney Docket No.106546-796518-4139 pharmaceutical compositions disclosed herein may comprise about 5% to about 99%, about 10%, about 95%, or about 15% to about 90% total amount of one or more surface-acting reagents or detergents by total weight of the composition.

[0243] In certain aspects, pharmaceutical compositions disclosed herein may comprise one or more stabilizers. As used herein, a “stabilizer” refers to a compound used to stabilize an active agent against physical, chemical, or biochemical process that would otherwise reduce the therapeutic activity of the agent. Suitable stabilizers include, by way of example and without limitation, succinic anhydride, albumin, sialic acid, creatinine, glycine and other amino acids, niacinamide, sodium acetyltryptophonate, zinc oxide, sucrose, glucose, lactose, sorbitol, mannitol, glycerol, polyethylene glycols, sodium caprylate and sodium saccharin and others known to those of ordinary skill in the art. In some aspects, pharmaceutical compositions disclosed herein may comprise at least 5%, at least 10%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50% total amount of one or more stabilizers by total weight of the composition. In some aspects, pharmaceutical compositions disclosed herein may comprise about 5% to about 99%, about 10%, about 95%, or about 15% to about 90% total amount of one or more stabilizers by total weight of the composition.

[0244] In some aspects, pharmaceutical compositions disclosed herein may comprise one or more tonicity agents. As used herein, a “tonicity agents” refers to a compound that can be used to adjust the tonicity of the liquid formulation. Suitable tonicity agents include, but are not limited to, glycerin, lactose, mannitol, dextrose, sodium chloride, sodium sulfate, sorbitol, trehalose and others known to those or ordinary skill in the art. Osmolarity in a composition may be expressed in milliosmoles per liter (mOsm / L). Osmolarity may be measured using methods commonly known in the art. In some aspects, a vapor pressure depression method is used to calculate the osmolarity of the compositions disclosed herein. In some aspects, the amount of one or more tonicity agents comprising a pharmaceutical composition disclosed herein may result in a composition osmolarity of about 150 mOsm / L to about 500 mOsm / L, about 250 mOsm / L to about 500 mOsm / L, about 250 mOsm / L to about 350 mOsm / L, about 280 mOsm / L to about 370 mOsm / L or about 250 mOsm / L to about 320 mOsm / L. In some aspects, a composition herein may have an osmolality ranging from about 100 mOsm / kg to about 1000 mOsm / kg, from about 200 mOsm / kg to about 800 mOsm / kg, from about 250 mOsm / kg to about 500 mOsm / kg, or from about 250 mOsm / kg to about 320 mOsm / kg, or from about 250 mOsm / kg to about 350 mOsm / kg or from about 280 mOsm / kg to about 320 mOsm / kg. In some aspects, a pharmaceutical composition described herein may have an osmolarity of about 100 mOsm / L to about 1000 mOsm / L, about 200 mOsm / L to about 800 mOsm / L, about 250 mOsm / L to about 500 mOsm / L, about 250 mOsm / L to about 350 mOsm / L,Attorney Docket No.106546-796518-4139 about 250 mOsm / L to about 320 mOsm / L, or about 280 mOsm / L to about 320 mOsm / L. In some aspects, pharmaceutical compositions disclosed herein may comprise at least 5%, at least 10%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50% total amount of one or more tonicity modifiers by total weight of the composition. In some aspects, pharmaceutical compositions disclosed herein may comprise about 5% to about 99%, about 10%, about 95%, or about 15% to about 90% total amount of one or more tonicity modifiers by total weight of the composition.

[0245] In some aspects, concentrations of antibodies disclosed herein can be a pre- determined concentration or a standard concentration. In some aspects, the antibodies disclosed herein can be in a concentration of about 1 micrograms / milliliters (mg / ml) to about 500 mg / ml, about 1 mg / ml to about 250 mg / ml, about 1 mg / ml to about 200 mg / ml, about 1 mg / ml to about 150 mg / ml, about 1 mg / ml to about 100 mg / ml, about 1 mg / ml to about 75 mg / ml, about 1 mg / ml to about 50 mg / ml, about 0.1 mg / ml to about 100 mg / ml, or other suitable concentration. In some embodiments, the antibody is formulated to a concentration of about 30 mg / ml. In some embodiments, the antibody is lyophilized. In some aspects, the antibody is diluted in a suitable solution to a suitable concentration prior to administration (e.g., in a therapeutic application described below).

[0246] In some aspects, pharmaceutical compositions described herein can further comprise active agents in addition to the antibodies, fragments thereof or polynucleotides provided herein. Non limiting examples of additional active agents include but are not restricted to antibiotics, anti-pyrectics, antimicrobials, antifungals, NSAIDs, chemotherapeutic and anticancer agents.

[0247] Chemotherapeutic and anticancer agents commonly used to treat cancer, and which may be used in combination with any of the compositions disclosed herein include but are not limited to platinum compounds (such as cisplatin or carboplatin), and taxane compounds such as paclitaxel (Taxol®) or docetaxel (Taxotere®). Other chemotherapeutic agents used to treat cancer and which may be used in combination with any of the compositions disclosed herein, include but are not limited to: Albumin bound paclitaxel (nab-paclitaxel, Abraxane®), Pemetrexed (Alimta®), Irinotecan (CPT-11, Camptosar®), Cyclophosphamide (Cytoxan®), Liposomal doxorubicin (Doxil®), Gemcitabine (Gemzar®), Altretamine (Hexalen®), Ifosfamide (Ifex®), Melphalan (Alkeran), Vinorelbine (Navelbine®), Topotecan (Hycamtin), Etoposide (VP-16), and Capecitabine (Xeloda®).

[0248] In some aspects, the administration of the composition comprising disclosed antibody, fragment thereof, or polynucleotides encoding the antibodies, can decreases and / or inhibits activity, function, expression and / or accumulation of PCDH7.Attorney Docket No.106546-796518-4139

[0249] In some aspects, the administration of the composition comprising disclosed antibody, fragment thereof, or polynucleotides encoding the antibodies, results in reduction of expression of phosphorylated ERK (p-ERK) in the subject. In some aspects, the administration of the composition comprising antibody, fragment thereof, or polynucleotides encoding the antibodies described herein results in reduction of expression of p-ERK by at least about 10%, e.g., 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or above, as compared to expression of p-ERK before administration of the antibody, fragment thereof, or polynucleotides encoding the antibodies (baseline) or a control subject not receiving the treatment. In some aspects, the administration of the composition comprising antibody, fragment thereof, or polynucleotides encoding the antibodies described herein results in reduction of expression of p-ERK by at least 25%. Non-limiting example of a method that can be used to measure p-ERK include Western quantification.

[0250] In some aspects of, the level of serum antibody or fragment thereof is stable for at least 10-60 days after administration of the composition comprising antibody or fragment thereof in the subject. In some aspects, the serum antibody or fragment thereof level is stable for at least 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 49 days, 50 days, 51 days, 52 days 53 days, 54 days, 55 days, or 60 days. In some aspects, the serum antibody or fragment thereof level is stable for at least 10 days after administration of the composition comprising antibody or fragment thereof in the subject. In some aspects, the serum antibody or fragment thereof level is stable for at least 20 days after administration of the composition comprising antibody or fragment thereof in the subject. In some aspects, the serum antibody or fragment thereof level is stable for at least 30 days after administration of the antibody in the subject. The levels of serum antibody or fragment thereof can be measured using any known methods in the art, non-limiting examples of which include ELISA, immunofluorescence assays, antigen microarray and immunoassays.

[0251] In some aspects, the administration of the composition comprising antibody, fragment thereof, or polynucleotides encoding the antibodies described herein results in reduction of tumor volume by at least about 10%, e.g., 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or above, as compared to tumor volume before administration of the antibody, fragment thereof, or polynucleotides encoding the antibodies (baseline) or a control subject not receiving the treatment. In some aspects, the administration of the composition comprising antibody or fragment thereof or polynucleotides encoding the antibodies results in reduction of tumor growth by about 10% to about 50%. Tumor volume in a subject can be assessedAttorney Docket No.106546-796518-4139 using any conventional methods known in the art, non-limiting examples of which include, diagnostic techniques such as X ray, CT scan, bone marrow biopsy, serum protein electrophoresis (SPEP), or MRI.

[0252] In some aspects, the administration of the composition comprising antibody, fragment thereof, or polynucleotides encoding the antibodies described herein results in reduction of expression of one or more genes listed in Tables 10 and 11. In some aspects, reduction in expression of one or more genes listed in Tables 10 and 11 is by at least about 10%, e.g., 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or above, as compared to expression of the genes before administration of the antibody, fragment thereof, or polynucleotides encoding the antibodies (baseline) or a control subject not receiving the treatment. Any known method in the art can be used for measuring the expression levels of genes. By way of non-limiting examples, expression levels of genes can be measured using RNA-seq, nanopore sequencing, Nanostring, multiplex RT-PCR, single-plex RT-PCR, NASBA, Fluorescence measurements or spectrophotometry.

[0253] In some aspects, the administration the composition described herein, results in limited treatment associated toxicity in the subject. In some aspects, the administration of the composition comprising disclosed antibody, fragment thereof, or polynucleotides encoding the antibody limits treatment associated toxicity in the subject, by at least 10%, e.g., 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or above, as compared to treatment associated toxicity in a subject receiving a different cancer treatment. In some aspects, treatment associated toxicity is measured in terms of body weight loss. In such aspects, the administration of the composition comprising disclosed antibody, fragment thereof, or polynucleotides encoding the antibody limits body weight loss in the subject, by at least 10%, e.g., 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or above, as compared to body weight loss in a subject receiving a different cancer treatment.

[0254] In some aspects, the administration of the composition comprising antibody or fragment thereof, or polynucleotides encoding the antibody results in increased Fc-mediated immune effector killing of cancer cells in the subject. In some aspects, the administration of the composition comprising disclosed antibody, fragment thereof, or polynucleotides encoding the antibody increase Fc-mediated immune effector killing and / or lysis of cancer cells in the subject, by at least 10%, e.g., 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or above, as compared to killing and / or lysis of cancer cells in the subject before administration of the composition comprising antibody, fragment thereof, or polynucleotides encoding the antibodies (baseline) or a control subject not receiving the treatment. In some aspects, the administration of the composition comprising disclosed antibody, fragment thereof, or polynucleotides encoding the antibody increase Fc-mediated immune effector killing and / orAttorney Docket No.106546-796518-4139 lysis of at least about 20% of the cancer cells in the subject. Cancer cell death and / or lysis may be determined using any known methods in the art for measuring cell apoptosis or cell viability, including bioluminescent imaging or flow cytometry.

[0255] In some aspects, the administration of the composition comprising antibody or fragment thereof, or polynucleotides encoding the antibody results in increased antibody dependent cellular cytotoxicity (ADCC) in the subject. In some aspects, the administration of the composition comprising disclosed antibody, fragment thereof, or polynucleotides encoding the antibody increase ADCC killing and / or lysis of cancer cells in the subject, by at least 10%, e.g., 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or above, as compared to killing and / or lysis of cancer cells in the subject before administration of the composition comprising antibody, fragment thereof, or polynucleotides encoding the antibodies (baseline) or a control subject not receiving the treatment. In some aspects, the administration of the composition comprising disclosed antibody, fragment thereof, or polynucleotides encoding the antibody increase ADCC killing and / or lysis of at least about 20% of the cancer cells in the subject. Cancer cell death and / or lysis may be determined using any known methods in the art for measuring cell apoptosis or cell viability, including bioluminescent imaging or flow cytometry.

[0256] In some aspects, the administration of the composition comprising antibody or fragment thereof, or polynucleotides encoding the antibody results in increased granzyme B production in the subject. In some aspects, the administration of the composition comprising disclosed antibody, fragment thereof, or polynucleotides encoding the antibody increase granzyme B production in the subject, by at least 10%, e.g., 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or above, as compared to granzyme B production in the subject before administration of the antibody, fragment thereof, or polynucleotides encoding the antibodies (baseline) or a control subject not receiving the treatment. In some aspects, the disclosed administration results in about 50% granzyme B production in the subject. Any known method in the art can be used to measure granzyme B production in a subject, non-limiting examples of which include ELISA.

[0257] In some aspects, compositions described herein can further comprise a MEK inhibitor. In some aspects, MEK inhibitor is Trametinib, Binimetinib, Selumetinib, Cobimetinib, PD-325901, CI-1040, TAK-733, or any combination thereof. In some aspects, the composition comprising the antibodies, fragments thereof, or polynucleotides encoding the antibodies described herein can sensitize the cancer cells to a MEK inhibitor. In some aspects, the combination antibodies, fragments thereof, or polynucleotides encoding the antibodies with an MEK inhibitor can result in synergistic tumor inhibition. In some aspects, the combination antibodies, fragments thereof, or polynucleotides encoding the antibodies with an MEK inhibitor reduces the tumor volume in a subject by at least 10%, e.g., 20%, 30%, 40%, 50%,Attorney Docket No.106546-796518-4139 60%, 70%, 80%, 90%, 95% or above, as compared to tumor volume before administration of the combination antibodies, fragments thereof, or polynucleotides encoding the antibodies with an MEK inhibitor (baseline), a control subject not receiving the treatment, or a subject receiving antibodies, fragments thereof, or polynucleotides encoding the antibodies, or receiving an MEK inhibitor alone.

[0258] In some aspects, compositions described herein can further comprise an EGFR inhibitor. In some aspects, the EGFR inhibitor is Afatinib, Almonertinib, Brigatinib, Dacomitinib, Erlotinib, Gefitinib, Icotinib, Laptinib, Neratinib, Olmutinib, Osimertinib, Pyrotinib, Simotinib, Vandetanib, or any combination thereof. In some aspects, the composition comprising the antibodies, fragments thereof or polynucleotides encoding the antibodies described herein can sensitize the cancer cells to a EGFR inhibitor. In some aspects, the combination antibodies, fragments thereof, or polynucleotides encoding the antibodies with an EGFR inhibitor can result in synergistic tumor inhibition. In some aspects, the combination antibodies, fragments thereof, or polynucleotides encoding the antibodies with an EGFR inhibitor reduces the tumor volume in a subject by at least 10%, e.g., 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or above, as compared to tumor volume before administration of the combination antibodies, fragments thereof, or polynucleotides encoding the antibodies with a EGFR inhibitor (baseline), a control subject not receiving the treatment, or a subject receiving antibodies, fragments thereof, or polynucleotides encoding the antibodies alone, or receiving a EGFR inhibitor alone.

[0259] In further aspects, the disclosed compositions can further comprise an KRAS inhibitor. In some aspects, the KRAS inhibitor is Adagrasib, Sotorasib, AMG 510, or any combination thereof. In some aspects, the composition comprising the antibodies, fragments thereof or polynucleotides encoding the antibodies described herein can sensitize the cancer cells to a KRAS inhibitor. In some aspects, the combination antibodies, fragments thereof, or polynucleotides encoding the antibodies with a KRAS inhibitor can result in synergistic tumor inhibition. In certain aspects, the combination antibodies, fragments thereof, or polynucleotides encoding the antibodies with a KRAS inhibitor reduces the tumor volume in a subject by at least 10%, e.g., 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or above, as compared to tumor volume before administration of the combination antibodies, fragments thereof, or polynucleotides encoding the antibodies with a KRAS inhibitor (baseline), a control subject not receiving the treatment, or a subject receiving antibodies, fragments thereof, or polynucleotides encoding the antibodies alone, or receiving a KRAS inhibitor alone.

[0260] The actual dosage amount of a composition according to the present disclosure, and the selection of any combination treatment to be administered to a subject can be determined by physical and physiological factors such as body weight, severity of condition,Attorney Docket No.106546-796518-4139 the type of disease being treated, previous or concurrent therapeutic interventions, idiopathy of the patient and on the route of administration. The practitioner responsible for administration will, in any event, determine the concentration of active ingredient(s) in a composition and appropriate dose(s) for the individual subject. IV. Methods of Treatment

[0261] The present disclosure further provides a method of treating a subject with cancer. In some aspects, methods described herein may comprise administering to a subject in need thereof an effective amount of one or more of the PCDH7 antibodies disclosed herein, or fragments thereof, or one or more of the compositions disclosed herein. In another aspect, method comprises administering to a subject in need thereof an effective amount of a multispecific or bispecific antibody comprising a PCDH7 biding site and a T cell engager (for e.g., CD3) binding site. The disclosed methods may comprise administering an antibody or fragment thereof to a subject in need thereof wherein the subject is a human subject. In some aspects, methods herein may comprise administering to a subject in need thereof wherein the subject is a human subject having, suspected of having, or at risk for a cancer. In some aspects, the cancer is a cancer comprising cancer cells with increased endogenous PCDH7 expression. In some aspects the cancer is a lung cancer. In some aspects, the cancer is a non-small cell lung cancer. In some aspects, cancer is an adenocarcinoma, squamous cell carcinoma, or large cell carcinoma.

[0262] In some aspects, the disclosure further provides a method for treating a subject having a cancer, wherein the cancer comprises cancer cells that express PCDH7 at high endogenous levels. Such cancer cells express PCDH7 at higher levels than normal cells (e.g., control lung cells) or cancer cells, when compared to cancer cells across patient samples. Such cells express PCDH7 at levels higher than average levels expressed by a population of cancer cells (e.g., average levels of PCDH7 expression in NSCLC cells). In some aspects, the cancer cells express PCDH7 at levels at least 10% higher, for e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, or more, higher than normal cells (e.g., control lung cells) or higher than cancer cells, when compared to cancer cells across patient samples. In such aspects, the method comprises administering to the subject, a therapeutically effective amount of plurality of one or more of the PCDH7 antibodies disclosed herein, or fragments thereof, multispecific or bispecific PCDH7 antibodies, or fragments thereof, or one or more of the pharmaceutical compositions disclosed herein.

[0263] A suitable, non-limiting example of a dosage according to the present disclosure may be from about 1 ng / kg to about 5000 mg / kg. In general, however, doses employed for adult human treatment typically may be in the range of 0.0001 mg / kg / day to 0.0010 mg / kg / day,Attorney Docket No.106546-796518-4139 0.0010 mg / kg / day to 0.010 mg / kg / day, 0.010 mg / kg / day to 0.10 mg / kg / day, 0.10 mg / kg / day to 1 .0 mg / kg / day, 1 .00 mg / kg / day to about 200 mg / kg / day, 200 mg / kg / day to about 5000 mg / kg / day. For example, the dosage may be about 1 mg / kg / day to about 100 mg / kg / day, such as, e.g., 2-10 mg / kg / day, 10-50 mg / kg / day, or 50-100 mg / kg / day. The dosage can also be selected from about 1 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, 50 mg / kg, 60 mg / kg, 70 mg / kg, 80 mg / kg, 90 mg / kg, 100 mg / kg, 125 mg / kg, 150 mg / kg, 175 mg / kg, 200 mg / kg, 250 mg / kg, 300 mg / kg, 400 mg / kg, 500 mg / kg, 600 mg / kg, 700 mg / kg, 800 mg / kg, 900 mg / kg, 1000 mg / kg, 1100 mg / kg, 1200 mg / kg, 1300 mg / kg, 1400 mg / kg, 1500 mg / kg, 1600 mg / kg, 1700 mg / kg, 1800 mg / kg, 1900 mg / kg, 2000 mg / kg, 2100 mg / kg, 2200 mg / kg, 2300 mg / kg, 2400 mg / kg, 2500 mg / kg, 2600 mg / kg, 2700 mg / kg, 2800 mg / kg, 2900 mg / kg, 3000 mg / kg, 3500 mg / kg, 4000 mg / kg, or 5000 mg / kg.

[0264] The antibody, fragment thereof, or polynucleotides encoding the antibodies described herein, can be administered to the subject daily or more than once daily. In some aspects, the disclosed antibody, fragment thereof, or polynucleotides encoding the antibodies can be administered every 2, 3, 4, 5, 6, 7, 14, or every 30 days. The disclosed antibody, fragment thereof, or polynucleotides encoding the antibodies can be administered over a period ranging from about 1 day to about 1 year, from about 1 day to about 1 week, from about 3 days to about 1 month, from about 2 weeks to about 6 months, or from about 2 months to about 4 months. The disclosed antibody, fragment thereof, or polynucleotides encoding the antibodies can also be administered over a period of about 1 day, about 7 days, about 30 days, about 60 days, about 120 days, or about 180 days or more. In some aspects, the disclosed antibody, fragment thereof, or polynucleotides encoding the antibodies is administered over a period of about 57 weeks, about 148 weeks, about 208 weeks, or indefinitely.

[0265] Dosage amount and interval may be adjusted individually to provide plasma levels of the antibodies, or fragments thereof, which are sufficient to maintain therapeutic or prophylactic effect. For example, the antibodies, or fragments thereof may be administered once per week, several times per week (e.g., every other day), once per day or multiple times per day, depending upon, among other things, the mode of administration, the specific indication being treated and the judgment of the prescribing physician. In cases of local administration or selective uptake, such as local topical administration, the effective local concentration of antibodies, or fragments thereof may not be related to plasma concentration. Skilled artisans will be able to optimize effective dosages without undue experimentation.

[0266] In some aspects, the administration of the disclosed antibody, fragment thereof, or polynucleotides encoding the antibodies, can decreases and / or inhibits activity, function, expression and / or accumulation of PCDH7.Attorney Docket No.106546-796518-4139

[0267] In some aspects, the method of administration of the disclosed antibody, fragment thereof, or polynucleotides encoding the antibodies, results in reduction of expression of phosphorylated ERK (p-ERK) in the subject. In some aspects, the method of administration of the antibody, fragment thereof, or polynucleotides encoding the antibodies described herein results in reduction of expression of p-ERK by at least about 10%, e.g., 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or above, as compared to expression of p-ERK before administration of the antibody, fragment thereof, or polynucleotides encoding the antibodies (baseline) or a control subject not receiving the treatment. In some aspects, the method of administration of the antibody, fragment thereof, or polynucleotides encoding the antibodies described herein results in reduction of expression of p-ERK by at least 25%. Non-limiting example of a method that can be used to measure p-ERK include Western quantification.

[0268] In some aspects of the method, the level of serum antibody or fragment thereof is stable for at least 10-60 days after administration of the antibody or fragment thereof in the subject. In some aspects, the serum antibody or fragment thereof level is stable for at least 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 49 days, 50 days, 51 days, 52 days 53 days, 54 days, 55 days, or 60 days. In some aspects, the serum antibody or fragment thereof level is stable for at least 10 days after administration of the antibody or fragment thereof in the subject. In some aspects, the serum antibody or fragment thereof level is stable for at least 20 days after administration of the antibody or fragment thereof in the subject. In some aspects, the serum antibody or fragment thereof level is stable for at least 30 days after administration of the antibody in the subject. The levels of serum antibody or fragment thereof can be measured using any known methods in the art, non-limiting examples of which include ELISA, immunofluorescence assays, antigen microarray and immunoassays.

[0269] In some aspects, the method of administration of the antibody, fragment thereof, or polynucleotides encoding the antibodies described herein results in reduction of tumor volume by at least about 10%, e.g., 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or above, as compared to tumor volume before administration of the antibody, fragment thereof, or polynucleotides encoding the antibodies (baseline) or a control subject not receiving the treatment. In some aspects, the administration of the antibody or fragment thereof or polynucleotides encoding the antibodies results in reduction of tumor growth by about 10% to about 50%. Tumor volume in a subject can be assessed using any conventional methods known in the art, non-limiting examples of which include, diagnostic techniques such as X ray, CT scan, bone marrow biopsy, serum protein electrophoresis (SPEP), or MRI.Attorney Docket No.106546-796518-4139

[0270] In some aspects, the method of administration of the antibody, fragment thereof, or polynucleotides encoding the antibodies described herein results in reduction of expression of one or more genes listed in Tables 10 and 11. In some aspects, reduction in expression of one or more genes listed in Tables 10 and 11 is by at least about 10%, e.g., 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or above, as compared to expression of the genes before administration of the antibody, fragment thereof, or polynucleotides encoding the antibodies (baseline) or a control subject not receiving the treatment. Any known method in the art can be used for measuring the expression levels of genes. By way of non-limiting examples, expression levels of genes can be measured using RNA-seq, nanopore sequencing, Nanostring, multiplex RT-PCR, single-plex RT-PCR, NASBA, Fluorescence measurements or spectrophotometry.

[0271] In some aspects, the method of administration described herein, results in limited treatment associated toxicity in the subject. In some aspects, the administration of the disclosed antibody, fragment thereof, or polynucleotides encoding the antibody reduces treatment toxicity in the subject, by at least 10%, e.g., 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or above, as compared to treatment associated toxicity in a subject receiving a different cancer treatment. In some aspects, treatment associated toxicity is measured in terms of body weight loss. In such aspects, the method of administration of the composition comprising disclosed antibody, fragment thereof, or polynucleotides encoding the antibody limits body weight loss in the subject, by at least 10%, e.g., 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or above, as compared to body weight loss in a subject receiving a different cancer treatment

[0272] In some aspects, the method of administration of the antibody or fragment thereof, or polynucleotides encoding the antibody results in increased Fc-mediated immune effector killing of cancer cells in the subject. In some aspects, the administration of the disclosed antibody, fragment thereof, or polynucleotides encoding the antibody increase Fc-mediated immune effector killing and / or lysis of cancer cells in the subject, by at least 10%, e.g., 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or above, as compared to killing and / or lysis of cancer cells in the subject before administration of the antibody, fragment thereof, or polynucleotides encoding the antibodies (baseline) or a control subject not receiving the treatment. In some aspects, the administration of the disclosed antibody, fragment thereof, or polynucleotides encoding the antibody increase Fc-mediated immune effector killing and / or lysis of at least about 20% of the cancer cells in the subject. Cancer cell death and / or lysis may be determined using any known methods in the art for measuring cell apoptosis or cell viability, including bioluminescent imaging or flow cytometry.Attorney Docket No.106546-796518-4139

[0273] In some aspects, the method of administration of the antibody or fragment thereof, or polynucleotides encoding the antibody results in increased antibody dependent cellular cytotoxicity (ADCC) in the subject. In some aspects, the administration of the disclosed antibody, fragment thereof, or polynucleotides encoding the antibody increase ADCC killing and / or lysis of cancer cells in the subject, by at least 10%, e.g., 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or above, as compared to killing and / or lysis of cancer cells in the subject before administration of the antibody, fragment thereof, or polynucleotides encoding the antibodies (baseline) or a control subject not receiving the treatment. In some aspects, the administration of the disclosed antibody, fragment thereof, or polynucleotides encoding the antibody increase ADCC killing and / or lysis of at least about 20% of the cancer cells in the subject. Cancer cell death and / or lysis may be determined using any known methods in the art for measuring cell apoptosis or cell viability, including bioluminescent imaging or flow cytometry.

[0274] In some aspects, the method of administration of the antibody or fragment thereof, or polynucleotides encoding the antibody results in increased granzyme B production in the subject. In some aspects, the administration of the disclosed antibody, fragment thereof, or polynucleotides encoding the antibody increase granzyme B production in the subject, by at least 10%, e.g., 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or above, as compared to granzyme B production in the subject before administration of the antibody, fragment thereof, or polynucleotides encoding the antibodies (baseline) or a control subject not receiving the treatment. In some aspects, the disclosed method results in about 50% granzyme B production in the subject. Any known method in the art can be used to measure granzyme B production in a subject, non-limiting examples of which include ELISA.

[0275] In some aspects, the method described herein may further comprise administration of a MEK inhibitor. In some aspects, MEK inhibitor is Trametinib, Binimetinib, Selumetinib, Cobimetinib, PD-325901, CI-1040, TAK-733, or any combination thereof. In some aspects, the MEK inhibitor can be administered before, during or after the administration of disclosed antibodies, fragments thereof, or polynucleotides encoding the antibodies. In some aspects, the administration of the disclosed antibodies, fragments thereof, or polynucleotides encoding the antibodies can sensitize the cancer cells to an MEK inhibitor. In some aspects, the combined administration of antibodies, fragments thereof, or polynucleotides encoding the antibodies with an MEK inhibitor can result in synergistic tumor inhibition. In some aspects, the combined administration antibodies, fragments thereof, or polynucleotides encoding the antibodies with an MEK inhibitor reduces the tumor volume in a subject by at least 10%, e.g., 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or above, as compared to tumor volume before administration of the combination antibodies, fragments thereof, or polynucleotidesAttorney Docket No.106546-796518-4139 encoding the antibodies with an MEK inhibitor (baseline), a control subject not receiving the treatment, or a subject receiving antibodies, fragments thereof, or polynucleotides encoding the antibodies, or receiving an MEK inhibitor alone.

[0276] In some aspects, the method described herein further comprise an EGFR inhibitor. In some aspects, the EGFR inhibitor is Afatinib, Almonertinib, Brigatinib, Dacomitinib, Erlotinib, Gefitinib, Icotinib, Laptinib, Neratinib, Olmutinib, Osimertinib, Pyrotinib, Simotinib, Vandetanib, or any combination thereof. In some aspects, the EGFR inhibitor can be administered before, during or after the administration of disclosed antibodies, fragments thereof, or polynucleotides encoding the antibodies. In some aspects, administration of the antibodies, fragments thereof or polynucleotides encoding the antibodies described herein can sensitize the cancer cells to an EGFR inhibitor. In some aspects, the combined administration of antibodies, fragments thereof, or polynucleotides encoding the antibodies with an EGFR inhibitor can result in synergistic tumor inhibition. In some aspects, the combined administration of antibodies, fragments thereof, or polynucleotides encoding the antibodies with an EGFR inhibitor reduces the tumor volume in a subject by at least 10%, e.g., 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or above, as compared to tumor volume before administration of the combination antibodies, fragments thereof, or polynucleotides encoding the antibodies with an EGFR inhibitor (baseline), a control subject not receiving the treatment, or a subject receiving antibodies, fragments thereof, or polynucleotides encoding the antibodies alone, or receiving an EGFR inhibitor alone.

[0277] In further aspects, the method further comprise an KRAS inhibitor. In some aspects, the KRAS inhibitor is Adagrasib, Sotorasib, AMG 510, or any combination thereof. In some aspects, the KRAS inhibitor may be administered before, during or after the administration of disclosed antibodies, fragments thereof, or polynucleotides encoding the antibodies. In some aspects, administration of the antibodies, fragments thereof or polynucleotides encoding the antibodies described herein can sensitize the cancer cells to a KRAS inhibitor. In some aspects, the combined administration of antibodies, fragments thereof, or polynucleotides encoding the antibodies with a KRAS inhibitor can result in synergistic tumor inhibition. In some aspects, the combined administration of antibodies, fragments thereof, or polynucleotides encoding the antibodies with a KRAS inhibitor reduces the tumor volume in a subject by at least 10%, e.g., 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or above, as compared to tumor volume before administration of the combination antibodies, fragments thereof, or polynucleotides encoding the antibodies with a KRAS inhibitor (baseline), a control subject not receiving the treatment, or a subject receiving antibodies, fragments thereof, or polynucleotides encoding the antibodies alone, or receiving a KRAS inhibitor alone.Attorney Docket No.106546-796518-4139

[0278] In some aspects, the disclosed methods can further comprise modifying one or more of the administrations of the antibody, fragment thereof, or polynucleotides encoding the antibodies described herein. For example, modifying one or more of steps of the method of administration can comprise modifying or changing one or more features or aspects of one or more steps of a disclosed method. For example, in an aspect, a method can be altered by changing the amount of one or more of the disclosed the antibody, fragment thereof, or polynucleotides encoding the antibodies, disclosed pharmaceutical formulations, or a combination thereof administered to a subject, or by changing the frequency of administration of one or more of the disclosed the antibody, fragment thereof, or polynucleotides encoding the antibodies, pharmaceutical formulations, or a combination thereof to a subject, or by changing the duration of time one or more of the disclosed the antibody, fragment thereof, or polynucleotides encoding the antibodies, disclosed pharmaceutical formulations, or a combination are administered to a subject. V. Kits

[0279] The present disclosure provides kits comprising one or more PCDH7 antibodies, fragment thereof, multispecific or bispecific PCDH7 antibodies, fragment thereof, or polynucleotides encoding the antibodies for use with a method of the disclosure. The kits may comprise a composition comprising a PCDH7 antibody, fragment thereof, multispecific or bispecific PCDH7 antibodies, fragment thereof, or polynucleotide encoding the antibody or a pharmaceutical composition thereof, and instructions for administering the antibody fragment thereof, or polynucleotide encoding the antibody or a pharmaceutical composition thereof to a subject in need thereof. The kit could further comprise a MEK inhibitor, a EGFR inhibitor, and / or a KRAS inhibitor that can be administered in combination with the PCDH7 antibody, fragment thereof, multispecific or bispecific PCDH7 antibodies, fragment thereof, or polynucleotide encoding the antibody. In some aspects, the kits can further comprise a sterile, pharmaceutically acceptable carrier, buffer or other diluent. The kits provided herein generally include instructions for carrying out the methods. Instructions included in the kits may be affixed to packaging material or may be included as a package insert. While the instructions are typically written or printed materials, they are not limited to such. Any medium capable of storing such instructions and communicating them to an end user is contemplated by this disclosure. Such media include, but are not limited to, electronic storage media (e.g., magnetic discs, tapes, cartridges, chips), optical media (e.g., CD ROM), and the like. As used herein, the term “instructions” may include the address of an internet site that provides the instructions.

[0280] The disclosed kits may have a single container that contains the disclosed PCDH7 antibody, fragment thereof, or polynucleotide encoding the antibody with or without anyAttorney Docket No.106546-796518-4139 additional components, or they may have distinct containers for each desired agent. Where combined therapeutics are provided, a single solution may be pre-mixed, either in a molar equivalent combination, or with one component in excess of the other. Alternatively, each of the antibody, fragment thereof, or polynucleotide encoding the antibody and other anti-cancer agent components of the kit may be maintained separately within distinct containers prior to administration to a patient.

[0281] When the components of the kit are provided in one or more liquid solutions, the liquid solution is preferably an aqueous solution, with a sterile aqueous solution being particularly preferred. However, the components of the kit may be provided as dried powder(s). When reagents or components are provided as a dry powder, the powder can be reconstituted by the addition of a suitable solvent. It is envisioned that the solvent may also be provided in another container.

[0282] The containers of the kit will generally include at least one vial, test tube, flask, bottle, syringe or other container means, into which the disclosed PCDH7 antibody, fragment thereof, multispecific or bispecific PCDH7 antibodies, fragment thereof, or polynucleotide encoding the antibody, and any other desired agent, may be placed and, preferably, suitably aliquoted. Where separate components are included, the kit will also generally contain a second vial or other container into which these are placed, enabling the administration of separated designed doses. The kits may also comprise a second / third container means for containing a sterile, pharmaceutically acceptable buffer or other diluent.

[0283] The kits may also contain a means by which to administer the disclosed PCDH7 antibody, fragment thereof, or polynucleotide encoding the antibody to an animal or patient, e.g., one or more needles or syringes, or even an eye dropper, pipette, or other such like apparatus, from which the formulation may be injected into the animal or applied to a diseased area of the body. The kits of the present invention will also typically include a means for containing the vials, or such like, and other component, in close confinement for commercial sale, such as, e.g., injection or blow-molded plastic containers into which the desired vials and other apparatus are placed and retained.

[0284] Having described several aspects, it will be recognized by those skilled in the art that various modifications, alternative constructions, and equivalents may be used without departing from the spirit of the present disclosure. Additionally, a number of well-known processes and elements have not been described in order to avoid unnecessarily obscuring the present disclosure. Accordingly, this description should not be taken as limiting the scope of the present disclosure.Attorney Docket No.106546-796518-4139

[0285] Those skilled in the art will appreciate that the presently disclosed aspects teach by way of example and not by limitation. Therefore, the matter contained in this description or shown in the accompanying drawings should be interpreted as illustrative and not in a limiting sense. The following claims are intended to cover all generic and specific features described herein, as well as all statements of the scope of the method and assemblies, which, as a matter of language, might be said to fall there between. EXAMPLES

[0286] The following examples are included to demonstrate aspects of the disclosure. It should be appreciated by those of skill in the art that the techniques disclosed in the examples that follow represent techniques discovered by the inventor to function well in the practice of the present disclosure, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific aspects which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the present disclosure. Materials and Methods Rabbit immunization and single memory B cell isolation

[0287] Human PCDH7 protein (extracellular domains: ECD) was used for antibody generation and was expressed in insect cells. The protein has a 6XHIS-tag (at the N-terminus) and was purified to >95% purity using Ni-NTA resin (Sino Biologicals). For generation of antibodies from immunized rabbits, two rabbits (NZW, Charles River) were immunized with the recombinantly produced PCDH7 using a series of immunization (3 boost injections after primary priming) procedure. Titers of anti-PCDH7 sera were determined by a series of dilutions of serum in ELISA for binding on PCDH7 protein coated on 96-well plates (high binding plates, Fisher Scientific). When serum titer reached >106and peripheral blood samples were collected from the immunized rabbits for B cell isolation from the freshly prepared peripheral blood mononuclear cells (PBMCs) using a fluorescence assisted cell sorting (FACS) instrument (BD FACSAria™ III, BD Biosciences). Sorted single B cells were collected in 96-well cell culture plates (Fisher Scientific) and cultured for 7-10 days in a cell culture incubator with 5% CO2 and 95% humidity in RPMI culture media with 10% FBS and added cytokines and growth factors for enhanced antibody expression. The antibodies in the culture supernatants were screened for PCDH7 bindings. Cells from the positive binding wells were used for cloning antibody sequences. Total RNA was isolated from individual positive B cell cultures and cDNA was synthesized using a superscript reverse transcriptase II (Invitrogen) according toAttorney Docket No.106546-796518-4139 manufacturer’s suggestion. DNA sequences of antibody variable regions from both heavy chains and light chains were amplified by polymerase chain reaction (PCR) using a set of primers and cloned into a vector for sequencing and antibody expression. Phage Display Antibody Panning

[0288] PCDH7 ECD proteins were coated on high binding tubes for capture (3ml vial) binding antibodies displayed on phage. After 3 rounds of panning selection with increased washing stringency, phage with antibody binders were rescued by infecting TG1 E. coli cells in culture. PCDH7 binding antibody hits in E. coli were screened using ELISA. Plasmid DNA from positive E. coli clones in ELISA were isolated and sequenced. Confirmed scFv antibody sequences were constructed for expression of full-length antibodies using a mammalian expression vector system in human embryonic kidney (HEK293) cells (Invitrogen). Antibodies were purified using protein A affinity resin using a fast protein liquid chromatography (FPLC). Mice mice, NSG-SGM3, and athymic nude (NU / J) mice were ordered from The Jackson Laboratory (RRID: IMSR_JAX:005557, IMSR_JAX:013062, and IMSR_JAX:002019). All procedures involving mice were approved by the Institutional Animal Care and Use Committee of UTSW Medical Center Cell lines

[0290] CDK4 / TERT-immortalized HBEC3 (HBEC3-KT) cells with stable inhibition of TP53 and ectopic expression of KRASG12V(HBEC shp53;KRASG12V) were obtained and maintained in complete KSFM growth medium (keratinocyte free-media (Gibco; 17005042) supplemented with 1% antibiotic-antimycotic (ThermoFisher; 15240062), 50 mg / ml bovine pituitary extract and 5 ng / ml of EGF (supplied with medium). HBECs with enforced expression of PCDH7-V5 (HBEC shp53-KRASG12V;PCDH7-V5) or PCDH7ΔC1-V5 (HBEC-shp53- KRASG12V;PCDH7ΔC1-V5) were generated by infecting cells with PCDH7-V5;GFP or PCDH7ΔC1-V5:GFP lentivirus and sorting for GFP+cells. H1944 and H1975 cells were obtained and maintained in complete RPMI 1640 growth medium (RPMI 1640 (Invitrogen; A1049101) and supplemented with 5% fetal bovine serum (Sigma-Aldrich; F2442) and 1% antibiotic-antimycotic). PCDH7 depletion in H1944 and H1975 cells was performed using Lenti-CRISPRv2 followed by selection with 2ug / ml puromycin (ThermoFisher; A1113803). All cell lines were cultured in a standard tissue culture incubator at 37°C with 5% CO2and tested for mycoplasma by PCR before xenograft transplantation. PlasmidsAttorney Docket No.106546-796518-4139

[0291] LentiCRISPRv2 sgPCDH7 and sgControl constructs were used for PCDH7 depletion in H1944 and H1975 cell lines. PCDH7-V5: GFP and PCDH7ΔC1-V5: GFP lentiviral constructs were generated using VectorBuilder. In vitro screening of antibody candidates

[0292] For in-cell western and MTT antibody screening, 1x103LUAD cells were incubated with 10µg / mL PCDH7-neutralizing antibody candidates in complete RPMI 1640 growth medium. Each plate also included corresponding isotype control antibodies in triplicate at 10 µg / mL: The in-house made rabbit IgG isotype control was used for rabbit B cell derived antibodies, the Ultra-LEAF™ Purified Human IgG1 Isotype Control Recombinant Antibody (Biolegend; 403501) was used for phage display antibodies. Cells were cultured at 37°C with 5% CO2for 96h before analysis. For MEKi and TKI combination studies, cells were treated with 0.02uM trametinib (Fisher Scientific; NC0596487) and 0.1 uM osimertinib (Selleck Chemicals; S7297), respectively. ERK phospho-activation was assessed by in-cell western. Growth media was aspirated and cells were immediately fixed for 15 min with 3.7% formaldehyde (Electron Microscopy Sciences; 15710) in TBS. Samples were washed and permeabilized 3 times with Triton wash buffer (TBS + 0.2% Triton-X 100) before blocking with LI-COR Intercept (TBS) Blocking Buffer (LI-COR; 927-60001) for 1.5h. Cells were incubated overnight with mouse anti-phospho-p44 / 42 MAPK (Cell Signaling Technologies; 9106L) diluted 1:50 in LI-COR Intercept (TBS) Blocking Buffer plus 0.2% Triton-X 100 at 4°C with gentle rocking. Following primary antibody incubation, samples were washed 5 times with Tween wash buffer (TBS + 0.1% Tween-20), then incubated for 2h with IRDye-800CW- conjugated goat anti-mouse secondary antibody (LI-COR; 926-32210) diluted 1:800 and CellTag 700 Stain diluted 1:500 (LI-COR; 926-41090) in LI-COR Intercept (TBS) Blocking Buffer. Samples were washed 5 times with Tween wash buffer, then once with TBS before imaging with the LI-COR Odyssey DLx system. All washes were performed for 5 min each with gentle rocking at room temperature. Cell viability was measured using the CellTiter 96 Non-Radioactive cell proliferation assay (Promega; G4000) according to manufacturer’s instructions.

[0293] Binding constants (EC50) of a panel of monoclonal antibodies were estimated using 4-parameter curve fitting with GraphPad Prism program. For antibody affinity measurement, antibody (30 µg / mL) was loaded onto the protein A biosensors for 4 min. Following incubation in kinetics buffer to establish baseline. Antibody loaded biosensors were exposed to a series of recombinant PCDH7 protein (extracellular domain with HIS tag at C terminus) at 0.1-200 nM and background subtraction was used to correct sensor drifting. All experiments were performed with shaking at 1,000 rpm accordingly to the manufacturer’sAttorney Docket No.106546-796518-4139 suggestion. Background wavelength shifts were measured from reference biosensors that were loaded with antibody and no analyte. Xenograft assays

[0294] 1x106lung cancer cells were injected subcutaneously into the right flanks of 4- week-old NSG mice or 16-week-old humanized mice in RPMI 1640 without supplement. Following formation of a palpable tumors (tumor volume ~20 mm3) mice were randomized into equal groups and treated once per week with 5-10 mg / kg of the designated antibodies in PBS via intraperitoneal (I.P.) injection. For trametinib combination experiments, mice received daily trametinib vehicle (0.5% hydroxypropylmethyl cellulose and 0.2% Tween-80 in ddH2O) or trametinib at 1 mg / kg via oral gavage. Tumors were measured using a caliper every 3 days until endpoint. Tumor volume was calculated using the formula (length×width2) / 2. Where indicated, blood serum was collected 7 days after the first antibody injection and at experimental endpoint. RNA extraction and RNA-seq sequencing

[0295] 30-50 mg tumor tissue chunks were homogenized using a polytron and RNA was extracted using Trizol (Ambion by Life Technologies; 15596018). Extracted RNA was cleaned up by RNeasy Mini Kit (Qiagen; 74104) then sequenced at the McDermott Center Next Generation Sequencing Core at UT Southwestern Medical Center. Gene Set Enrichment analyses, functional overrepresentation analyses, and Ingenuity pathway analyses were performed at the McDermott Center Bioinformatics lab. Pathway and network analysis were conducted using gene set enrichment analysis (GSEA) software and Qiagen’s IPA Analysis Match tool (QIAGEN; 836508). For GSEA, all genes were ranked with logCPM > 0 and thresholds FDR< 0.25. Functional Overrepresentation analysis was performed using WebGestalt 2019 with databases GO (Biological Process), KEGG, and REACTOME with thresholds FDR < 0.05 and logCPM > 0. Immunohistochemistry

[0296] TUNEL assays on formalin-fixed paraffin embedded tumor tissue sections was performed using DeadEnd Fluorometric TUNEL System (Promega; G3250) according to manufacturer instructions. Slides were mounted using Vectashield Hardset antifade mounting medium (Vector Laboratories; H-1400). Ki67, pERK1 / 2, and TUNEL index

[0297] Ki67-positive and pERK1 / 2-positive cells were quantified by counting brown nuclei and hematoxylin (blue) counterstain. TUNEL-positive cells were quantified by counting green nuclei and DAPI counterstain. The Ki67, pERK1 / 2, and TUNEL index for each mouse wasAttorney Docket No.106546-796518-4139 calculated as follows: percent positive cells = number of positive nuclei / total cell nuclei × 100. For Ki67 quantification, n=2 animals / group were analyzed, and 5 independent fields / animal were quantified. For pERK1 / 2 quantification, n=3 animals / group were analyzed, and 10 independent fields were quantified / animal. For TUNEL quantification, n=3 animals / group were analyzed, and 10 independent fields were quantified / animal. Humanized mice and human cord blood sample processing

[0298] 4-week-old female NSG or NSG-SGM3 recipient mice were given enrofloxacin in water ad libitum beginning 3 days before humanization and continuing for 2 weeks after humanization. Mice were irradiated with 100cGy (X-ray irradiation with X-RAD320 irradiator) to ablate bone marrow 6h before engraftment. Heparinized human cord blood samples were obtained from UT Southwestern (UTSW) Parkland Hospital according to regulation and use of human cord blood guidelines at UTSW (IRB: STU 112010-047). Human granulocytes were isolated by Ficoll-Paque PLUS (Cytiva; 17144003) density gradient centrifugation according to manufacturer instructions. Human CD34+cells were further purified using EasySep Human CD34 Positive Selection kit (STEMCELL Technologies; catalog no. 17856) according to manufacturer’s instructions and resuspended in PBS.5x104CD34+cells were intravenously injected into recipient mice.12 weeks after engraftment, humanization was validated by flow cytometry analysis of peripheral blood. Humanized mice with >30% human CD45+cell reconstitution were included in xenograft tumor studies. Human cord blood samples were obtained from UT Southwestern (UTSW) Parkland Hospital in compliance to the regulation and the use approval of human cord blood (STU 112010-047) at UTSW Medical Center. Sterile blood was obtained at the time of cesarean section from de-identified human umbilical cords that are normally discarded. The procedure was approved through a protocol exempt from informed consent as approved by the institutional review board of UTSW and the Office for Human Research Protections (OHRP) supported by the U.S. Department of Health and Human Services. To maintain anonymity, links between the donor’s medical and social histories including fetal sex are not maintained. Orthotopic transplantation

[0299] 6-8-week-old female humanized NSG mice were transplanted with 0.3x106- luciferase-expressing H1944 lung cancer cells in serum-free medium containing 50% Matrigel. Mice were anesthetized with 2.5% isoflurane and oxygen mixture. Cells were injected ~1.5 cm above the lower left rib line through the intercostal region. Mice were then placed on a heating pad and observed until they revived from anesthesia. Mice were randomized and treated with either control or Hu-mAb7 (10 mg / kg) by weekly IP injection. Tumor growth was monitoredAttorney Docket No.106546-796518-4139 once per week using BLI (AMI-HTX system, Spectral Instruments) after administration of luciferin (Gold Biotechnology; catalog no. LUCK-2G). Body weights were recorded weekly. A...

Claims

Attorney Docket No.106546-796518-4139 CLAIMS What is claimed is:

1. An isolated antibody or fragment thereof that binds to an extracellular domain of protocadherin 7(PCDH7) comprising any one or more of the amino acid sequences listed in Tables 3, 4, 7, or 8.

2. An isolated antibody or fragment thereof that binds to an extracellular domain of protocadherin 7(PCDH7) comprising a variable heavy chain region (VH) complementary determining region 1 (CDR1) that comprises at least 90% identity to the amino acid sequence set forth in SEQ ID NO: 227, 236, 278, or 242, a VHCDR2 that comprises at least 90% identity to the amino acid sequence set forth in SEQ ID NO: 228, 237, 279, or 243, a VH CDR3 that comprises at least 90% identity to the amino acid sequence set forth in SEQ ID NO: 229, 238, 280, or 244, or any combination thereof, a variable light chain region (VL) CDR1 that comprises at least 90% identity to the amino acid sequence set forth in SEQ ID NO: 162, 168, 196, or 172, a VLCDR2 that comprises at least 90% identity to the amino acid sequence NVS, RAS, EVT, or QAS, and / or a VLCDR3 that comprises at least 90% identity to the amino acid sequence set forth in SEQ ID NO: 163, 169, 197, or 173, or any combination thereof.

3. The isolated antibody or fragment thereof of any one of the preceding claims, wherein the extracellular domain of PCDH7 is EC1.

4. The isolated antibody or fragment thereof of any one of the preceding claims, wherein the antibody binds to PCDH7 with high affinity.

5. The isolated antibody or fragment thereof of claim 4, wherein the antibody or fragment thereof binds to PCDH7 with at least a dissociation equilibrium constant K (KD) of less than about 0.02 nM to about 20nM.

6. The isolated antibody or fragment thereof of any of the preceding claims, wherein the antibody is a scFv.

7. The isolated antibody or fragment thereof of any one of the preceding claims, wherein the antibody comprises a VHcomprising an amino acid sequence at least 90% identical to the sequence set forth in SEQ ID NO: 378, 381, 395, or 383.Attorney Docket No.106546-796518-4139 8. The isolated antibody or fragment thereof of any one of the preceding claims, wherein the antibody comprises a VLcomprising an amino acid sequence at least 90% identical to the sequence set forth in SEQ ID NO: 410, 413, 427, or 415.

9. The isolated antibody or fragment thereof of any one of the preceding claims, wherein the antibody is an IgG, IgM, IgA or an antigen binding fragment thereof.

10. An isolated antibody or fragment thereof of any one of the preceding claims, wherein the isolated antibody or fragment thereof is a chimeric, CDR grafted, humanized, muranized, human antibody, or an immunoreactive fragment thereof.

11. The isolated antibody or fragment thereof of claim 10, wherein the antibody is a humanized antibody or de-immunized antibody.

12. The isolated antibody or fragment thereof of claim 11, wherein the antibody comprises a VH comprising a sequence at least 90% identical to the sequence set forth in SEQ ID NO:

406.

13. The isolated antibody or fragment thereof of claim 11, wherein the antibody comprises a VL comprising a sequence at least 90% identical to the sequence set forth in SEQ ID NO:

438.

14. An isolated antibody or fragment thereof that binds to an extracellular domain of protocadherin 7(PCDH7) comprising a VH CDR1 that comprises at least 90% identity to the polynucleotide sequence set forth in SEQ ID NO: 72, 81, 87, or 123, a VHCDR2 that comprises at least 90% identity to the polynucleotide sequence set forth in SEQ ID NO: 73, 82, 88, or 124, a VHCDR3 that comprises at least 90% identity to the polynucleotide sequence set forth in SEQ ID NO: 74, 83, 89, or 125, or any combination thereof, a VLCDR1 that comprises at least 90% identity to the polynucleotide sequence set forth in SEQ ID NO: 7, 13, 17, or 41, a VLCDR2 that comprises at least 90% identity to the polynucleotide sequence aatgtatcg, agggcatcc, caggcatcc, or gaggtcact, and / or a VLCDR3 that comprises at least 90% identity to the polynucleotide sequence set forth in SEQ ID NO: 8, 14, 18, or 173, or any combination thereof.

15. The isolated antibody or fragment thereof of any one of the preceding claims, wherein the antibody comprises a VHcomprising a polynucleotide sequence at least 90% identical to the sequence set forth in SEQ ID NO: 314, 317, 319, 331, or 342; and / or a VLcomprising a polynucleotide sequence at least 90% identical to the sequence set forth in SEQ ID NO: 346, 349, 351, 363, or 374.

16. A vector comprising one or more polynucleotide sequence of claim 14 or claim 15.Attorney Docket No.106546-796518-4139 17. A cell comprising the vector of claim 16.

18. A composition for treatment of cancer in a subject in need thereof, the composition comprising an antibody or fragment thereof of any one of the preceding claims.

19. A method for treatment of cancer in a subject in need thereof, the method comprising administering to the subject a composition comprising an antibody or fragment thereof of any one of the claims 1-15.

20. The composition of claim 18 or the method of claim 19, wherein the cancer comprises cells with increased endogenous PCDH7 expression.

21. The composition of claim 18 or the method of claim 19, wherein the cancer is a lung cancer.

22. The composition of claim 18 or the method of claim 19, wherein the cancer is a non- small cell lung cancer.

23. The composition of claim 18 or the method of claim 19, wherein the cancer is an adenocarcinoma, squamous cell carcinoma, or large cell carcinoma.

24. The composition of claim 18 or the method of claim 19, wherein the administration of the antibody or fragment thereof results in reduction of tumor volume by about 10% to about 50%.

25. The composition of claim 18 or the method of claim 19, wherein the administration of the antibody or fragment thereof results in reduction of tumor growth by about 10% to about 50%.

26. The composition of claim 18 or the method of claim 19, wherein the administration of the antibody or fragment thereof results in reduction of expression of one or more genes listed in Tables 10 and / or 11.

27. The composition of claim 18 or the method of claim 19, wherein the serum antibody or fragment thereof level is stable for at least 10 days after administration of the antibody or fragment thereof in the subject.

28. The composition of claim 18 or the method of claim 19, wherein the serum antibody or fragment thereof level is stable for at least 20 days after administration of the antibody or fragment thereof in the subject.

29. The composition of claim 18 or the method of claim 19, wherein the serum antibody or fragment thereof level is stable for at least 30 days after administration of the antibody in the subject.Attorney Docket No.106546-796518-4139 30. The composition of claim 18 or the method of claim 19, wherein the administration of the antibody or fragment thereof results in limited treatment associated toxicity in the subject.

31. The composition of claim 18 or the method of claim 19, wherein the administration of the antibody or fragment thereof results in increased Fc-mediated immune effector killing of cancer cells in the subject.

32. The composition of claim 18 or the method of claim 19, wherein the administration of the antibody or fragment thereof results in increased antibody dependent cellular cytotoxicity (ADCC) in the subject.

33. The composition or method of any one of the claims 31 or 32, wherein the increased Fc-mediated immune effector killing or ADCC results in lysis of at least about 20% of the cancer cells.

34. The composition of claim 18 or method of claim 19, wherein the administration results in granzyme B production in the subject by about 50%.

35. The composition of claim 18 or the method of claim 19, wherein the administration of the antibody or fragment thereof results in reduction of expression of phosphorylated ERK (p-ERK) in the subject by at least 25%.

36. The composition of claim 18 or the method of claim 19, wherein the administration of the antibody or fragment thereof results in sensitization of the cancer cells to a MEK inhibitor.

37. The composition of claim 18 or the method of claim 19, wherein the antibody or fragment thereof is administered in combination with a MEK inhibitor.

38. The composition or method of claims 36 or 37, wherein the MEK inhibitor is Trametinib, Binimetinib, Selumetinib, Cobimetinib, PD-325901, CI-1040, TAK-733, or any combination thereof.

39. The composition of claim 18 or the method of claim 19, wherein the antibody or fragment thereof is administered in combination with an EGFR inhibitor.

40. The composition or method of claim 39, wherein the EGFR inhibitor is Afatinib, Almonertinib, Brigatinib, Dacomitinib, Erlotinib, Gefitinib, Icotinib, Laptinib, Neratinib, Olmutinib, Osimertinib, Pyrotinib, Simotinib, Vandetanib, or any combination thereof.

41. The composition of claim 18 or the method of claim 19, wherein the administration of the antibody or fragment thereof results in sensitization of the cancer cells to a KRAS inhibitor.Attorney Docket No.106546-796518-4139 42. The composition of claim 18 or the method of claim 19, wherein the antibody or fragment thereof is administered in combination with a KRAS inhibitor.

43. The composition or method of claim 42, wherein the KRAS inhibitor is Adagrasib, Sotorasib, AMG 510, or any combination thereof.

44. A multispecific antibody comprising: a first binding site that specifically binds to an extracellular domain of protocadherin 7(PCDH7) comprising any one or more of the amino acid sequences listed in Tables 3, 4, 7, or 8.

45. The multispecific antibody of claim 44, wherein the first binding site comprises a variable heavy chain region (VH) complementary determining region 1 (CDR1) that comprises at least 90% identity to the amino acid sequence set forth in SEQ ID NO: 227, 236, 278, or 242, a VHCDR2 that comprises at least 90% identity to the amino acid sequence set forth in SEQ ID NO: 228, 237, 279, or 243, a VH CDR3 that comprises at least 90% identity to the amino acid sequence set forth in SEQ ID NO: 229, 238, 280, or 244, or any combination thereof, a variable light chain region (VL) CDR1 that comprises at least 90% identity to the amino acid sequence set forth in SEQ ID NO: 162, 168, 196, or 172, a VLCDR2 that comprises at least 90% identity to the amino acid sequence NVS, RAS, EVT, or QAS, and / or a VLCDR3 that comprises at least 90% identity to the amino acid sequence set forth in SEQ ID NO: 163, 169, 197, or 173, or any combination thereof.

46. The multispecific antibody of claim 44, wherein the first binding site comprises a VHcomprising an amino acid sequence at least 90% identical to the sequence set forth in SEQ ID NO: 406, and / or a VLcomprising an amino acid sequence at least 90% identical to the sequence set forth in SEQ ID NO:

438.

47. The multispecific antibody of claim 44, further comprising a second binding site that specifically binds to a T cell engager wherein the T cell engager binds to T cell, and activates T cell signaling.

48. The multispecific antibody of claim 47, wherein the T cell engager is a CD3.

49. The multispecific antibody of any one of claim 47 or 48, wherein the second binding site is a CD3 scFv.

50. The multispecific antibody of claim 44, wherein the antibody is bispecific.

51. A composition for treatment of cancer in a subject in need thereof, the composition comprising the multispecific antibody or fragment thereof of claim 44.Attorney Docket No.106546-796518-4139 52. A method for treatment of cancer in a subject in need thereof, the method comprising administering to the subject a composition comprising the multispecific antibody or fragment thereof of claim 44.

53. The composition of claim 51 or the method of claim 52, wherein the cancer is a lung cancer.

54. The composition of claim 51 or the method of claim 52, wherein the cancer is a non- small cell lung cancer.

55. The composition of claim 51 or the method of claim 52, wherein the cancer is an adenocarcinoma, squamous cell carcinoma, or large cell carcinoma.

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