Combination therapies with ULBP2 targeting antibodies for treating cancers

Abstract

The present disclosure provides anti-ULBP2 antibodies or antigen binding fragments thereof, including bispecific. The antibodies are administered in combination with a chemotherapy agent, a radiation therapy, and / or an immune checkpoint inhibitor for treatment of basal squamous cancer. The present disclosure also relates to methods and kits for detecting a predisposition to, determining the risk of, and guiding therapy for ULBP2 related disorders.

Description

COMBINATION THERAPIES WITH ULBP2 TARGETING ANTIBODIES FOR TREATING CANCERSRELATED APPLICATIONS

[0001] This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Application, U.S.S.N. 63 / 590,755, filed October 16, 2023, the entire contents of which are herein incorporated by reference.REFERENCE TO AN ELECTRONIC SEQUENCE LISTING

[0002] The contents of the electronic sequence listing (E070170008WO00-SEQ-LJG.xml; Size: 509,870 bytes; and Date of Creation: October 15, 2024) are herein incorporated by reference in its entirety.FIELD

[0003] This disclosure relates to pharmaceutical compositions of antibodies that bind ULBP2 and their use. This disclosure relates to combination therapies for diseases associated with cells expressing ULBP2, such as bladder cancers. This disclosure also relates to a method and kits for detecting a predisposition to, determining risk of, and guiding therapy for cancers.BACKGROUND

[0004] UL16 binding protein 2 (ULBP2) is a cell surface glycoprotein related to MHC class I. ULBP2 functions as a stress-induced ligand for NKG2D receptor. ULBP2 encoded protein undergoes further processing to generate the mature protein that is either anchored to membrane via a glycosylphosphatidylinositol moiety or secreted.

[0005] NKG2D ligands are shown to be upregulated by a range of primary tumors, including lung, kidney, prostate, breast and colon cancer. Immune response induced by ULBP2- NKG2D may play an important role in the eradication of tumors by T and / or NK cells.SUMMARY

[0006] The present disclosure, at least in part, is based on the discovery that certain combinations of an anti-ULBP2 antibody or antigen binding fragment thereof (e.g., a bispecific antibody that binds ULBP2 and CD3) and a chemotherapy, radiotherapy, or animmune checkpoint inhibitor (e.g., pembrolizumab) increases efficacy relative to the anti- ULBP2 therapy alone in a subject having cancer (e.g., cancers with increased ULBP2 expression level). The present disclosure provides a method of decreasing a population of cancer cells in a subject, the method comprising administering to the subject: a) an anti- ULBP2 antibody or antigen binding fragment thereof, and b) a chemotherapy agent, a radiation therapy, and / or an immune checkpoint inhibitor, wherein the plurality of cancer cells express UL16 binding protein 2 (ULBP2) and wherein the subject has cancer (e.g., a squamous cancer).

[0007] In some embodiments, the method results in a decrease of about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90% in the number of ULBP2 expressing cancer cells in the subject relative to the number of ULBP2 expressing cancer cells in the subject prior to the administration of the anti-ULBP2 antibody or antigen binding fragment thereof and the chemotherapy agent and / or the radiation therapy.

[0008] The disclosure also provides a method for treating a human subject having a cancer (e.g., a basal squamous cancer) comprising the steps of: a) obtaining a biological sample from a human subject having cancer (e.g., a basal squamous cancer); b) detecting the expression levels of ULBP2; c) comparing the detected expression level of ULBP2 with a control level of ULBP2 expression; d) identifying the subject as a responder when the detected expression level of ULBP2 is greater than the control level of ULBP2 expression; and e) administering an anti-ULBP2 antibody or fragment thereof in an amount sufficient to alleviate a symptom of the cancer (e.g., basal squamous cancer) when the subject is identified as a responder.

[0009] In some embodiments, the method comprises: i) detecting the expression levels of TROP2, PDL1, HLA-E, NECTIN4 and / or HER2; ii) comparing the detected expression levels of TROP2, PDL1, HLA-E, NECTIN4 and / or HER2 to a control levels of expression; iii) identifying the subject as a responder when the detected expression level of TROP2 is greater than the control level of TROP2 expression; the detected expression level of PDL1 is greater than the control level of PDL1 expression; the detected expression level of HLA-E is greater than the control level of HLA-E expression; the detected expression level of NECTIN4 is less than the control level of NECTIN4 expression; and / or the detected expression level of HER2 is less than the control level of HER2 expression.

[0010] In some embodiments, the anti-ULBP2 antibody or fragment thereof comprises: a) a complementarity determining region 1 (VH2CDRI) comprising the amino acid sequence of SEQ ID NO: 428; a complementarity determining region 2 (VH2CDR2) comprising the amino acid sequence of SEQ ID NO: 430; a complementarity determining region 3 (VH2CDR3) comprising the amino acid sequence of SEQ ID NO: 432; a complementarity determining region 1 (VL2CDRI) comprising the amino acid sequence of SEQ ID NO: 433; a complementarity determining region 2 (VL2CDR2) comprising the amino acid sequence of SEQ ID NO: 434; and a complementarity determining region 3 (VL2CDR3) comprising the amino acid sequence of SEQ ID NO: 435; or b) a complementarity determining region 1 (VH2CDRI) comprising the amino acid sequence of SEQ ID NO: 5; a complementarity determining region 2 (VH2CDR2) comprising the amino acid sequence of SEQ ID NO: 7; a complementarity determining region 3 (VH2CDR3) comprising the amino acid sequence of SEQ ID NO: 9; a complementarity determining region 1 (VL2CDRI) comprising the amino acid sequence of SEQ ID NO: 10; a complementarity determining region 2 (VL2CDR2) comprising the amino acid sequence of SEQ ID NO: 11; and a complementarity determining region 3 (VL2CDR3) comprising the amino acid sequence of SEQ ID NO: 12.

[0011] In some embodiments, the anti-ULBP2 antibody or fragment thereof is a bispecific antibody that specifically binds ULBP2 and CD3 or wherein the anti-ULBP2 antibody or fragment thereof is a bispecific antibody that specifically binds ULBP2 and PD1. In some embodiments, a CD58 polypeptide or a fragment thereof is fused to the C-terminus of a heavy chain polypeptide of the bispecific antibody. In some embodiments, the CD58 comprises the amino acid sequence of SEQ ID NO: 49.

[0012] In some embodiments, the bispecific antibody comprises an anti-ULBP2 antibody or antigen binding fragment thereof comprising a light chain variable region (VL2) that comprises the amino acid sequence of SEQ ID NO: 1, and a heavy chain variable region (VH2) that comprises the amino acid sequence of SEQ ID NO: 629. In some embodiments, the anti-ULBP2 antibody or antigen binding fragment thereof comprises a light chain (L2) that comprises the amino acid sequence of SEQ ID NO: 67, or a heavy chain (H2) that comprises the amino acid sequence of SEQ ID NO: 621.

[0013] In some embodiments, the bispecific antibody comprises an anti-CD3 antibody or antigen binding fragment thereof comprising a light chain variable region (VL1) thatcomprises the amino acid sequence of SEQ ID NO: 22, and a heavy chain variable region (VH1) that comprises the amino acid sequence of SEQ ID NO: 17. In some embodiments, wherein the CD58 polypeptide or a fragment thereof is fused to the C-terminus of a heavy chain of the anti-CD3 antibody or antigen fragment thereof of the bispecific antibody. In some embodiments, the anti-CD3 antibody or antigen binding fragment thereof comprises a light chain (LI) comprising the amino acid sequence of SEQ ID NO: 69, and a heavy chain fused to the CD58 polypeptide (Hl) comprising the amino acid sequence of SEQ ID NO: 622.

[0014] Any suitable chemotherapy can be used in combination with an anti-ULBP2 antibody or antigen binding fragment described herein. In some embodiments, chemotherapy agents suitable for use in the present disclosure include but are not limited to a topoisomerase inhibitor, an anthracycline doxorubicin, a DNA break inducing antibiotic, a pyrimidine antagonist, or a platinum alkylating agent.

[0015] In some embodiments, the radiation therapy is selected from the group consisting of 3D conformal radiation therapy (3DCRT), image-guided radiation therapy (IGRT), intensity modulated radiation therapy (IMRT), volumetric modulated arc therapy (VMAT), brachytherapy, intraoperative radiation therapy (IORT), stereotactic radiosurgery (SRS), proton therapy, MRI linear accelerator, and / or stereotactic body radiation therapy (SBRT).

[0016] The disclosure also provides a method for identifying a human subject having a cancer (e.g., basal squamous cancer) that is suitable for therapy with an anti-UL16 binding protein 2 (ULBP2) antibody or antigen binding fragment thereof comprising the steps of: a) obtaining a biological sample a human subject having cancer (e.g., basal squamous cancer); b) detecting the expression levels of ULBP2; c) comparing the detected expression level of ULBP2 with a control level of ULBP2 expression; and d) identifying the subject as a responder when the detected expression level of ULBP2 is greater than the control level of ULBP2 expression. In some embodiments, the method further comprises: e) administering an anti-ULBP2 antibody or fragment thereof in an amount sufficient to alleviate a symptom of the cancer (e.g. basal squamous cancer) when the subject is identified as a responder.

[0017] In some embodiments, the subject has a squamous cancer. In some embodiments, the squamous cancer is a basal squamous cancer. In some embodiments, the subject has a bladder cancer, a lung cancer, a head and neck cancer, a cervical cancer, esophageal cancer, anal cancer, vulvar cancer, penile cancer, thymic cancer, skin cancer cell, or adrenocortical cancer.

[0018] In some embodiments, the subject has an adenocarcinoma. In some embodiments, the adenocarcinoma is lung adenocarcinoma, pancreatic adenocarcinoma, bladder adenocarcinoma, esophageal adenocarcinoma, or colon adenocarcinoma.

[0019] In some embodiments, the subject has an EGFR activating mutation or an EGFR copy number alteration. In some embodiments, the subject has been previously treated with a tyrosine kinase inhibitors (TKI). In some embodiments, the TKI is Osimertinib. In some embodiments, the TKI does not decrease ULBP2 expression level in the cancer. In some embodiments, the subject previously received TKI has relapsed cancer after TKI treatment.

[0020] In some embodiments, the cancer is a metastatic cancer. In some embodiments, the subject with metastatic cancer has non-primary lesions in the liver, lung, bone, brain, or lymph node originated from a primary cancer. In some embodiments, the primary cancer is a squamous cancer or an adenocarcinoma. In some embodiments, the primary cancer is a squamous cancer comprising a bladder cancer, a lung cancer, a head and neck cancer, a cervical cancer, esophageal cancer, anal cancer, vulvar cancer, penile cancer, thymic cancer, skin cancer cell, or adrenocortical cancer. In some embodiments, the primary cancer is an adenocarcinoma including lung adenocarcinoma, pancreatic adenocarcinoma, bladder adenocarcinoma, esophageal adenocarcinoma, or colon adenocarcinoma.

[0021] In some embodiments, the subject is previously administered immune checkpoint inhibitor. In some embodiments, the immune checkpoint inhibitor is an PD1 / PDL1 inhibitor or a CTLA4 inhibitor. In some embodiments, the immune checkpoint inhibitor is pembrolizumab, nivolumab, atezolizumab, ipilimumab, or tremelimumab. In some embodiments, the immune checkpoint inhibitor does not decrease ULBP2 expression level in the cancer.

[0022] In some embodiments, the subject is simultaneously administered or previously administered with a therapeutically effective amount of a therapeutic agent.

[0023] In some embodiments, the therapeutic agent is a chemotherapy agent. Any suitable chemotherapy can be used in combination with an anti-ULBP2 antibody or antigen binding fragment described herein. In some embodiments, chemotherapy agents suitable for use in the present disclosure include but are not limited to a topoisomerase inhibitor, an anthracycline doxorubicin, a DNA break inducing antibiotic, a pyrimidine antagonist, or a platinum alkylating agent.

[0024] In some embodiments, the therapeutic agent is a radiation therapy selected from the group consisting of 3D conformal radiation therapy (3DCRT), image-guided radiation therapy (IGRT), intensity modulated radiation therapy (IMRT), volumetric modulated arc therapy (VMAT), brachytherapy, intraoperative radiation therapy (IORT), stereotactic radiosurgery (SRS), proton therapy, MRI linear accelerator, and / or stereotactic body radiation therapy (SBRT).

[0025] In some embodiments, the therapeutic agent is a CAR-T cell therapy, an immune checkpoint inhibitor, a co-stimulatory ligand or a cytokine. In some embodiments, the immune checkpoint inhibitor is pembrolizumab, nivolumab, atezolizumab, ipilimumab, or tremelimumab.

[0026] In some embodiments, the anti-ULBP2 antibody or antigen binding fragment thereof and the chemotherapy agent, radiation therapy , and / or immune checkpoint inhibitor are administered sequentially. In some embodiments, the anti-ULBP2 antibody or antigen binding fragment thereof and the chemotherapy agent, radiation therapy, and / or immune checkpoint inhibitor are administered concurrently.BRIEF DESCRIPTION OF THE DRAWINGS

[0027] FIGS. 1A-1B are a series of heat maps showing the average levels of a set of luminal / adeno genes (top) and basal / squamous genes (bottom) in bladder and lung TCGA datasets and the Cancer Cell Line Encyclopedia (CCLE) when clustered using these same genes and others (immune infiltration, neuronal). The levels in a subset of cell lines are shown and labeled by their category for bladder (luminal, luminal-infiltrated, or basal-squamous) or lung (mixed / infiltrated or basal-squamous). FIG. 1A shows the bladder dataset and FIG. IB shows the lung dataset.

[0028] FIG. 2 is a heatmap depicting quantified immunoblots for luminal (FOXA1, PPARG, GATA3) and basal / squamous (KRT5, KRT6, and SERPINB3) markers at the protein level in several cell lines (shown on the x-axis). ULBP2 protein levels from flow cytometry antigen binding density are also shown for the same cell lines.

[0029] FIGS. 3A-3D are a series of graphs depicting gene levels in the bladder cancer TCGA dataset of the same clustered groups as defined and shown in FIG. 1. FIG. 3A shows the target ULBP2. FIG. 3B shows TROP2. FIG. 3C shows HER2. FIG. 3D shows NECTIN4. p> 0.05 is denoted with *; p < 0.01 is denoted with **; p < 0.001 is denoted with ***; and, p < 0.0001 is denoted with ****.

[0030] FIGS. 4A-4D are a series of graphs depicting gene levels in the bladder cancer TCGA dataset of the same clustered groups as defined and shown in FIG. 1. FIG. 4A shows the luminal gene FOXA1. FIG. 4B shows the luminal gene PPARG. FIG. 4C shows the basal / squamous gene KRT5. FIG. 4D shows SERPINB3.

[0031] FIGS. 5A-5D are a series of graphs depicting gene levels in the bladder cancer TCGA dataset of the same clustered groups as defined and shown in FIG. 1. FIG. 5A shows the immune gene PDL1. FIG. 5B shows the T cell gene PD1. FIG. 5C shows the T cell gene CD8A. FIG. 5D shows the T cell gene Granzyme B.

[0032] FIGS. 6A-6D are a series of graphs depicting gene levels in the lung cancer TCGA dataset bifurcated with either adenocarcinoma or squamous indication. FIG. 6A shows the target ULBP2. FIG. 6B shows TROP2. FIG. 6C shows HER2. FIG. 6D shows NECTIN4. p> 0.05 is denoted with *; p < 0.01 is denoted with **; p < 0.001 is denoted with ***; and p < 0.0001 is denoted with ****.

[0033] FIGS. 7A-7D are a series of graphs depicting gene levels in the lung cancer TCGA dataset bifurcated with either adenocarcinoma or squamous indication. FIG. 7A shows the luminal gene FOXA1. FIG. 7B shows the luminal gene PPARG. FIG. 7C shows the basal / squamous gene KRT5. FIG. 7D shows SERPINB3.

[0034] FIGS. 8A-8D are a series of graphs depicting gene levels in the lung cancer TCGA dataset bifurcated with either adenocarcinoma or squamous indication. FIG. 8A shows the immune gene PDL1. FIG. 8B shows the T cell gene PD1. FIG. 8C shows the T cell gene CD8A. FIG. 8D shows the T cell gene Granzyme B.

[0035] FIGS. 9A-9F are a series of graphs depicting T cell dependent cell cytotoxicity and cytokine release data in the bladder squamous cell line 5637 with anti-ULBP2 antibody EIP0820 and the negative control EIP0607 in combination with either pembrolizumab or the IgG4 isotype control. FIG. 9A shows tumor killing at Day 5 with Donor 1 A. FIG. 9B shows tumor killing at Day 5 with Donor 2A. FIG. 9C shows tumor killing at Day 5 with Donor 3A. FIG. 9D shows IFNg cytokine release at Day 2 with Donor 1A. FIG. 9B shows IFNg cytokine release at Day 2 with Donor 2A. FIG. 9C shows IFNg cytokine release at Day 2 with Donor 3A.

[0036] FIGS. 10A-10B are a series of graphs depicting upregulation of ULBP2 and other markers (HER2, CD58, PDL1, TROP2, and B7H4) with a series of chemotherapy agents (bleomycin, cisplatin, docetaxel, doxorubicin, gemcitabine, irinotecan, and vinblastine) at their EC50 concentrations. FIG. 10A shows the bladder squamous cell line 5637. FIG. 10B shows the lung adenosquamous cell line A549.

[0037] FIG. 11 is a graph depicting T cell dependent cell cytotoxicity data in 5637 cells with EIP0820 and the negative control EIP0607 in combination with irinotecan chemotherapy.

[0038] FIG. 12 is a graph depicting T cell dependent cell cytotoxicity in squamous bladder cancer 5637 cell with EIP0820 and the negative control EIP0614 in combination with gemcitabine / cisplatin (“Cis / Gem”).

[0039] FIG. 13 is a graph depicting gene levels in an esophageal cancer dataset from The Cancer Genome Atlas (TCGA), bifurcated by either adenocarcinoma or squamous indication.

[0040] FIGS. 14A -C depict associations between ULBP2 expression, basal-squamous molecular subtype, and CD8 T cell infiltration, as outlined in Table 14. FIG. 14A shows ULBP2 expression versus basal / squamous subtype. FIG. 14B shows ULBP2 expression versus CD8 T cell infiltration. FIG. 14C shows basal / squamous subtype versus CD8 T cell infiltration.

[0041] FIG. 15 shows ULBP2 expression of primary and non-primary site tumor sites in lung cancer from GSE248249.

[0042] FIGs. 16A-16E depict gene levels in five different datasets, each bifurcated by either HPV negative or HPV positive status of the patients. FIG. 16A shows TCGA, FIG. 16B shows GSE65858, FIG. 16C shows GSE39366, FIG. 16D shows GSE40774, and FIG. 16E shows GSE6791.

[0043] FIGs. 17A-17D depict ULBP2 expression in either lung or bladder datasets. Samples are stratified by grade and stage of cancer and subtype (squamous or adeno). FIG. 17A shows GSE42127, FIG. 17B shows GSE14814, FIG. 17C shows TCGA lung squamous, and FIG. 17D shows TCGA bladder subtyped by molecular characterization to only basal / squamous as in FIG. 3.

[0044] FIGs. 18A-18H depict ULBP2 expression in either head and neck, lung, or bladder cancers. Pre / post treatment of check point inhibitors of paired or unpaired samples, with lung stratified by basal and squamous is shown. FIG. 18A shows GSE179730 (head and neck),FIG. 18B shows GSE195832 (head and neck), FIGs. 18C and 18D show GES248249 (lung) with either paired or unpaired samples, FIGs. 18D and 18E show GSE248378 (lung) with either adeno or squamous breakout, FIG. 18G shows GSE248249 (lung) with outcome data from checkpoint inhibitors, and FIG. 18H shows GSE212810 (bladder) with outcome data.

[0045] FIGs. 19A-19D depict ULBP2 expression from TCGA in patients that have EGFR mutations (FIG. 19A), highest and lowest quartile of EGFR expression (FIG. 19B), EGFR copy number alterations (FIG. 19C), and primary patients that have activating mutations that most likely will be prescribed the tyrosine kinase inhibitor (TKI) osimertinib (FIG. 19D).

[0046] FIG. 20 is a graph showing ULBP2 expression in a bladder cancer dataset that stratifies patients into non-squamous disease and pure squamous cell carcinoma from GSE186691.

[0047] FIGs. 21A-21C show ULBP2 expression in tumors from non-TCGA squamous datasets. FIG. 21A shows anal cancer dataset GSE253560. LGSIL = low-grade squamous intraepithelial lesion; HGSIL = high-grade squamous intraepithelial lesion; ASCC = anal squamous cell carcinoma. FIG. 21B shows cervical, endometrial, and vulvar cancer dataset GSE63678. FIG. 21C shows vulvar cancer stratified on patient HPV status.DETAILED DESCRIPTION

[0048] Provided herein are methods of identifying and treating a human subject having a ULBP2 expressing cancer (e.g., squamous cancer such as basal squamous cancer including bladder cancer, lung cancer, esophageal cancer, head and neck cancer, etc., adenocarcinoma including lung adenocarcinoma, pancreatic adenocarcinoma, bladder adenocarcinoma, esophageal adenocarcinoma, or colon adenocarcinoma, or metastatic cancer) that is suitable for therapy with an anti-ULBP2 antibody or antigen binding fragment thereof. This is based in part on the observation that certain cancer (e.g., basal squamous cancer, adenocarcinoma, or metastatic cancer) patient tumors indicated higher ULBP2 levels in tumors. Further, it was observed that ULBP2 positive cancer such as basal squamous cancers, especially bladder cancer, display higher T cell infiltration (as seen by the expression of PDL1, PD1 and granzyme B). Without being bound by theory, together this suggests a high potential for efficacy of T cell engager therapies in this subset of patients. Further, it was observed that acombination therapy of anti-ULBP2 antibody or antigen binding fragment thereof with a immune checkpoint inhibitor (e.g., an anti-PD-1 antibody) was advantageous for treating basal squamous cancers. Without being bound by theory, the use of PD1 checkpoint inhibitors can further increase immune infiltration in subtypes where immune infiltration is lower, resulting in higher therapeutic potential.

[0049] Using specific chemotherapies or radiation therapy will induce ULBP2 in any subtype (even and especially in the adeno / luminal where it is lower). Therefore, a combination treatment and / or an anti-ULBP2 antibody or antigen binding fragment thereof treatment shortly following chemotherapy or radiation therapy will increase potency of the anti-ULBP2 antibody or antigen binding fragment thereof.

[0050] Also provided herein are methods of treating a subject using an anti-ULBP2 antibody or antigen binding fragment thereof and a radiation therapy, chemotherapy, and / or an immune checkpoint inhibitor. Without being bound by theory, the use of chemotherapy may increase tumor ULBP2 levels (e.g., triggered by chemotherapy induced DNA damage) found on cancer cells (e.g., basal squamous bladder cancer and lung cancer cells, adenocarcinoma cells, metastatic cancers). Accordingly, this provides high therapeutic potential for the use of the anti-ULBP2 antibodies in cancers (e.g., squamous cancer such as bladder cancer and lung cancer, adenocarcinomas, or metastatic cancers).

[0051] Accordingly, the disclosure provides a method for treating a cancer that expresses ULBP2. In some embodiments, the disclosure provides a method of decreasing a population of cancer cells in a subject. In some embodiments, the method of treating a cancer comprises administering an effective amount of an anti-ULBP2 antibody or antigen binding fragment thereof. In some embodiments, the method of treating a cancer comprises administering an effective amount of an anti-ULBP2 antibody or antigen binding fragment thereof and a chemotherapy agent, a radiation therapy, and / or an immune checkpoint inhibitor. In some embodiments, the cancer expresses UL16 binding protein 2 (ULBP2). In some embodiments, the cancer expresses KRT5 and / or SERPINB3. In some embodiments, the cancer is a squamous cancer (e.g., basal squamous cancer). In certain embodiments, the basal squamous cancer is bladder cancer. In certain embodiments, the basal squamous cancer is lung cancer. In certain embodiments, the basal squamous cancer is esophageal cancer. In certain embodiments, the basal squamous cancer is head and neck cancer. In some embodiments, thecancer is an adenocarcinoma (e.g., lung adenocarcinoma, pancreatic adenocarcinoma, bladder adenocarcinoma, esophageal adenocarcinoma, or colon adenocarcinoma). In some embodiments, the cancer is metastatic cancer.ULBP2 Binding Proteins

[0052] The present disclosure provides a bispecific antibody comprising a first antigen binding domain that binds to a CD3 or PD1 expressed on a T-cell, and a second antigen binding domain that binds to a ULBP2 antigen on the surface of a cancer cell. Antibodies of the disclosure are useful, for example, for treating or delaying the progression of a cell proliferative disorder (e.g., cancer expressing ULBP2).

[0053] UL16 Binding Protein 2 (ULBP2) is a major histocompatibility complex (MHC) class I-related molecule that binds to the NKG2D receptor on natural killer (NK) cells to trigger release of multiple cytokines and chemokines that in turn contribute to the recruitment and activation of NK cells. The encoded protein undergoes further processing to generate the mature protein that is either anchored to membrane via a glycosyl-phosphatidylinositol moiety, or secreted. Many malignant cells secrete the encoded protein to evade immuno surveillance by NK cells.

[0054] The terms “ULBP2” and “ULBP2 antigen” are used interchangeably herein, and include any variants, isoforms and species homologs of human ULBP2 which are naturally expressed by cells or are expressed on cells transfected with the ULBP2 gene. Binding of an antibody of the disclosure to the ULBP2 antigen mediate the killing of cells expressing ULBP2 (e.g., a tumor cell) by inactivating ULBP2. The killing of the cells expressing ULBP2 may occur by one or more of the following mechanisms: Cell death / apoptosis induction, ADCC and CDC.

[0055] The term “anti-ULBP2 antibody” according to the disclosure is an antibody that binds specifically to ULBP2 antigen. Depending on binding properties and biological activities of anti-ULBP2 antibodies to the ULBP2 antigen, two types of anti-ULBP2 antibodies (type I and type II anti-ULBP2 antibodies) can be distinguished according to Cragg, M. S., et al., Blood 103 (2004) 2738-2743; and Cragg, M. S„ et al., Blood 101 (2003) 1045-1052.

[0056] In some instances, ULBP2 may be expressed in low copy number on the target cell (e.g. tumor cell). For example, in some instances, ULBP2 is expressed or present at less than35,000 copies per target cell. In some embodiments, the low copy number cell surface ULBP2 is present between 100 and 35,000 copies per target cell; between 100 and 30,000 copies per target cell; between 100 and 25,000 copies per target cell; between 100 and 20,000 copies per target cell; between 100 and 15,000 copies per target cell; between 100 and 10,000 copies per target cell; between 100 and 5,000 copies per target cell; between 100 and 2,000 copies per target cell; between 100 and 1,000 copies per target cell; or between 100 and 500 copies per target cell. Copy number of the cell surface ULBP2 can be determined, for example, using a standard Scratchcard plot.

[0057] ULBP2 is broadly and differentially expressed in multiple solid tumor indications. ULBP2 expression in melanoma and breast cancer is associated with poor prognosis and latestage disease. The present disclosure is the first to demonstrate that ULBP2 is highly expressed in bladder cancers including but not limited to, transitional cell carcinoma, basal cell cancer, squamous cell cancer, basal-squamous cell cancer, adenocarcinoma, metastatic cancer, and carcinosarcoma. In particular, ULBP2 is highly expressed basal molecular lineages of bladder cancer and squamous molecular lineages of bladder cancer.

[0058] Senescence is a stress-induced cellular state that limits tumorigenesis by preventing cell proliferation and promoting immune-mediated clearance of damaged cells through the induction of senescence-associated secretory phenotype (SASP) (Rodier, F. et al. Persistent DNA damage signaling triggers senescence-associated inflammatory cytokine secretion. Nat. Cell Biol. 11, 973-979 (2009)). Senescence is also implicated in age-related tissue pathologies where the accumulation of SASP-positive cells can induce tissue inflammation resulting in tissue dysfunction that manifests in aged patients as arthritis, autoimmunity, diabetes, fibrosis, and delayed wound healing (Childs, B. G. et al. Senescent cells: an emerging target for diseases of ageing. Nat. Rev. Drug Discov. 16, 718-735 (2017)). SASP- positive cells express a complex assortment of both secreted and cell surface proteins including immune-activating cytokines, tissue remodeling matrix metalloprotease, and cell surface proteins that include MHCI-like NKG2D ligands that mediate the recognition and activation of NK and T cell effectors through NKG2D costimulatory receptors. These proteins together promote the elimination of senescent cells. However, age-related decline in immune cell activities and other factors like chemotherapy treatment of cancer accelerates the induction of SASP-positive cells in tissues and limits the clearance of senescent cells by theimmune system (Jackola, D. R., Ruger, J. K. & Miller, R. A. Age-associated changes in human T cell phenotype and function. Aging Clin. Exp. Res. 6, 25-34 (1994); Demaria, M. et al. Cellular Senescence Promotes Adverse Effects of Chemotherapy and Cancer Relapse. Cancer Discov. 7, 165-176 (2017)). Therapeutic strategies to eliminate SASP-positive cells provide an opportunity to supplement senescent immuno surveillance and alleviate an underlying etiology of many age-related diseases and lasting side effects of chemotherapy. In addition, the clearance of senescent cells cannot only reduce age-related disease, but these senolytic drugs also have the potential to extend life span (Baker, D. J. et al. Naturally occurring pl6Ink4a-positive cells shorten healthy lifespan. Nature 530, 184-189 (2016); Baker, D. J. et al. Clearance of pl6Ink4a-positive senescent cells delays ageing-associated disorders. Nature 479, 232-236 (2011)). ULBP2, an MHCI-like ligand, has emerged as a cell surface protein associated with stress-induced SASP-positive fibroblasts and cancer cells (Sagiv, A. et al. NKG2D ligands mediate immuno surveillance of senescent cells. Aging 8, 328-344 (2016); Ruscetti, M. et al. NK cell-mediated cytotoxicity contributes to tumor control by a cytostatic drug combination. Science 362, 1416-1422 (2018); Munoz, D. P. et al. Targetable mechanisms driving immunoevasion of persistent senescent cells link chemotherapy-resistant cancer to aging. JCI Insight 5, el24716, 124716 (2019)). ULBP2 or ULBP2 / 5 / 6 targeted drugs, in addition to eradicating cancer cells, have the potential to eliminate SASP-positive cells from tissues with the potential to improve tissue function which can prevent age-related disease and extend life span.

[0059] ULBP2 encompasses naturally occurring variants of ULBP2, including, for example, splice variants or allelic variants. ULBP2 includes, for example, human ULBP2 protein (UniProt ID: Q9BZM5), which is 246 amino acids in length.

[0060] In one aspect, the disclosure provides isolated antibodies that bind to ULBP2. In some instances the anti-ULBP2 antibody binds to a human ULBP2 polypeptide or a portion thereof. In some embodiments, the human ULBP2 polypeptide comprises the amino acid sequence of SEQ ID NO: 421.MAAAAATKIL LCLPLLLLLS GW S RAGRAD P HSLCYDI TVIPKFRPGPRWC AVQGQVDEKT FLHYDCGNKT VTPVSPLGKK LNVTTAWKAQ NPVLREWDI LTEQLRDIQL ENYTPKEPLT LQARMSCEQK AEGHS SGSWQ FSFDGQIFLL FDSEKRMWTT VHPGARKMKE KWENDKWAM SFHYFSMGDC IGWLEDFLMGMDSTLEP SAG APLAMS SGTT QLRATATTLI LCCLLI ILPCFILPGI SEQ ID NO : 421 )

[0061] ULBP5 (RAET1G) encompasses naturally occurring variants of ULBP5, including, for example, splice variants or allelic variants. ULBP5 includes, for example, human ULBP5 protein (UniProt ID: Q6H3X3), which is 334 amino acids in length.

[0062] In one aspect, the disclosure provides isolated antibodies that bind to ULBP5 (RAET1G). In some instances the anti-ULBP5 antibody binds to a human ULBP5 polypeptide or a portion thereof. In some embodiments, the human ULBP5 polypeptide comprises the amino acid sequence of SEQ ID NO: 422.MAAAASPAFL LRLPLLLLLS SWCRTGLADP HSLCYDITVIPKFRPGPRWC AVQGQVDEKT FLHYDCGSKT VTPVSPLGKKLNVTTAWKAQ NPVLREWDI LTEQLLDIQL ENYIPKEPLTLQARMSCEQK AEGHGSGSWQ LSFDGQIFLL FDSENRMWTTVHPGARKMKE KWENDKDMTM SFHYI SMGDC TGWLEDFLMGMDSTLEPSAG APPTMSSGTA QPRATATTLI LCCLLIMCLLICSRHSLTQS HGHHPQSLQP PPHPPLLHPT WLLRRVLWSDSYQIAKRPLS GGHVTRVTLP I IGDDSHSLP CPLALYTINNGAARYSEPLQ VSI S SEQ ID NO : 422 )

[0063] ULBP6 (RAET1L) encompasses naturally occurring variants of ULBP6, including, for example, splice variants or allelic variants. ULBP6 includes, for example, human ULBP6 protein (UniProt ID: Q5VY80), which is 246 amino acids in length.

[0064] In one aspect, the disclosure provides isolated antibodies that bind to ULBP6 (RAET1L). In some instances the anti-ULBP6 antibody binds to a human ULBP6 polypeptide or a portion thereof. In some embodiments, the human ULBP6 polypeptide comprises the amino acid sequence of SEQ ID NO: 423.MAAAAIPALL LCLPLLFLLF GWSRARRDDP HSLCYDITVIPKFRPGPRWC AVQGQVDEKT FLHYDCGNKT VTPVSPLGKKLNVTMAWKAQ NPVLREWDI LTEQLLDIQL ENYTPKEPLTLQARMSCEQK AEGHSSGSWQ FSIDGQTFLL FDSEKRMWTTVHPGARKMKE KWENDKDVAM SFHYI SMGDC TGWLEDFLMGMDSTLEPSAG APLAMSSGTT QLRATATTLI LCCLLI ILPCFILPGI ( SEQ ID NO : 423 )Anti-ULBP2 / 5 / 6 Antibodies

[0065] Provided herein are antibodies that bind to anti-ULBP2 / 5 / 6. In some embodiments, alanine scanning mutagenesis may be performed on the “E12” anti-ULBP2 / 5 / 6 antibody to produce affinity modulated anti-ULBP2 / 5 / 6 antibodies. Also provided herein are antibodies that bind to anti-ULBP2. In some embodiments, alanine scanning mutagenesis may beperformed on the “A06” anti-ULBP2 antibody to produce affinity modulated anti-ULBP2 antibodies. / W)66J\\\ some embodiments, an anti-ULBP2 / 5 / 6 antibody of the disclosure comprises any one of the VH and VL sequences listed in Table 1. In Table 1, the underlined sequences are CDR sequence according to Kabat and the bolded sequences are CDR sequences according to Chothia.

[0067] In some embodiments, an anti-ULBP2 antibody of the disclosure comprises: a) a heavy chain variable region (VH) comprising a VH complementarity determining region 1 (VHCDRI), a VH complementarity determining region 2 (VHCDR2) and a VH complementarity determining region 3 (VHCDRI); and b) a light chain variable region (VL) comprising a VL complementarity determining region 1 (VLCDRI), a VL complementarity determining region 2 (VLCDR2) and a VL complementarity determining region 3 (VLCDRI). Tables 2 and 3 provide exemplary CDR sequences of the anti-ULBP2 antibodies provided herein.Table 1. Exemplary Anti-ULBP2 / 5 / 6 Variable Heavy Chain and Variable Light ChainDomainsTable 2. Exemplary Anti-ULBP2 / 5 / 6 Heavy Chain CDRsTable 3. Exemplary Anti-ULBP2 / 5 / 6 Light Chain CDRs

[0068] In some embodiments, the disclosure provides an antibody (e.g. including antibody fragments, such as single chain variable fragments (scFvs) which specifically bind to ULBP2,wherein the antibody comprises a) a heavy chain variable region (VH) comprising a i) a VH complementarity determining region 1 (VHCDRI) comprising the amino acid sequence of SEQ ID NO: 5 or 6, ii) a VH complementarity determining region 2 (VHCDR2) comprising the amino acid sequence of SEQ ID NO: 7 or 8, iii) a VH complementarity determining region 3 (VHCDRS) comprising the amino acid sequence of SEQ ID NO: 9; and b) a light chain variable region (VL) comprising a i) a VL complementarity determining region 1 (VLCDRI) comprising the amino acid sequence of SEQ ID NO: 10, ii) a VL complementarity determining region 2 (VLCDR2) comprising the amino acid sequence of SEQ ID NO: 11, iii) a VL complementarity determining region 3 (VLCDRS) comprising the amino acid sequence of SEQ ID NO: 12.

[0069] Exemplary anti-ULBP2 antibodies of the disclosure include ULBP2-01, ULBP2-02, E12, A06.

[0070] In some embodiments, the anti-ULBP2 antibody ULBP2-01 has a VH region comprising a VHCDRI comprising the amino acid sequence of SEQ ID NO: 5, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 7, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 9; and a VL region comprising a VLCDRI comprising the amino acid sequence of SEQ ID NO: 10, a VLCDR2 comprising the amino acid sequence of SEQ ID NO: 11, and a VLCDR3 comprising the amino acid sequence of SEQ ID NO: 12.

[0071] In some embodiments, the anti-ULBP2 antibody ULBP2-01 has a VH region comprising the amino acid sequence shown in SEQ ID NO: 2 and a VL region comprising the amino acid sequence shown in SEQ ID NO: 1.

[0072] In some embodiments, the anti-ULBP2 antibody ULBP2-02 has a VH region comprising a VHCDRI comprising the amino acid sequence of SEQ ID NO: 5, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 7, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 9; and a VL region comprising a VLCDRI comprising the amino acid sequence of SEQ ID NO: 10, a VLCDR2 comprising the amino acid sequence of SEQ ID NO: 11, and a VLCDR3 comprising the amino acid sequence of SEQ ID NO: 12.

[0073] In some embodiments, the anti-ULBP2 antibody ULBP2-02 has a VH region comprising the amino acid sequence shown in SEQ ID NO: 4 and a VL region comprising the amino acid sequence shown in SEQ ID NO: 3.

[0074] In some embodiments, the anti-ULBP2 antibody E12 has a VH region comprising a VHCDRI comprising the amino acid sequence of SEQ ID NO: 5, a VHCDR2 comprising theamino acid sequence of SEQ ID NO: 7, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 9; and a VL region comprising a VLCDRI comprising the amino acid sequence of SEQ ID NO: 10, a VLCDR2 comprising the amino acid sequence of SEQ ID NO: 11, and a VLCDR3 comprising the amino acid sequence of SEQ ID NO: 12.

[0075] In some embodiments, the anti-ULBP2 antibody E12 has a VH region comprising the amino acid sequence shown in SEQ ID NO: 425 and a VL region comprising the amino acid sequence shown in SEQ ID NO: 424.

[0076] In some embodiments, the anti-ULBP2 antibody A06 has a VH region comprising a VHCDRI comprising the amino acid sequence of SEQ ID NO: 428, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 430, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 432; and a VL region comprising a VLCDRI comprising the amino acid sequence of SEQ ID NO: 433, a VLCDR2 comprising the amino acid sequence of SEQ ID NO: 434, and a VLCDR3 comprising the amino acid sequence of SEQ ID NO: 435.

[0077] In some embodiments, the anti-ULBP2 antibody A06 has a VH region comprising the amino acid sequence shown in SEQ ID NO: 427 and a VL region comprising the amino acid sequence shown in SEQ ID NO: 426.Bispecific Anti-ULBP2 / 5 / 6 Antibodies

[0078] Provided herein are bispecific antibodies comprising a first antigen binding domain that binds a first antigen (e.g. cell surface antigen, CD3s) and a second antigen binding domain that binds to a second antigen (e.g. ULBP2 / 5 / 6).

[0079] In some embodiments the bispecific antibody has the following structure: a first heavy chain polypeptide (Hl) comprising a variable region (VH1), and a constant region (CHI) having a constant region 1 domain (CH1H1), a hinge region (H1H), a constant region 2 domain (CH1H2) and a constant region 3 domain (CH1H3); and a first light chain polypeptide (LI) comprising a variable region (VL1) and a constant region (CL1), and a second heavy chain polypeptide (H2) comprising a variable region (VH2), and a constant region (CH2) having a constant region 1 domain (CH2H1), a hinge region (H2H), a constant region 2 domain (CH2H2) and a constant region 3 domain (CH2H3); and second light chain polypeptide (L2) comprising a variable region (VL2) and a constant region (CL2).

[0080] In some embodiments, the bispecific antibody of the disclosure comprises a second antigen binding domain (e.g. binding to ULBP2 / 5 / 6) comprising any one of the VH2 and VL2sequences listed in Table 1. In Table 1, the underlined sequences are CDR sequence according to Kabat and the bolded sequences are CDR sequences according to Chothia.

[0081] In some embodiments, the bispecific antibody of the disclosure comprises a second antigen binding domain (e.g. binding to ULBP2) comprising: a) a heavy chain variable region (VH2) comprising a VH complementarity determining region 1 (VH2CDR1), a VH complementarity determining region 2 (VH2CDR2) and a VH2 complementarity determining region 3 (VH2CDR3); and b) a light chain variable region (VL2) comprising a VL complementarity determining region 1 (VL2CDR1), a VL complementarity determining region 2 (VL2CDR2) and a VL complementarity determining region 3 (VL2CDR3). Tables 11 and 12 provide exemplary CDR sequences of the anti-ULBP2 antibodies provided herein.

[0082] In some embodiments, the bispecific antibody comprises any one of the anti- ULBP2 / 5 / 6 antibodies of the disclosure. Exemplary anti-ULBP2 / 5 / 6 antibodies of the disclosure include ULBP2-01, ULBP2-02 and E12. In some embodiments, the bispecific antibody comprises any one of the anti-ULBP2 antibodies of the disclosure. Exemplary anti- ULBP2 antibodies of the disclosure include A06.

[0083] In some embodiments, the disclosure provides an isolated antibody (e.g. monospecific antibody or bispecific antibody) which specifically binds to ULPB2 / 5 / 6 and competes with any of the foregoing antibodies.

[0084] In some embodiments, the present disclosure provides an antibody (e.g. monospecific antibody or bispecific antibody) that binds to ULBP2 / 5 / 6 and competes with an antibody as described herein, including ULBP2-01, ULBP2-02, A06 and E12.

[0085] In some embodiments, the disclosure also provides CDR portions of antibodies to ULBP2 / 5 / 6 antibodies based on CDR contact regions. CDR contact regions are regions of an antibody that imbue specificity to the antibody for an antigen. In general, CDR contact regions include the residue positions in the CDRs and Vernier zones which are constrained in order to maintain proper loop structure for the antibody to bind a specific antigen. See, e.g., Makabe et al., J. Biol. Chem., 283:1156-1166, 2007. Determination of CDR contact regions is well within the skill of the art.

[0086] The binding affinity (KD) of the ULBP2 / 5 / 6 antibody (e.g. monospecific antibody or bispecific antibody) as described herein to ULBP2 / 5 / 6 (such as human ULBP2 (e.g., (SEQID NO: 421), ULBP5 (SEQ ID NO: 422), ULBP6 (SEQ ID NO: 423)) can be about 0.001 to about 5000 nM.

[0087] In some embodiments, the binding affinity is about any of 5000 nM, 4500 nM, 4000 nM, 3500 nM, 3000 nM, 2500 nM, 2000 nM, 1789 nM, 1583 nM, 1540 nM, 1500 nM, 1490 nM, 1064 nM, 1000 nM, 933 nM, 894 nM, 750 nM, 705 nM, 678 nM, 532 nM, 500 nM, 494 nM, 400 nM, 349 nM, 340 nM, 353 nM, 300 nM, 250 nM, 244 nM, 231 nM, 225 nM, 207 nM, 200 nM, 186 nM, 172 nM, 136 nM, 113 nM, 104 nM, 101 nM, 100 nM, 90 nM, 83 nM, 79 nM, 74 nM, 54 nM, 50 nM, 45 nM, 42 nM, 40 nM, 35 nM, 32 nM, 30 nM, 25 nM, 24 nM, 22 nM, 20 nM, 19 nM, 18 nM, 17 nM, 16 nM, 15 nM, 12 nM, 10 nM, 9 nM, 8 nM, 7.5 nM, 7 nM, 6.5 nM, 6 nM, 5.5 nM, 5 nM, 4 nM, 3 nM, 2 nM, 1 nM, 0.5 nM, 0.3 nM, 0.1 nM, 0.01 nM, or 0.001 nM.

[0088] In some embodiments, the binding affinity is less than about any of 5000 nM, 4000 nM, 3000 nM, 2000 nM, 1000 nM, 900 nM, 800 nM, 250 nM, 200 nM, 100 nM, 50 nM, 30 nM, 20 nM, 10 nM, 7.5 nM, 7 nM, 6.5 nM, 6 nM, 5 nM, 4.5 nM, 4 nM, 3.5 nM, 3 nM, 2.5 nM, 2 nM, 1.5 nM, 1 nM, or 0.5 nM.

[0089] In some embodiments, the disclosure provides a nucleic acid encoding any of the foregoing isolated anti-ULBP2 / 5 / 6 antibodies (e.g. monospecific antibody or bispecific antibody). In some embodiments, the disclosure provides a vector comprising such a nucleic acid. In some embodiments, the disclosure provides a host cell comprising such a nucleic acid.CD3 Antibodies

[0090] In some embodiments, the disclosure provides anti-CD3 antibodies. In some embodiments, the anti-CD3 antibodies are multispecific (e.g., bispecific) and bind, in addition to CD3 or a fragment thereof, a second biological molecule (e.g., a cell surface antigen, e.g., a disease associated antigen ). Antibodies of the disclosure are useful, for example, for treating or delaying the progression of a cell proliferative disorder (e.g., cancer) or an autoimmune disorder, or for enhancing immune function in a subject having such a disorder.

[0091] The term “cluster of differentiation 3” or “CD3,” as used herein, refers to any native CD3 from any vertebrate source, including mammals such as primates (e.g. humans, cynomolgus monkey) and rodents (e.g., mice and rats), unless otherwise indicated, including,for example, CD3s, CD3y, CD3a, and CD3P chains. CD3 is a cell surface complex expressed on T cells in association with the T cell receptor. The CD3 complex is required for the activation of CD8+ and CD4+ T lymphocytes. It is formed of three different but highly related chains: one CD3 gamma chain, one CD3 delta chain, and two CD3 epsilon chains, which associate with each other to form a CD3 epsilon / gamma heterodimer, and a CD3 epsilon / delta heterodimer. The two CD3 heterodimers, together with the T cell receptor (TCR) and the signal-transducing zeta chain homodimer form the T cell receptor complex.

[0092] The term encompasses “full-length” unprocessed CD3 (e.g., unprocessed or unmodified CD3s or CD3y), as well as any form of CD3 that results from processing in the cell. The term also encompasses naturally occurring variants of CD3, including, for example, splice variants or allelic variants. CD3 includes, for example, human CD3s protein (NCBI RefSeq No. NP_000724), which is 207 amino acids in length.

[0093] In some embodiments, the disclosure provides isolated antibodies that bind to CD3. In some embodiments, the disclosure provides antibodies that bind to CD3s. In some instances the anti-CD3s antibody binds to a human CD3s polypeptide or a cynomolgus monkey (cyno) CD3s polypeptide. In some instances, the human CD3 polypeptide or the cyno CD3 polypeptide is a human CD3s polypeptide (SEQ ID NO: 419) or a cyno CD3s polypeptide (SEQ ID NO: 420), respectively. In some instances, the anti-CD3 antibody binds to an epitope within a fragment of CD3s (e.g., human CD3s) consisting of amino acid residues 1-26 or amino acid residues 1-27 of human CD3s (SEQ ID NO: 419).

[0094] A useful method for identification of residues or regions of an antibody that may be targeted for mutagenesis is called “alanine scanning mutagenesis” as described by Cunningham and Wells (1989) Science, 244:1081-1085. In this method, a residue or group of target residues (e.g., charged residues such as Arg, Asp, His, Lys, and Glu) are identified and replaced by a neutral or negatively charged amino acid (e.g., alanine or polyalanine) to determine whether the interaction of the antibody with antigen is affected. Further substitutions may be introduced at the amino acid locations demonstrating functional sensitivity to the initial substitutions. Alternatively, or additionally, a crystal structure of an antigen-antibody complex is used to identify contact points between the antibody and antigen. Such contact residues and neighboring residues may be targeted or eliminated ascandidates for substitution. Variants may be screened to determine whether they contain the desired properties.Anti- CD3 s Antibodies

[0095] Provided herein are anti-CD3s antibodies. In some embodiments, alanine scanning mutagenesis was performed on the “SP34” anti-CD3s antibody to produce affinity modulated anti-CD3s antibodies of the disclosure.

[0096] In some embodiments, an anti-CD3s antibody of the disclosure comprises any one of the VH and VL sequences listed in Table 4. In Table 4, the underlined sequences are CDR sequence according to Kabat and the bolded sequences are CDR sequences according to Chothia.

[0097] In some embodiments, an anti-CD3 antibody of the disclosure comprises: a) a heavy chain variable region (VH) comprising a VH complementarity determining region 1 (VHCDRI), a VH complementarity determining region 2 (VHCDR2) and a VH complementarity determining region 3 (VHCDRI); and b) a light chain variable region (VL) comprising a VL complementarity determining region 1 (VLCDRI), a VL complementarity determining region 2 (VLCDR2) and a VL complementarity determining region 3 (VLCDRI). Tables 8 and 9 provide exemplary CDR sequences of the anti-CD3 antibodies provided herein.Table 4. Anti-CD3 Variable Heavy Chain and Variable Light Chain DomainsTable 5. Anti-CD3 Heavy Chain CDRsTable 6. Anti-CD3 Light Chain CDRs

[0098] In some embodiments, the disclosure provides an antibody (e.g. including antibody fragments, such as single chain variable fragments (scFvs) which specifically bind to CD3s, wherein the antibody comprises a) a heavy chain variable region (VH) comprising a i) a VH complementarity determining region 1 (VHCDRI) comprising the amino acid sequence of SEQ ID NO: 29, 30, 31, 32 or 33, ii) a VH complementarity determining region 2 (VHCDR2) comprising the amino acid sequence of SEQ ID NO: 34, 35 or 36, iii) a VH complementarity determining region 3 (VHCDRI) comprising the amino acid sequence of SEQ ID NO: 37, 38, 39, 40 or 41 ; and b) a light chain variable region (VL) comprising a i) i) a VL complementarity determining region 1 (VLCDRI) comprising the amino acid sequence of SEQ ID NO: 42, ii) a VL complementarity determining region 2 (VLCDR2) comprising the amino acid sequence of SEQ ID NO: 43 or 44, iii) a VL complementarity determining region 3 (VLCDRI) comprising the amino acid sequence of SEQ ID NO: 45, 46, 47 or 48.

[0099] Exemplary anti-CD3 antibodies of the disclosure include CD3-A1, CD3-A2, CD3- A3, CD3-A4, CD3-A5, CD3-A6, CD3-A7, CD3-A8, CD3-A9, CD3-A10, CD3-A11, CD3- A12 and CD3-A13.

[0100] In some embodiments, the anti-CD3 antibody CD3-A1 comprises a VH region comprising a VHCDRI comprising the amino acid sequence of SEQ ID NO: 29, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 34, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 37; and a VL region comprising a VLCDRI comprising the amino acid sequence of SEQ ID NO: 42, a VLCDR2 comprising the amino acid sequence of SEQ ID NO: 43, and a VLCDR3 comprising the amino acid sequence of SEQ ID NO: 46.

[0101] In some embodiments, the anti-CD3 antibody CD3-A1 comprises a VH region comprising the amino acid sequence shown in SEQ ID NO: 13 and a VL region comprising the amino acid sequence shown in SEQ ID NO: 25.

[0102] In some embodiments, the anti-CD3 antibody CD3-A2 comprises a VH region comprising a VHCDRI comprising the amino acid sequence of SEQ ID NO: 29, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 34, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 37; and a VL region comprising a VLCDRI comprising the amino acid sequence of SEQ ID NO: 42, a VLCDR2 comprising the amino acid sequence of SEQ ID NO: 44, and a VLCDR3 comprising the amino acid sequence of SEQ ID NO: 45.

[0103] In some embodiments, the anti-CD3 antibody CD3-A2 comprises a VH region comprising the amino acid sequence shown in SEQ ID NO: 13 and a VL region comprising the amino acid sequence shown in SEQ ID NO: 27.

[0104] In some embodiments, the anti-CD3 antibody CD3-A3 comprises a VH region comprising a VHCDRI comprising the amino acid sequence of SEQ ID NO: 29, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 34, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 37; and a VL region comprising a VLCDRI comprising the amino acid sequence of SEQ ID NO: 42, a VLCDR2 comprising the amino acid sequence of SEQ ID NO: 43, and a VLCDR3 comprising the amino acid sequence of SEQ ID NO: 45.

[0105] In some embodiments, the anti-CD3 antibody CD3-A3 comprises a VH region comprising the amino acid sequence shown in SEQ ID NO: 14 and a VL region comprising the amino acid sequence shown in SEQ ID NO: 23.

[0106] In some embodiments, the anti-CD3 antibody CD3-A4 comprises a VH region comprising a VHCDRI comprising the amino acid sequence of SEQ ID NO: 29, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 34, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 38; and a VL region comprising a VLCDRI comprising the amino acid sequence of SEQ ID NO: 42, a VLCDR2 comprising the amino acid sequence of SEQ ID NO: 43, and a VLCDR3 comprising the amino acid sequence of SEQ ID NO: 47.

[0107] In some embodiments, the anti-CD3 antibody CD3-A4 comprises a VH region comprising the amino acid sequence shown in SEQ ID NO: 15 and a VL region comprising the amino acid sequence shown in SEQ ID NO: 26.

[0108] In some embodiments, the anti-CD3 antibody CD3-A5 comprises a VH region comprising a VHCDRI comprising the amino acid sequence of SEQ ID NO: 29, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 34, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 39; and a VL region comprising a VLCDRI comprising theamino acid sequence of SEQ ID NO: 42, a VLCDR2 comprising the amino acid sequence of SEQ ID NO: 43, and a VLCDR3 comprising the amino acid sequence of SEQ ID NO: 47.

[0109] In some embodiments, the anti-CD3 antibody CD3-A5 comprises a VH region comprising the amino acid sequence shown in SEQ ID NO: 16 and a VL region comprising the amino acid sequence shown in SEQ ID NO: 26.

[0110] In some embodiments, the anti-CD3 antibody CD3-A6 comprises a VH region comprising a VHCDRI comprising the amino acid sequence of SEQ ID NO: 30, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 34, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 37; and a VL region comprising a VLCDRI comprising the amino acid sequence of SEQ ID NO: 42, a VLCDR2 comprising the amino acid sequence of SEQ ID NO: 43, and a VLCDR3 comprising the amino acid sequence of SEQ ID NO: 45.

[0111] In some embodiments, the anti-CD3 antibody CD3-A6 comprises a VH region comprising the amino acid sequence shown in SEQ ID NO: 17 and a VL region comprising the amino acid sequence shown in SEQ ID NO: 22.

[0112] In some embodiments, the anti-CD3 antibody CD3-A7 comprises a VH region comprising a VHCDRI comprising the amino acid sequence of SEQ ID NO: 29, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 35, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 38; and a VL region comprising a VLCDRI comprising the amino acid sequence of SEQ ID NO: 42, a VLCDR2 comprising the amino acid sequence of SEQ ID NO: 43, and a VLCDR3 comprising the amino acid sequence of SEQ ID NO: 45.

[0113] In some embodiments, the anti-CD3 antibody CD3-A7 comprises a VH region comprising the amino acid sequence shown in SEQ ID NO: 18 and a VL region comprising the amino acid sequence shown in SEQ ID NO: 22.

[0114] In some embodiments, the anti-CD3 antibody CD3-A8 comprises a VH region comprising a VHCDRI comprising the amino acid sequence of SEQ ID NO: 29, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 35, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 38; and a VL region comprising a VLCDRI comprising the amino acid sequence of SEQ ID NO: 42, a VLCDR2 comprising the amino acid sequence of SEQ ID NO: 43, and a VLCDR3 comprising the amino acid sequence of SEQ ID NO: 47.

[0115] In some embodiments, the anti-CD3 antibody CD3-A8 comprises a VH region comprising the amino acid sequence shown in SEQ ID NO: 18 and a VL region comprising the amino acid sequence shown in SEQ ID NO: 26.

[0116] In some embodiments, the anti-CD3 antibody CD3-A9 comprises a VH region comprising a VHCDRI comprising the amino acid sequence of SEQ ID NO: 29, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 34, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 40; and a VL region comprising a VLCDRI comprising the amino acid sequence of SEQ ID NO: 42, a VLCDR2 comprising the amino acid sequence of SEQ ID NO: 43, and a VLCDR3 comprising the amino acid sequence of SEQ ID NO: 47.

[0117] In some embodiments, the anti-CD3 antibody CD3-A9 comprises a VH region comprising the amino acid sequence shown in SEQ ID NO: 19 and a VL region comprising the amino acid sequence shown in SEQ ID NO: 26.

[0118] In some embodiments, the anti-CD3 antibody CD3-A10 comprises a VH region comprising a VHCDRI comprising the amino acid sequence of SEQ ID NO: 29, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 34, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 41; and a VL region comprising a VLCDRI comprising the amino acid sequence of SEQ ID NO: 42, a VLCDR2 comprising the amino acid sequence of SEQ ID NO: 43, and a VLCDR3 comprising the amino acid sequence of SEQ ID NO: 47.

[0119] In some embodiments, the anti-CD3 antibody CD3-A10 comprises a VH region comprising the amino acid sequence shown in SEQ ID NO: 20 and a VL region comprising the amino acid sequence shown in SEQ ID NO: 26.

[0120] In some embodiments, the anti-CD3 antibody CD3-A11 comprises a VH region comprising a VHCDRI comprising the amino acid sequence of SEQ ID NO: 31, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 34, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 37; and a VL region comprising a VLCDRI comprising the amino acid sequence of SEQ ID NO: 42, a VLCDR2 comprising the amino acid sequence of SEQ ID NO: 43, and a VLCDR3 comprising the amino acid sequence of SEQ ID NO: 45.

[0121] In some embodiments, the anti-CD3 antibody CD3-A11 comprises a VH region comprising the amino acid sequence shown in SEQ ID NO: 21 and a VL region comprising the amino acid sequence shown in SEQ ID NO: 22.

[0122] In some embodiments, the anti-CD3 antibody CD3-A12 comprises a VH region comprising a VHCDRI comprising the amino acid sequence of SEQ ID NO: 29, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 34, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 37; and a VL region comprising a VLCDRI comprising the amino acid sequence of SEQ ID NO: 42, a VLCDR2 comprising the amino acid sequence of SEQ ID NO: 43, and a VLCDR3 comprising the amino acid sequence of SEQ ID NO: 45.

[0123] In some embodiments, the anti-CD3 antibody CD3-A12 comprises a VH region comprising the amino acid sequence shown in SEQ ID NO: 13 and a VL region comprising the amino acid sequence shown in SEQ ID NO: 24.

[0124] In some embodiments, the anti-CD3 antibody CD3-A13 comprises a VH region comprising a VHCDRI comprising the amino acid sequence of SEQ ID NO: 29, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 34, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 39; and a VL region comprising a VLCDRI comprising the amino acid sequence of SEQ ID NO: 42, a VLCDR2 comprising the amino acid sequence of SEQ ID NO: 43, and a VLCDR3 comprising the amino acid sequence of SEQ ID NO: 48.

[0125] In some embodiments, the anti-CD3 antibody CD3-A13 comprises a VH region comprising the amino acid sequence shown in SEQ ID NO: 16 and a VL region comprising the amino acid sequence shown in SEQ ID NO: 28.Bispecific Anti-CD3s Antibodies

[0126] Provided herein are bispecific antibodies comprising a first antigen binding domain that binds a first antigen (e.g. CD3s) and a second antigen binding domain that binds to a second antigen (e.g. disease associated antigen).

[0127] In some embodiments the bispecific antibody has the following structure: a first heavy chain polypeptide (Hl) comprising a variable region (VH1), and a constant region (CHI) having a constant region 1 domain (CHIHI), a hinge region (H1H), a constant region 2 domain (CH1H2) and a constant region 3 domain (CH I m); and a first light chain polypeptide (LI) comprising a variable region (VL1) and a constant region (CL1), and a second heavy chain polypeptide (H2) comprising a variable region (VH2), and a constant region (CH2) having a constant region 1 domain (CH2HI), a hinge region (H2H), a constant region 2 domain (CH2H2) and a constant region 3 domain (CH2H3); and second light chain polypeptide (L2) comprising a variable region (VL2) and a constant region (CL2).

[0128] In some embodiments, the bispecific antibody of the disclosure comprises a first antigen binding domain (e.g. binding to CD3) comprising any one of the VH1 and VL1 sequences listed in Table 4. In Table 4, the underlined sequences are CDR sequence according to Kabat and the bolded sequences are CDR sequences according to Chothia.

[0129] In some embodiments, the bispecific antibody of the disclosure comprises a first antigen binding domain (e.g. binding to CD3s) comprising: a) a heavy chain variable region (VH1) comprising a VH complementarity determining region 1 (VHICDRI), a VH complementarity determining region 2 (VH1CDR2) and a VH complementarity determining region 3 (VHICDRS); and b) a light chain variable region (VL) comprising a VL complementarity determining region 1 (VLICDRI), a VL complementarity determining region 2 (VL1CDR2) and a VL complementarity determining region 3 (VLICDRS). Tables 8 and 9 provide exemplary CDR sequences of the anti-CD3 antibodies provided herein.

[0130] In some embodiments, the bispecific antibody comprises any one of the anti-CD3 antibodies of the disclosure. Exemplary anti-CD3 antibodies of the disclosure include CD3- Al, CD3-A2, CD3-A3, CD3-A4, CD3-A5, CD3-A6, CD3-A7, CD3-A8, CD3-A9, CD3-A10, CD3-A11, CD3-A12 and CD3-A13.

[0131] In some embodiments, the disclosure provides an isolated antibody (e.g. monospecific antibody or bispecific antibody) which specifically binds to CD3s and competes with any of the foregoing antibodies.

[0132] In some embodiments, the present disclosure provides an antibody (e.g. monospecific antibody or bispecific antibody) that binds to CD3s and competes with an antibody as described herein, including CD3-A1, CD3-A2, CD3-A3, CD3-A4, CD3-A5, CD3-A6, CD3- A7, CD3-A8, CD3-A9, CD3-A10, CD3-A11, CD3-A12 and CD3-A13.

[0133] In some embodiments, the disclosure also provides CDR portions of antibodies to CD3s antibodies based on CDR contact regions. CDR contact regions are regions of an antibody that imbue specificity to the antibody for an antigen. In general, CDR contact regions include the residue positions in the CDRs and Vernier zones which are constrained in order to maintain proper loop structure for the antibody to bind a specific antigen. See, e.g. , Makabe et al., J. Biol. Chem., 283:1156-1166, 2007. Determination of CDR contact regions is well within the skill of the art.

[0134] The binding affinity (KD) of the anti-CD3s antibodies of the disclosure (e.g. monospecific antibody or bispecific antibody) to human CD3s (such as human CD3s (e.g., (SEQ ID NO: 419)) can be about 0.001 to about 5000 nM.

[0135] In some embodiments, the binding affinity is about any of 5000 nM, 4500 nM, 4000 nM, 3500 nM, 3000 nM, 2500 nM, 2000 nM, 1789 nM, 1583 nM, 1540 nM, 1500 nM, 1490 nM, 1064 nM, 1000 nM, 933 nM, 894 nM, 750 nM, 705 nM, 678 nM, 532 nM, 500 nM, 494 nM, 400 nM, 349 nM, 340 nM, 353 nM, 300 nM, 250 nM, 244 nM, 231 nM, 225 nM, 207 nM, 200 nM, 186 nM, 172 nM, 136 nM, 113 nM, 104 nM, 101 nM, 100 nM, 90 nM, 83 nM, 79 nM, 74 nM, 54 nM, 50 nM, 45 nM, 42 nM, 40 nM, 35 nM, 32 nM, 30 nM, 25 nM, 24 nM, 22 nM, 20 nM, 19 nM, 18 nM, 17 nM, 16 nM, 15 nM, 12 nM, 10 nM, 9 nM, 8 nM, 7.5 nM, 7 nM, 6.5 nM, 6 nM, 5.5 nM, 5 nM, 4 nM, 3 nM, 2 nM, 1 nM, 0.5 nM, 0.3 nM, 0.1 nM, 0.01 nM, or 0.001 nM.

[0136] In some embodiments, the binding affinity is less than about any of 5000 nM, 4000 nM, 3000 nM, 2000 nM, 1000 nM, 900 nM, 800 nM, 250 nM, 200 nM, 100 nM, 50 nM, 30 nM, 20 nM, 10 nM, 7.5 nM, 7 nM, 6.5 nM, 6 nM, 5 nM, 4.5 nM, 4 nM, 3.5 nM, 3 nM, 2.5 nM, 2 nM, 1.5 nM, 1 nM, or 0.5 nM.

[0137] The binding affinity (KD) of the anti- CD3s antibodies of the disclosure (e.g. monospecific antibody or bispecific antibody) to cynomolgus CD3s (such as cynomolgus CD3s (e.g., (SEQ ID NO: 422)) can be about 0.001 to about 5000 nM.

[0138] In some embodiments, the binding affinity is about any of 5000 nM, 4500 nM, 4000 nM, 3500 nM, 3000 nM, 2500 nM, 2000 nM, 1789 nM, 1583 nM, 1540 nM, 1500 nM, 1490 nM, 1064 nM, 1000 nM, 933 nM, 894 nM, 750 nM, 705 nM, 678 nM, 532 nM, 500 nM, 494 nM, 400 nM, 349 nM, 340 nM, 353 nM, 300 nM, 250 nM, 244 nM, 231 nM, 225 nM, 207 nM, 200 nM, 186 nM, 172 nM, 136 nM, 113 nM, 104 nM, 101 nM, 100 nM, 90 nM, 83 nM, 79 nM, 74 nM, 54 nM, 50 nM, 45 nM, 42 nM, 40 nM, 35 nM, 32 nM, 30 nM, 25 nM, 24 nM, 22 nM, 20 nM, 19 nM, 18 nM, 17 nM, 16 nM, 15 nM, 12 nM, 10 nM, 9 nM, 8 nM, 7.5 nM, 7 nM, 6.5 nM, 6 nM, 5.5 nM, 5 nM, 4 nM, 3 nM, 2 nM, 1 nM, 0.5 nM, 0.3 nM, 0.1 nM, 0.01 nM, or 0.001 nM.

[0139] In some embodiments, the binding affinity is less than about any of 5000 nM, 4000 nM, 3000 nM, 2000 nM, 1000 nM, 900 nM, 800 nM, 250 nM, 200 nM, 100 nM, 50 nM, 30nM, 20 nM, 10 nM, 7.5 nM, 7 nM, 6.5 nM, 6 nM, 5 nM, 4.5 nM, 4 nM, 3.5 nM, 3 nM, 2.5 nM, 2 nM, 1.5 nM, 1 nM, or 0.5 nM.

[0140] In some embodiments, the disclosure provides a nucleic acid encoding any of the foregoing isolated anti-CD3s antibodies (e.g. monospecific antibody or bispecific antibody). In some embodiments, the disclosure provides a vector comprising such a nucleic acid. In some embodiments, the disclosure provides a host cell comprising such a nucleic acid.Exemplary Bispecific Antibodies That Bind to CD3s and ULBP2 / 5 / 6

[0141] Provided herein are bispecific antibodies comprising a first antigen binding domain that binds a first antigen (e.g. CD3s) and a second antigen binding domain that binds to a second antigen (e.g. ULBP2 / 5 / 6).

[0142] In some embodiments the bispecific antibody has the following structure: a first heavy chain polypeptide (Hl) comprising a variable region (VH1), and a constant region (CHI) having a constant region 1 domain (CHIHI), a hinge region (H1H), a constant region 2 domain (CH1H2) and a constant region 3 domain (CH I ns); and a first light chain polypeptide (LI) comprising a variable region (VL1) and a constant region (CL1), and a second heavy chain polypeptide (H2) comprising a variable region (VH2), and a constant region (CH2) having a constant region 1 domain (CH2HI), a hinge region (H2H), a constant region 2 domain (CH2H2) and a constant region 3 domain (CH2H3); and second light chain polypeptide (L2) comprising a variable region (VL2) and a constant region (CL2).

[0143] In some embodiments, the bispecific antibody of the disclosure comprises a first antigen binding domain (e.g. binding to CD3s) comprising: a) a heavy chain variable region (VH1) comprising a VH complementarity determining region 1 (VHICDRI), a VH complementarity determining region 2 (VH1CDR2) and a VH complementarity determining region 3 (VHICDRS); and b) a light chain variable region (VL) comprising a VL complementarity determining region 1 (VLICDRI), a VL complementarity determining region 2 (VL1CDR2) and a VL complementarity determining region 3 (VLICDRS); and a second antigen binding domain (e.g. binding to ULBP2 / 5 / 6) comprising: a) a heavy chain variable region (VH2) comprising a VH complementarity determining region 1 (VH2CDRI), a VH complementarity determining region 2 (VH2CDR2) and a VH2 complementarity determining region 3 (VH2CDR3); and b) a light chain variable region (VL2) comprising a VL complementarity determining region 1 (VL2CDRI), a VL complementarity determining region2 (VL2CDR2) and a VL complementarity determining region 3 (VL2CDR3). Tables 5 and 6 provide exemplary CDR sequences of the anti-CD3s antibodies provided herein. Tables 2 and 3 provide exemplary CDR sequences of the anti-ULBP2 / 5 / 6 antibodies provided herein.

[0144] In some embodiments, the bispecific antibody of the disclosure comprises a first antigen binding domain (e.g. binding to CD3s) comprising any one of the VH1 and VL1 sequences listed in Table 4 and a second antigen binding domain (e.g. binding to ULBP2 / 5 / 6) comprising any one of the VH2 and VL2 sequences listed in Table 1.

[0145] In some embodiments, the bispecific antibody of the disclosure comprises a first heavy chain polypeptide (Hl) and a first light chain polypeptide (LI); and a second heavy chain polypeptide (H2) and a second light chain polypeptide (L2) comprising any one of the sequences listed in Table 7 and Table 8. The italicized sequences are the heavy chain variable regions and the light chain variable regions. The underlined sequences are CDRs according to Kabat and the bolded sequences are CDRs according to Chothia.

[0146] In some embodiments, the bispecific antibody of the disclosure provided herein comprises a Hl that is 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 at least 100% identical to the amino acid sequence of the Hl sequences listed in Table 7 and Table 8.

[0147] In some embodiments, the bispecific antibody of the disclosure provided herein comprises a LI that is 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 at least 100% identical to the amino acid sequence of the LI sequences listed in Table 7 and Table 8.

[0148] In some embodiments, the bispecific antibody of the disclosure provided herein comprises a H2 that is 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 at least 100% identical to the amino acid sequence of the H2 sequences listed in Table 7 and Table 8.

[0149] In some embodiments, the bispecific antibody of the disclosure provided herein comprises a L2 that is 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 at least 100% identical to the amino acid sequence of the L2 sequences listed in Table 7 and Table 8.

[0150] In some embodiments, the Hl amino acid sequence is numbered in accordance with SEQ ID NO: 439. In some embodiments the LI amino acid sequence is numbered inaccordance with SEQ ID NO: 438. In some embodiments, the H2 amino acid sequence is numbered in accordance with SEQ ID NO: 437. In some embodiments, the L2 amino acid sequence is numbered in accordance with SEQ ID NO: 436.Table 7. Exemplary Bispecific Antibodies that bind CD3s and ULBP2 / 5 / 6

[0151] Exemplary, CD3s x ULBP2 / 5 / 6 bispecific antibodies of the disclosure include EIP0174, EIP0175, EIP0187, EIP0205, EIP0206, EIP0207, EIP0208, EIP0294, EIP0295, EIP0306, EIP0307, EIP0318, EIP0340, EIP0342, EIP0354, EIP0356, EIP0367, EIP0377, EIP0404, EIP0406, EIP0473, and EIP0598.

[0152] Bispecific antibodies EIP0174, EIP0175, EIP0187, EIP0205, EIP0206, EIP0207, EIP0208, EIP0294, EIP0295, EIP0306, EIP0307, EIP0318, EIP0340, EIP0342, EIP0354, EIP0356, EIP0367, EIP0377, EIP0404, EIP0406, EIP0473, and EIP0598 comprise a first antigen binding domain that binds CD3s which comprising a VH1, comprising a VHICDRI having the amino acid sequence of SEQ ID NO: 29; a VH1CDR2 having the amino acid sequence of SEQ ID NO: 34; and a VH1CDR3 having the amino acid sequence of SEQ ID NO: 37; and a VL1, comprising a VLICDRI having the amino acid sequence of SEQ ID NO: 42; a VL1CDR2 having the amino acid sequence of SEQ ID NO: 43; and a VL1CDR3 having the amino acid sequence of SEQ ID NO: 45.

[0153] Bispecific antibodies EIP0174, EIP0175, EIP0187, EIP0205, EIP0206, EIP0207, EIP0208, EIP0294, EIP0295, EIP0306, EIP0307, EIP0318, EIP0340, EIP0342, EIP0354, EIP0356, EIP0367, EIP0377, EIP0404, EIP0406, EIP0473, and EIP0598 comprise a second antigen binding domain that binds ULBP2 / 5 / 6 comprising a VH2, comprising VH2CDRI having the amino acid sequence of SEQ ID NO: 5; a VH2CDR2 having the amino acid sequence of SEQ ID NO: 7; and a VH2CDR3 having the amino acid sequence of SEQ ID NO: 9; and a VL2, having VL2CDRI having the amino acid sequence of SEQ ID NO: 10; a VL2CDR2 having the amino acid sequence of SEQ ID NO: 11; and a VL2CDR3 having the amino acid sequence of SEQ ID NO: 12.

[0154] In addition to the specific complementarity determining regions recited above, the bispecific antibody EIP0174 comprises the following amino acids substitutions in the Hl and LI: the amino acid at position 39 (Kabat numbering) of the VH1 is a K and the amino acid at position 38 (Kabat numbering) of the VL1 is a D; the amino acid at position 185 (EU numbering) of the CHIHI is a K and the amino acid at position 137 (EU numbering) of the CL1 is a D; the amino acid at position 128 (EU numbering) of the CHIHI is a C and the amino acid at position 118 (EU numbering) of the CL1 is a C; the amino acid at position 220 (EU numbering) of the H1H is a S and the amino acid at position 214 (EU numbering) of the CL1is an S; the amino acids at positions 234, 235, and 237 (EU numbering) in the H1H are an A; the amino acid at position 349 (EU numbering) of the CH1H3 is a C; the amino acid at position 366 (EU numbering) of the CH1H3 is a S; the amino acid at position 368 (EU numbering) of the CH1H3 is a A; the amino acid at position 407 (EU numbering) of CH1H3 is a V; and the amino acid at position 447 (EU numbering) of the CHlm is deleted, when numbered in accordance with Hl amino acid sequence of SEQ NO: 439 and LI amino acid sequence of SEQ NO: 438.

[0155] In addition to the specific complementarity determining regions recited above, the bispecific antibody EIP0174 comprises the following amino acids substitutions in the H2 and L2: the amino acid at position 39 (Kabat numbering) of the VH2 is a D and the amino acid at position 38 (Kabat numbering) of the VL2 is a K; the amino acid at position 147 (EU numbering) of the CH2HI is a D and the amino acid at position 180 (EU numbering) of the CL2 is a R; the amino acids at positions 234, 235, and 237 (EU numbering) of the H2H are an A; the amino acid at position 354 (EU numbering) of the CH2H3 is a C; the amino acid at position 366 (EU numbering) of the CH2H3 is a W; and the amino acid at position 447 (EU numbering) of the CH2H3 is deleted, when numbered in accordance with H2 amino acid sequence of SEQ NO: 437 and L2 amino acid sequence of SEQ NO: 436.

[0156] In some embodiments, the bispecific antibody EIP0174 comprises a VH1 comprising the amino acid sequence of SEQ ID NO: 13, a VL1 comprising the amino acid sequence of SEQ ID NO: 22, a VH2 comprising the amino acid sequence of SEQ ID NO: 2, and a VL2 comprising the amino acid sequence of SEQ ID NO: 1.

[0157] In some embodiments, the bispecific antibody EIP0174 comprises a Hl comprising the amino acid sequence of SEQ ID NO: 58, a LI comprising the amino acid sequence of SEQ ID NO: 57, a H2 comprising the amino acid sequence of SEQ ID NO: 56, and a L2 comprising the amino acid sequence of SEQ ID NO: 55.

[0158] In addition to the specific complementarity determining regions recited above, the bispecific antibody EIP0175 comprises the following amino acids substitutions in the Hl and LI: the amino acid at position 39 (Kabat numbering) of the VH1 is a K and the amino acid at position 38 (Kabat numbering) of the VL1 is a D; the amino acid at position 185 (EU numbering) of the CHIHI is a K and the amino acid at position 137 (EU numbering) of the CL1 is a D; the amino acids at positions 234, 235, and 237 (EU numbering) in the H1H arean A; the amino acid at position 349 (EU numbering) of the CH1H3 is a C; the amino acid at position 366 (EU numbering) of the CH1H3 is a S; the amino acid at position 368 (EU numbering) of the CH1H3 is a A; the amino acid at position 407 (EU numbering) of CH1H3 is a V; and the amino acid at position 447 (EU numbering) of the CH1H3 is deleted, when numbered in accordance with Hl amino acid sequence of SEQ NO: 439 and LI amino acid sequence of SEQ NO: 438.

[0159] In addition to the specific complementarity determining regions recited above, the bispecific antibody EIP0175 comprises the following amino acids substitutions in the H2 and L2: the amino acid at position 39 (Kabat numbering) of the VH2 is a D and the amino acid at position 38 (Kabat numbering) of the VL2 is a K; the amino acid at position 147 (EU numbering) of the CH2HI is a D and the amino acid at position 180 (EU numbering) of the CL2 is a R; the amino acid at position 134 (EU numbering) of the CH2HI is a C and the amino acid at position 116 (EU numbering) of the CL2 is a C; the amino acid at position 220 (EU numbering) in the H2H is a S and the amino acid at position 214 (EU numbering) of the CL2 is a S; the amino acids at positions 234, 235, and 237 (EU numbering) of the H2H are an A; the amino acid at position 354 (EU numbering) of the CH2H3 is a C; the amino acid at position 366 (EU numbering) of the CH2H3 is a W; and the amino acid at position 447 (EU numbering) of the CH2H3 is deleted, when numbered in accordance with H2 amino acid sequence of SEQ NO: 437 and L2 amino acid sequence of SEQ NO: 436.

[0160] In some embodiments, the bispecific antibody EIP0175 comprises a VH1 comprising the amino acid sequence of SEQ ID NO: 13, a VH2 comprising the amino acid sequence of SEQ ID NO: 2, a VL1 comprising the amino acid sequence of SEQ ID NO: 22, and a VL2 comprising the amino acid sequence of SEQ ID NO: 1.

[0161] In some embodiments, the bispecific antibody EIP0175 comprises a Hl comprising the amino acid sequence of SEQ ID NO: 62, a H2 comprising the amino acid sequence of SEQ ID NO: 60, a LI comprising the amino acid sequence of SEQ ID NO: 61, and a L2 comprising the amino acid sequence of SEQ ID NO: 59.

[0162] In addition to the specific complementarity determining regions recited above, the bispecific antibody EIP0187 comprises the following amino acids substitutions in the Hl and LI: the amino acid at position 39 (Kabat numbering) of the VH1 is a K and the amino acid at position 38 (Kabat numbering) of the VL1 is a D; the amino acid at position 185 (EUnumbering) of the CHIHI is a K and the amino acid at position 137 (EU numbering) of the CL1 is a D; the amino acids at positions 234, 235, and 237 (EU numbering) in the H1H are an A; the amino acid at position 349 (EU numbering) of the CH1H3 is a C; the amino acid at position 366 (EU numbering) of the CH1H3 is a S; the amino acid at position 368 (EU numbering) of the CH1H3 is a A; the amino acid at position 407 (EU numbering) of CH1H3 is a V; and the amino acid at position 447 (EU numbering) of the CH1H3 is deleted, when numbered in accordance with Hl amino acid sequence of SEQ NO: 439 and LI amino acid sequence of SEQ NO: 438.

[0163] In addition to the specific complementarity determining regions recited above, the bispecific antibody EIP0187 comprises the following amino acids substitutions in the H2 and L2: the amino acid at position 39 (Kabat numbering) of the VH2 is a D and the amino acid at position 38 (Kabat numbering) of the VL2 is a K; the amino acid at position 147 (EU numbering) of the CH2HI is a D and the amino acid at position 180 (EU numbering) of the CL2 is a R; the amino acid at position 136 (EU numbering) of the CH2HI is a C and the amino acid at position 114 (EU numbering) of the CL2 is a C; the amino acid at position 220 (EU numbering) in the H2H is a S and the amino acid at position 214 (EU numbering) of the CL2 is a S; the amino acids at positions 234, 235, and 237 (EU numbering) of the H2H are an A; the amino acid at position 354 (EU numbering) of the CH2H3 is a C; the amino acid at position 366 (EU numbering) of the CH2H3 is a W; and the amino acid at position 447 (EU numbering) of the CH2H3 is deleted, when numbered in accordance with H2 amino acid sequence of SEQ NO: 437 and L2 amino acid sequence of SEQ NO: 436.

[0164] In some embodiments, the bispecific antibody EIP0187 comprises a VH1 comprising the amino acid sequence of SEQ ID NO: 13, a VH2 comprising the amino acid sequence of SEQ ID NO: 2, a VL1 comprising the amino acid sequence of SEQ ID NO: 22, and a VL2 comprising the amino acid sequence of SEQ ID NO: 1.

[0165] In some embodiments, the bispecific antibody EIP0187 comprises a Hl comprising the amino acid sequence of SEQ ID NO: 66, a H2 comprising the amino acid sequence of SEQ ID NO: 64, a LI comprising the amino acid sequence of SEQ ID NO: 65, and a L2 comprising the amino acid sequence of SEQ ID NO: 63.

[0166] In addition to the specific complementarity determining regions recited above, the bispecific antibody EIP0205 comprises the following amino acids substitutions in the Hl andLI: the amino acid at position 39 (Kabat numbering) of the VH1 is a K and the amino acid at position 38 (Kabat numbering) of the VL1 is a D; the amino acid at position 147 (EU numbering) of the CHIHI is a K and the amino acid at position 131 (EU numbering) of the CL1 is a D; the amino acid at position 173 (EU numbering) of the CHIHI is a C and the amino acid at position 162 (EU numbering) of the CL1 is a C; the amino acid at position 220 (EU numbering) of the H1H is a S and the amino acid at position 214 (EU numbering) of the CL1 is a S; the amino acids at positions 234, 235, and 237 (EU numbering) in the H1H are an A; the amino acid at position 349 (EU numbering) of the CHlm is a C;

[0167] the amino acid at position 366 (EU numbering) of the CHlm is a S; the amino acid at position 368 (EU numbering) of the CHlm is a A; the amino acid at position 407 (EU numbering) of CH1H3 is a V; and the amino acid at position 447 (EU numbering) of the CHlm is deleted, when numbered in accordance with Hl amino acid sequence of SEQ NO: 439 and LI amino acid sequence of SEQ NO: 438.

[0168] In addition to the specific complementarity determining regions recited above, the bispecific antibody EIP0205 comprises the following amino acids substitutions in the H2 and L2: the amino acid at position 39 (Kabat numbering) of the VH2 is a D and the amino acid at position 38 (Kabat numbering) of the VL2 is a K; the amino acid at position 147 (EU numbering) of the CH2HI is a D and the amino acid at position 180 (EU numbering) of the CL2 is a R; the amino acids at positions 234, 235, and 237 (EU numbering) of the H2H are an A; the amino acid at position 354 (EU numbering) of the CH2H3 is a C; the amino acid at position 366 (EU numbering) of the CH2H3 is a W; and the amino acid at position 447 (EU numbering) of the CH2H3 is deleted, when numbered in accordance with H2 amino acid sequence of SEQ NO: 437 and L2 amino acid sequence of SEQ NO: 436.

[0169] In some embodiments, the bispecific antibody EIP0205 comprises a VH1 comprising the amino acid sequence of SEQ ID NO: 13, a VH2 comprising the amino acid sequence of SEQ ID NO: 2, a VL1 comprising the amino acid sequence of SEQ ID NO: 22, and a VL2 comprising the amino acid sequence of SEQ ID NO: 1.

[0170] In some embodiments, the bispecific antibody EIP0205 comprises a Hl comprising the amino acid sequence of SEQ ID NO: 70, a H2 comprising the amino acid sequence of SEQ ID NO: 68, a LI comprising the amino acid sequence of SEQ ID NO: 69, and a L2 comprising the amino acid sequence of SEQ ID NO: 67.

[0171] In addition to the specific complementarity determining regions recited above, the bispecific antibody EIP0206 comprises the following amino acids substitutions in the Hl and LI: the amino acid at position 39 (Kabat numbering) of the VH1 is a K and the amino acid at position 38 (Kabat numbering) of the VL1 is a D; the amino acid at position 185 (EU numbering) of the CHIHI is a K and the amino acid at position 137 (EU numbering) of the CL1 is a D; the amino acid at position 173 (EU numbering) of the CHIHI is a C and the amino acid at position 162 (EU numbering) of the CL1 is a C; the amino acid at position 220 (EU numbering) in the H1H is a S and the amino acid at position 214 in CL1 is a S;

[0172] the amino acids at positions 234, 235, and 237 (EU numbering) in the H1H are an A; the amino acid at position 349 (EU numbering) of the CH1H3 is a C; the amino acid at position 366 (EU numbering) of the CH1H3 is a S; the amino acid at position 368 (EU numbering) of the CH1H3 is a A; the amino acid at position 407 (EU numbering) of CH1H3 is a V; and

[0173] the amino acid at position 447 (EU numbering) of the CH1H3 is deleted, when numbered in accordance with Hl amino acid sequence of SEQ NO: 439 and LI amino acid sequence of SEQ NO: 438.

[0174] In addition to the specific complementarity determining regions recited above, the bispecific antibody EIP0206 comprises the following amino acids substitutions in the H2 and L2: the amino acid at position 39 (Kabat numbering) of the VH2 is a D and the amino acid at position 38 (Kabat numbering) of the VL2 is a K; the amino acid at position 147 (EU numbering) of the CH2HI is a D and the amino acid at position 180 (EU numbering) of the CL2 is a R; the amino acid at position 134 (EU numbering) of the CH2HI is a C and the amino acid at position 116 (EU numbering) of the CL2 is a C; the amino acids at positions 234, 235, and 237 (EU numbering) of the H2H are an A; the amino acid at position 354 (EU numbering) of the CH2H3 is a C; the amino acid at position 366 (EU numbering) of the CH2H3 is a W; and the amino acid at position 447 (EU numbering) of the CH2H3 is deleted, when numbered in accordance with H2 amino acid sequence of SEQ NO: 437 and L2 amino acid sequence of SEQ NO: 436.

[0175] In some embodiments, the bispecific antibody EIP0206 comprises a VH1 comprising the amino acid sequence of SEQ ID NO: 13, a VH2 comprising the amino acid sequence of SEQ ID NO: 2, a VL1 comprising the amino acid sequence of SEQ ID NO: 22, and a VL2 comprising the amino acid sequence of SEQ ID NO: 1.

[0176] In some embodiments, the bispecific antibody EIP0206 comprises a Hl comprising the amino acid sequence of SEQ ID NO: 74, a H2 comprising the amino acid sequence of SEQ ID NO: 72, a LI comprising the amino acid sequence of SEQ ID NO: 73, and a L2 comprising the amino acid sequence of SEQ ID NO: 71.

[0177] In addition to the specific complementarity determining regions recited above, the bispecific antibody EIP0207 comprises the following amino acids substitutions in the Hl and LI: the amino acid at position 39 (Kabat numbering) of the VH1 is a K and the amino acid at position 38 (Kabat numbering) of the VL1 is a D; the amino acid at position 185 (EU numbering) of the CHIHI is a K and the amino acid at position 137 (EU numbering) of the CL1 is a D; the amino acids at positions 234, 235, and 237 (EU numbering) in the H1H are an A; the amino acid at position 349 (EU numbering) of the CH1H3 is a C; the amino acid at position 366 (EU numbering) of the CH1H3 is a S; the amino acid at position 368 (EU numbering) of the CH1H3 is a A; the amino acid at position 407 (EU numbering) of CH1H3 is a V; and the amino acid at position 447 (EU numbering) of the CH1H3 is deleted, when numbered in accordance with Hl amino acid sequence of SEQ NO: 439 and LI amino acid sequence of SEQ NO: 438.

[0178] In addition to the specific complementarity determining regions recited above, the bispecific antibody EIP0207 comprises the following amino acids substitutions in the H2 and L2: the amino acid at position 39 (Kabat numbering) of the VH2 is a D and the amino acid at position 38 (Kabat numbering) of the VL2 is a K; the amino acid at position 147 (EU numbering) of the CH2HI is a D and the amino acid at position 180 (EU numbering) of the CL2 is a R; the amino acid at position 131 (EU numbering) of the CH2HI is a C and the amino acid at position 114 (EU numbering) of the CL2 is a C; the amino acid at position 220 (EU numbering) in the H2H is a S and the amino acid at position 214 (EU numbering) of the CL2 is a S; the amino acids at positions 234, 235, and 237 (EU numbering) of the H2H are an A; the amino acid at position 354 (EU numbering) of the CH2H3 is a C; the amino acid at position 366 (EU numbering) of the CH2H3 is a W; and the amino acid at position 447 (EU numbering) of the CH2H3 is deleted, when numbered in accordance with H2 amino acid sequence of SEQ NO: 437 and L2 amino acid sequence of SEQ NO: 436.

[0179] In some embodiments, the bispecific antibody EIP0207 comprises a VH1 comprising the amino acid sequence of SEQ ID NO: 13, a VH2 comprising the amino acid sequence ofSEQ ID NO: 2, a VL1 comprising the amino acid sequence of SEQ ID NO: 22, and a VL2 comprising the amino acid sequence of SEQ ID NO: 1.

[0180] In some embodiments, the bispecific antibody EIP0207 comprises a Hl comprising the amino acid sequence of SEQ ID NO: 78, a H2 comprising the amino acid sequence of SEQ ID NO: 76, a LI comprising the amino acid sequence of SEQ ID NO: 77, and a L2 comprising the amino acid sequence of SEQ ID NO: 75.

[0181] In addition to the specific complementarity determining regions recited above, the bispecific antibody EIP0208 comprises the following amino acids substitutions in the Hl and LI: the amino acid at position 39 (Kabat numbering) of the VH1 is a K and the amino acid at position 38 (Kabat numbering) of the VL1 is a D; the amino acid at position 185 (EU numbering) of the CHIHI is a K and the amino acid at position 137 (EU numbering) of the CL1 is a D; the amino acids at positions 234, 235, and 237 (EU numbering) in the H1H are an A; the amino acid at position 349 (EU numbering) of the CH1H3 is a C; the amino acid at position 366 (EU numbering) of the CH1H3 is a S; the amino acid at position 368 (EU numbering) of the CH1H3 is a A; the amino acid at position 407 (EU numbering) of CH1H3 is a V; and the amino acid at position 447 (EU numbering) of the CH1H3 is deleted, when numbered in accordance with Hl amino acid sequence of SEQ NO: 439 and LI amino acid sequence of SEQ NO: 438.

[0182] In addition to the specific complementarity determining regions recited above, the bispecific antibody EIP0208 comprises the following amino acids substitutions in the H2 and L2: the amino acid at position 39 (Kabat numbering) of the VH2 is a D and the amino acid at position 38 (Kabat numbering) of the VL2 is a K; the amino acid at position 187 (EU numbering) of the CH2HI is a D and the amino acid at position 138 (EU numbering) of the CL2 is a K; the amino acid at position 170 (EU numbering) of the CH2HI is a C and the amino acid at position 162 (EU numbering) of the CL2 is a C; the amino acid at position 220 (EU numbering) in the H2H is a S and the amino acid at position 214 (EU numbering) of the CL2 is a S; the amino acids at positions 234, 235, and 237 (EU numbering) of the H2H are an A; the amino acid at position 354 (EU numbering) of the CH2H3 is a C; the amino acid at position 366 (EU numbering) of the CH2H3 is a W; and the amino acid at position 447 (EU numbering) of the CH2H3 is deleted, when numbered in accordance with H2 amino acid sequence of SEQ NO: 437 and L2 amino acid sequence of SEQ NO: 436.

[0183] In some embodiments, the bispecific antibody EIP0208 comprises a VH1 comprising the amino acid sequence of SEQ ID NO: 13, a VH2 comprising the amino acid sequence of SEQ ID NO: 2, a VL1 comprising the amino acid sequence of SEQ ID NO: 22, and a VL2 comprising the amino acid sequence of SEQ ID NO: 1.

[0184] In some embodiments, the bispecific antibody EIP0208 comprises a Hl comprising the amino acid sequence of SEQ ID NO: 82, a H2 comprising the amino acid sequence of SEQ ID NO: 80, a LI comprising the amino acid sequence of SEQ ID NO: 81, and a L2 comprising the amino acid sequence of SEQ ID NO: 79.

[0185] In addition to the specific complementarity determining regions recited above, the bispecific antibody EIP0294 comprises the following amino acids substitutions in the Hl and LI: the amino acid at position 39 (Kabat numbering) of the VH1 is a K and the amino acid at position 38 (Kabat numbering) of the VL1 is a D; the amino acid at position 185 (EU numbering) of the CHI HI is a E and the amino acid at position 137 (EU numbering) of the CL1 is a K and the amino acid at position 179 (EU numbering) of the CL1 is a E; the amino acids at positions 234, 235, and 237 (EU numbering) in the H1H are an A; the amino acid at position 349 (EU numbering) of the CH1H3 is a C; the amino acid at position 366 (EU numbering) of the CH1H3 is a S; the amino acid at position 368 (EU numbering) of the CH1H3 is a A; the amino acid at position 407 (EU numbering) of CH1H3 is a V; and

[0186] the amino acid at position 447 (EU numbering) of the CH1H3 is deleted, when numbered in accordance with Hl amino acid sequence of SEQ NO: 439 and LI amino acid sequence of SEQ NO: 438.

[0187] In addition to the specific complementarity determining regions recited above, the bispecific antibody EIP0294 comprises the following amino acids substitutions in the H2 and L2: the amino acid at position 39 (Kabat numbering) of the VH2 is a D and the amino acid at position 38 (Kabat numbering) of the VL2 is a K; the amino acid at position 187 (EU numbering) of the CH2HI is a D and the amino acid at position 138 (EU numbering) of the CL2 is a K; the amino acid at position 171 (EU numbering) of the CH2HI is a C and the amino acid at position 162 (EU numbering) of the CL2 is a C; the amino acid at position 220 (EU numbering) in the H2H is a S and the amino acid at position 214 (EU numbering) of the CL2 is a S; the amino acids at positions 234, 235, and 237 (EU numbering) of the H2H are an A; the amino acid at position 354 (EU numbering) of the CH2H3 is a C; the amino acid at position366 (EU numbering) of the CH2H3 is a W; and the amino acid at position 447 (EU numbering) of the CH2H3 is deleted, when numbered in accordance with H2 amino acid sequence of SEQ NO: 437 and L2 amino acid sequence of SEQ NO: 436.

[0188] In some embodiments, the bispecific antibody EIP0294 comprises a VH1 comprising the amino acid sequence of SEQ ID NO: 13, a VH2 comprising the amino acid sequence of SEQ ID NO: 2, a VL1 comprising the amino acid sequence of SEQ ID NO: 22, and a VL2 comprising the amino acid sequence of SEQ ID NO: 1.

[0189] In some embodiments, the bispecific antibody EIP0294 comprises a Hl comprising the amino acid sequence of SEQ ID NO: 86, a H2 comprising the amino acid sequence of SEQ ID NO: 84, a LI comprising the amino acid sequence of SEQ ID NO: 85, and a L2 comprising the amino acid sequence of SEQ ID NO: 83.

[0190] In addition to the specific complementarity determining regions recited above, the bispecific antibody EIP0295 comprises the following amino acids substitutions in the Hl and LI: the amino acid at position 39 (Kabat numbering) of the VH1 is a K and the amino acid at position 38 (Kabat numbering) of the VL1 is a D; the amino acid at position 185 (EU numbering) of the CHIHI is a K and the amino acid at position 137 (EU numbering) of the CL1 is a D; the amino acids at positions 234, 235, and 237 (EU numbering) in the H1H are an A; the amino acid at position 349 (EU numbering) of the CH1H3 is a C; the amino acid at position 366 (EU numbering) of the CH1H3 is a S; the amino acid at position 368 (EU numbering) of the CH1H3 is a A; the amino acid at position 407 (EU numbering) of CH1H3 is a V; and the amino acid at position 447 (EU numbering) of the CH1H3 is deleted, when numbered in accordance with Hl amino acid sequence of SEQ NO: 439 and LI amino acid sequence of SEQ NO: 438.

[0191] In addition to the specific complementarity determining regions recited above, the bispecific antibody EIP0295 comprises the following amino acids substitutions in the H2 and L2: the amino acid at position 39 (Kabat numbering) of the VH2 is a D and the amino acid at position 38 (Kabat numbering) of the VL2 is a K; the amino acid at position 187 (EU numbering) of the CH2HI is a D and the amino acid at position 138 (EU numbering) of the CL2 is a K; the amino acid at position 171 (EU numbering) of the CH2HI is a C and the amino acid at position 162 (EU numbering) of the CL2 is a C; the amino acid at position 220 (EU numbering) in the H2H is a S and the amino acid at position 214 (EU numbering) of the CL2is a S; the amino acids at positions 234, 235, and 237 (EU numbering) of the H2H are an A; the amino acid at position 354 (EU numbering) of the CH2H3 is a C; the amino acid at position 366 (EU numbering) of the CH2H3 is a W; and the amino acid at position 447 (EU numbering) of the CH2H3 is deleted, when numbered in accordance with H2 amino acid sequence of SEQ NO: 437 and L2 amino acid sequence of SEQ NO: 436.

[0192] In some embodiments, the bispecific antibody EIP0295 comprises a VH1 comprising the amino acid sequence of SEQ ID NO: 13, a VH2 comprising the amino acid sequence of SEQ ID NO: 2, a VL1 comprising the amino acid sequence of SEQ ID NO: 22, and a VL2 comprising the amino acid sequence of SEQ ID NO: 1.

[0193] In some embodiments, the bispecific antibody EIP0295 comprises a Hl comprising the amino acid sequence of SEQ ID NO: 90, a H2 comprising the amino acid sequence of SEQ ID NO: 88, a LI comprising the amino acid sequence of SEQ ID NO: 89, and a L2 comprising the amino acid sequence of SEQ ID NO: 87.

[0194] In addition to the specific complementarity determining regions recited above, the bispecific antibody EIP0306 comprises the following amino acids substitutions in the Hl and LI: the amino acid at position 39 (Kabat numbering) of the VH1 is a K and the amino acid at position 38 (Kabat numbering) of the VL1 is a D; the amino acid at position 185 (EU numbering) of the CHI HI is a E and the amino acid at position 137 (EU numbering) of the CL1 is a K and the amino acid at position 179 (EU numbering) of the CL1 is a E; the amino acid at position 185 (EU numbering) of the CHIHI is a E and the amino acid at position 179 (EU numbering) of the CL1 is a E; the amino acids at positions 234, 235, and 237 (EU numbering) in the H1H are an A; the amino acid at position 349 (EU numbering) of the CH1H3 is a C; the amino acid at position 366 (EU numbering) of the CH1H3 is a S;

[0195] the amino acid at position 368 (EU numbering) of the CHlm is a A; the amino acid at position 407 (EU numbering) of CHlm is a V; and the amino acid at position 447 (EU numbering) of the CHlm is deleted, when numbered in accordance with Hl amino acid sequence of SEQ NO: 439 and LI amino acid sequence of SEQ NO: 438.

[0196] In addition to the specific complementarity determining regions recited above, the bispecific antibody EIP0306 comprises the following amino acids substitutions in the H2 and L2: the amino acid at position 39 (Kabat numbering) of the VH2 is a D and the amino acid at position 38 (Kabat numbering) of the VL2 is a K; the amino acid at position 147 (EUnumbering) of the CH2HI is a D and the amino acid at position 180 (EU numbering) of the CL2 is a R; the amino acid at position 171 (EU numbering) of the CH2HI is a C and the amino acid at position 162 (EU numbering) of the CL2 is a C; the amino acid at position 220 (EU numbering) in the H2H is a S and the amino acid at position 214 (EU numbering) of the CL2 is a S; the amino acids at positions 234, 235, and 237 (EU numbering) of the H2H are an A; the amino acid at position 354 (EU numbering) of the CH2H3 is a C; the amino acid at position 366 (EU numbering) of the CH2H3 is a W; and the amino acid at position 447 (EU numbering) of the CH2H3 is deleted, when numbered in accordance with H2 amino acid sequence of SEQ NO: 437 and L2 amino acid sequence of SEQ NO: 436.

[0197] In some embodiments, the bispecific antibody EIP0306 comprises a VH1 comprising the amino acid sequence of SEQ ID NO: 13, a VH2 comprising the amino acid sequence of SEQ ID NO: 2, a VL1 comprising the amino acid sequence of SEQ ID NO: 22, and a VL2 comprising the amino acid sequence of SEQ ID NO: 1.

[0198] In some embodiments, the bispecific antibody EIP0306 comprises a Hl comprising the amino acid sequence of SEQ ID NO: 94, a H2 comprising the amino acid sequence of SEQ ID NO: 92, a LI comprising the amino acid sequence of SEQ ID NO: 93, and a L2 comprising the amino acid sequence of SEQ ID NO: 91.

[0199] In addition to the specific complementarity determining regions recited above, the bispecific antibody EIP0307 comprises the following amino acids substitutions in the Hl and LI: the amino acid at position 39 (Kabat numbering) of the VH1 is a K and the amino acid at position 38 (Kabat numbering) of the VL1 is a D; the amino acid at position 185 (EU numbering) of the CHIHI is a K and the amino acid at position 137 (EU numbering) of the CL1 is a D; the amino acids at positions 234, 235, and 237 (EU numbering) in the H1H are an A; the amino acid at position 349 (EU numbering) of the CH1H3 is a C; the amino acid at position 366 (EU numbering) of the CH1H3 is a S; the amino acid at position 368 (EU numbering) of the CH1H3 is a A; the amino acid at position 407 (EU numbering) of CH1H3 is a V; and the amino acid at position 447 (EU numbering) of the CH1H3 is deleted, when numbered in accordance with Hl amino acid sequence of SEQ NO: 439 and LI amino acid sequence of SEQ NO: 438.

[0200] In addition to the specific complementarity determining regions recited above, the bispecific antibody EIP0307 comprises the following amino acids substitutions in the H2 andL2: the amino acid at position 39 (Kabat numbering) of the VH2 is a D and the amino acid at position 38 (Kabat numbering) of the VL2 is a K; the amino acid at position 147 (EU numbering) of the CH2HI is a D and the amino acid at position 180 (EU numbering) of the CL2 is a R; the amino acid at position 171 (EU numbering) of the CH2HI is a C and the amino acid at position 162 (EU numbering) of the CL2 is a C; the amino acid at position 220 (EU numbering) in the H2H is a S and the amino acid at position 214 (EU numbering) of the CL2 is a S; the amino acids at positions 234, 235, and 237 (EU numbering) of the H2H are an A; the amino acid at position 354 (EU numbering) of the CH2H3 is a C; the amino acid at position 366 (EU numbering) of the CH2H3 is a W; and the amino acid at position 447 (EU numbering) of the CH2H3 is deleted, when numbered in accordance with H2 amino acid sequence of SEQ NO: 437 and L2 amino acid sequence of SEQ NO: 436.

[0201] In some embodiments, the bispecific antibody EIP0307 comprises a VH1 comprising the amino acid sequence of SEQ ID NO: 13, a VH2 comprising the amino acid sequence of SEQ ID NO: 2, a VL1 comprising the amino acid sequence of SEQ ID NO: 22, and a VL2 comprising the amino acid sequence of SEQ ID NO: 1.

[0202] In some embodiments, the bispecific antibody EIP0307 comprises a Hl comprising the amino acid sequence of SEQ ID NO: 98, a H2 comprising the amino acid sequence of SEQ ID NO: 96, a LI comprising the amino acid sequence of SEQ ID NO: 97, and a L2 comprising the amino acid sequence of SEQ ID NO: 95.

[0203] In addition to the specific complementarity determining regions recited above, the bispecific antibody EIP0318 comprises the following amino acids substitutions in the Hl and LI: the amino acid at position 39 (Kabat numbering) of the VH1 is a K and the amino acid at position 38 (Kabat numbering) of the VL1 is a D; the amino acid at position 147 (EU numbering) of the CHIHI is a K and the amino acid at position 131 (EU numbering) of the CL1 is a D; the amino acid at position 185 (EU numbering) of the CHIHI is a K and the amino acid at position 137 (EU numbering) of the CL1 is a D; the amino acids at positions 234, 235, and 237 (EU numbering) in the H1H are an A; the amino acid at position 349 (EU numbering) of the CH1H3 is a C; the amino acid at position 366 (EU numbering) of the CHlm is a S; the amino acid at position 368 (EU numbering) of the CH1H3 is a A;

[0204] the amino acid at position 407 (EU numbering) of CH1H3 is a V; and the amino acid at position 447 (EU numbering) of the CHlm is deleted, when numbered in accordance with Hl amino acid sequence of SEQ NO: 439 and LI amino acid sequence of SEQ NO: 438.

[0205] In addition to the specific complementarity determining regions recited above, the bispecific antibody EIP0318 comprises the following amino acids substitutions in the H2 and L2: the amino acid at position 39 (Kabat numbering) of the VH2 is a D and the amino acid at position 38 (Kabat numbering) of the VL2 is a K; the amino acid at position 147 (EU numbering) of the CH2HI is a D and the amino acid at position 180 (EU numbering) of the CL2 is a R; the amino acid at position 171 (EU numbering) of the CH2HI is a C and the amino acid at position 162 (EU numbering) of the CL2 is a C; the amino acid at position 220 (EU numbering) in the H2H is a S and the amino acid at position 214 (EU numbering) of the CL2 is a S; the amino acids at positions 234, 235, and 237 (EU numbering) of the H2H are an A; the amino acid at position 354 (EU numbering) of the CH2H3 is a C; the amino acid at position 366 (EU numbering) of the CH2H3 is a W; and the amino acid at position 447 (EU numbering) of the CH2H3 is deleted, when numbered in accordance with H2 amino acid sequence of SEQ NO: 437 and L2 amino acid sequence of SEQ NO: 436.

[0206] In some embodiments, the bispecific antibody EIP0318 comprises a VH1 comprising the amino acid sequence of SEQ ID NO: 13, a VH2 comprising the amino acid sequence of SEQ ID NO: 2, a VL1 comprising the amino acid sequence of SEQ ID NO: 22, and a VL2 comprising the amino acid sequence of SEQ ID NO: 1.

[0207] In some embodiments, the bispecific antibody EIP0318 comprises a Hl comprising the amino acid sequence of SEQ ID NO: 102, a H2 comprising the amino acid sequence of SEQ ID NO: 100, a LI comprising the amino acid sequence of SEQ ID NO: 101, and a L2 comprising the amino acid sequence of SEQ ID NO: 99.

[0208] In addition to the specific complementarity determining regions recited above, the bispecific antibody EIP0340 comprises the following amino acids substitutions in the Hl and LI: the amino acid at position 39 (Kabat numbering) of the VH1 is a D and the amino acid at position 38 (Kabat numbering) of the VL1 is a K; the amino acid at position 185 (EU numbering) of the CHI HI is a E and the amino acid at position 137 (EU numbering) of the CL1 is a K; the amino acids at positions 234, 235, and 237 (EU numbering) in the H1H are an A; the amino acid at position 349 (EU numbering) of the CH1H3 is a C; the amino acid atposition 366 (EU numbering) of the CH1H3 is a S; the amino acid at position 368 (EU numbering) of the CH1H3 is a A; the amino acid at position 407 (EU numbering) of CH1H3 is a V; and the amino acid at position 447 (EU numbering) of the CH1H3 is deleted, when numbered in accordance with Hl amino acid sequence of SEQ NO: 439 and LI amino acid sequence of SEQ NO: 438.

[0209] In addition to the specific complementarity determining regions recited above, the bispecific antibody EIP0340 comprises the following amino acids substitutions in the H2 and L2: the amino acid at position 39 (Kabat numbering) of the VH2 is a K and the amino acid at position 38 (Kabat numbering) of the VL2 is a D; the amino acid at position 187 (EU numbering) of the CH2HI is a D and the amino acid at position 138 (EU numbering) of the CL2 is a K; the amino acid at position 136 (EU numbering) of the CH2HI is a C and the amino acid at position 114 (EU numbering) of the CL2 is a C; the amino acid at position 220 (EU numbering) in the H2H is a S and the amino acid at position 214 (EU numbering) of the CL2 is a S; the amino acids at positions 234, 235, and 237 (EU numbering) of the H2H are an A; the amino acid at position 354 (EU numbering) of the CH2H3 is a C; the amino acid at position 366 (EU numbering) of the CH2H3 is a W; and the amino acid at position 447 (EU numbering) of the CH2H3 is deleted, when numbered in accordance with H2 amino acid sequence of SEQ NO: 437 and L2 amino acid sequence of SEQ NO: 436.

[0210] In some embodiments, the bispecific antibody EIP0340 comprises a VH1 comprising the amino acid sequence of SEQ ID NO: 14, a VH2 comprising the amino acid sequence of SEQ ID NO: 4, a VL1 comprising the amino acid sequence of SEQ ID NO: 23, and a VL2 comprising the amino acid sequence of SEQ ID NO: 3.

[0211] In some embodiments, the bispecific antibody EIP0340 comprises a Hl comprising the amino acid sequence of SEQ ID NO: 106, a H2 comprising the amino acid sequence of SEQ ID NO: 104, a LI comprising the amino acid sequence of SEQ ID NO: 105, and a L2 comprising the amino acid sequence of SEQ ID NO: 103.

[0212] In addition to the specific complementarity determining regions recited above, the bispecific antibody EIP0342 comprises the following amino acids substitutions in the Hl and LI: the amino acid at position 39 (Kabat numbering) of the VH1 is a D and the amino acid at position 38 (Kabat numbering) of the VL1 is a K; the amino acid at position 185 (EU numbering) of the CHI HI is a E and the amino acid at position 137 (EU numbering) of theCL1 is a K; the amino acids at positions 234, 235, and 237 (EU numbering) in the H1H are an A; the amino acid at position 349 (EU numbering) of the CH1H3 is a C; the amino acid at position 366 (EU numbering) of the CH1H3 is a S; the amino acid at position 368 (EU numbering) of the CH1H3 is a A; the amino acid at position 407 (EU numbering) of CH1H3 is a V; and the amino acid at position 447 (EU numbering) of the CH1H3 is deleted, when numbered in accordance with Hl amino acid sequence of SEQ NO: 439 and LI amino acid sequence of SEQ NO: 438.

[0213] In addition to the specific complementarity determining regions recited above, the bispecific antibody EIP0342 comprises the following amino acids substitutions in the H2 and L2: the amino acid at position 39 (Kabat numbering) of the VH2 is a K and the amino acid at position 38 (Kabat numbering) of the VL2 is a D; the amino acid at position 187 (EU numbering) of the CH2HI is a D and the amino acid at position 138 (EU numbering) of the CL2 is a K; the amino acid at position 171 (EU numbering) of the CH2HI is a C and the amino acid at position 162 (EU numbering) of the CL2 is a C; the amino acid at position 220 (EU numbering) in the H2H is a S and the amino acid at position 214 (EU numbering) of the CL2 is a S; the amino acids at positions 234, 235, and 237 (EU numbering) of the H2H are an A; the amino acid at position 354 (EU numbering) of the CH2H3 is a C; the amino acid at position 366 (EU numbering) of the CH2H3 is a W; and the amino acid at position 447 (EU numbering) of the CH2H3 is deleted, when numbered in accordance with H2 amino acid sequence of SEQ NO: 437 and L2 amino acid sequence of SEQ NO: 436.

[0214] In some embodiments, the bispecific antibody EIP0342 comprises a VH1 comprising the amino acid sequence of SEQ ID NO: 14, a VH2 comprising the amino acid sequence of SEQ ID NO: 4, a VL1 comprising the amino acid sequence of SEQ ID NO: 23, and a VL2 comprising the amino acid sequence of SEQ ID NO: 3.

[0215] In some embodiments, the bispecific antibody EIP0342 comprises a Hl comprising the amino acid sequence of SEQ ID NO: 110, a H2 comprising the amino acid sequence of SEQ ID NO: 108, a LI comprising the amino acid sequence of SEQ ID NO: 109, and a L2 comprising the amino acid sequence of SEQ ID NO: 107.

[0216] In addition to the specific complementarity determining regions recited above, the bispecific antibody EIP0354 comprises the following amino acids substitutions in the Hl and LI: the amino acid at position 39 (Kabat numbering) of the VH1 is a D and the amino acid atposition 38 (Kabat numbering) of the VL1 is a K; the amino acid at position 185 (EU numbering) of the CHIHI is a K and the amino acid at position 137 (EU numbering) of the CL1 is a D; the amino acids at positions 234, 235, and 237 (EU numbering) in the H1H are an A the amino acid at position 349 (EU numbering) of the CH1H3 is a C; the amino acid at position 366 (EU numbering) of the CH1H3 is a S; the amino acid at position 368 (EU numbering) of the CH1H3 is a A; the amino acid at position 407 (EU numbering) of CH1H3 is a V; and the amino acid at position 447 (EU numbering) of the CHlm is deleted, when numbered in accordance with Hl amino acid sequence of SEQ NO: 439 and LI amino acid sequence of SEQ NO: 438.

[0217] In addition to the specific complementarity determining regions recited above, the bispecific antibody EIP0354 comprises the following amino acids substitutions in the H2 and L2: the amino acid at position 39 (Kabat numbering) of the VH2 is a K and the amino acid at position 38 (Kabat numbering) of the VL2 is a D; the amino acid at position 187 (EU numbering) of the CH2HI is a D and the amino acid at position 138 (EU numbering) of the CL2 is a K; the amino acid at position 171 (EU numbering) of the CH2HI is a C and the amino acid at position 162 (EU numbering) of the CL2 is a C; the amino acid at position 220 (EU numbering) in the H2H is a S and the amino acid at position 214 (EU numbering) of the CL2 is a S; the amino acids at positions 234, 235, and 237 (EU numbering) of the H2H are an A; the amino acid at position 354 (EU numbering) of the CH2H3 is a C; the amino acid at position 366 (EU numbering) of the CH2H3 is a W; and the amino acid at position 447 (EU numbering) of the CH2H3 is deleted, when numbered in accordance with H2 amino acid sequence of SEQ NO: 437 and L2 amino acid sequence of SEQ NO: 436.

[0218] In some embodiments, the bispecific antibody EIP0354 comprises a VH1 comprising the amino acid sequence of SEQ ID NO: 14, a VH2 comprising the amino acid sequence of SEQ ID NO: 4, a VL1 comprising the amino acid sequence of SEQ ID NO: 23, and a VL2 comprising the amino acid sequence of SEQ ID NO: 3.

[0219] In some embodiments, the bispecific antibody EIP0354 comprises a Hl comprising the amino acid sequence of SEQ ID NO: 114, a H2 comprising the amino acid sequence of SEQ ID NO: 112, a LI comprising the amino acid sequence of SEQ ID NO: 113, and a L2 comprising the amino acid sequence of SEQ ID NO: 111.

[0220] In addition to the specific complementarity determining regions recited above, the bispecific antibody EIP0356 comprises the following amino acids substitutions in the Hl and LI: the amino acid at position 39 (Kabat numbering) of the VH1 is a D and the amino acid at position 38 (Kabat numbering) of the VL1 is a K; the amino acid at position 147 (EU numbering) of the CHIHI is a K and the amino acid at position 131 (EU numbering) of the CL1 is a D; the amino acid at position 185 (EU numbering) of the CHIHI is a E and the amino acid at position 137 (EU numbering) of the CL1 is a K; the amino acid at position 145 (EU numbering) of the CHIHI is a S and the amino acid at position 180 (EU numbering) of the CL1 is a E; the amino acids at positions 234, 235, and 237 (EU numbering) in the H1H are an A; the amino acid at position 349 (EU numbering) of the CH1H3 is a C; the amino acid at position 366 (EU numbering) of the CH1H3 is a S; the amino acid at position 368 (EU numbering) of the CH1H3 is a A; the amino acid at position 407 (EU numbering) of CH1H3 is a V; and the amino acid at position 447 (EU numbering) of the CH1H3 is deleted, when numbered in accordance with Hl amino acid sequence of SEQ NO: 439 and LI amino acid sequence of SEQ NO: 438.

[0221] In addition to the specific complementarity determining regions recited above, the bispecific antibody EIP0356 comprises the following amino acids substitutions in the H2 and L2: the amino acid at position 39 (Kabat numbering) of the VH2 is a K and the amino acid at position 38 (Kabat numbering) of the VL2 is a D; the amino acid at position 187 (EU numbering) of the CH2HI is a D and the amino acid at position 138 (EU numbering) of the CL2 is a K; the amino acid at position 170 (EU numbering) of the CH2HI is a C and the amino acid at position 162 (EU numbering) of the CL2 is a C; the amino acid at position 220 (EU numbering) in the H2H is a S and the amino acid at position 214 (EU numbering) of the CL2 is a S; the amino acids at positions 234, 235, and 237 (EU numbering) of the H2H are an A; the amino acid at position 354 (EU numbering) of the CH2H3 is a C; the amino acid at position 366 (EU numbering) of the CH2H3 is a W; and the amino acid at position 447 (EU numbering) of the CH2H3 is deleted, when numbered in accordance with H2 amino acid sequence of SEQ NO: 437 and L2 amino acid sequence of SEQ NO: 436.

[0222] In some embodiments, the bispecific antibody EIP0356 comprises a VH1 comprising the amino acid sequence of SEQ ID NO: 14, a VH2 comprising the amino acid sequence ofSEQ ID NO: 4, a VL1 comprising the amino acid sequence of SEQ ID NO: 23, and a VL2 comprising the amino acid sequence of SEQ ID NO: 3.

[0223] In some embodiments, the bispecific antibody EIP0356 comprises a Hl comprising the amino acid sequence of SEQ ID NO: 118, a H2 comprising the amino acid sequence of SEQ ID NO: 116, a LI comprising the amino acid sequence of SEQ ID NO: 117, and a L2 comprising the amino acid sequence of SEQ ID NO: 115.

[0224] In addition to the specific complementarity determining regions recited above, the bispecific antibody EIP0367 comprises the following amino acids substitutions in the Hl and LI: the amino acid at position 39 (Kabat numbering) of the VH1 is a K and the amino acid at position 38 (Kabat numbering) of the VL1 is a D; the amino acid at position 147 (EU numbering) of the CHIHI is a D and the amino acid at position 131 (EU numbering) of the CL1 is a K; the amino acid at position 185 (EU numbering) of the CHIHI is a E and the amino acid at position 137 (EU numbering) of the CL1 is a D; the amino acids at positions 234, 235, and 237 (EU numbering) in the H1H are an A; the amino acid at position 349 (EU numbering) of the CH1H3 is a C; the amino acid at position 366 (EU numbering) of the CH1H3 is a S; the amino acid at position 368 (EU numbering) of the CH1H3 is a A; the amino acid at position 407 (EU numbering) of CH1H3 is a V; and the amino acid at position 447 (EU numbering) of the CH1H3 is deleted, when numbered in accordance with Hl amino acid sequence of SEQ NO: 439 and LI amino acid sequence of SEQ NO: 438.

[0225] In addition to the specific complementarity determining regions recited above, the bispecific antibody EIP0367 comprises the following amino acids substitutions in the H2 and L2: the amino acid at position 39 (Kabat numbering) of the VH2 is a D and the amino acid at position 38 (Kabat numbering) of the VL2 is a K; the amino acid at position 187 (EU numbering) of the CH2HI is a D and the amino acid at position 137 (EU numbering) of the CL2 is a K and the amino acid at position 138 (EU numbering) of the CL2 is a R; the amino acid at position 170 (EU numbering) of the CH2HI is a C and the amino acid at position 162 (EU numbering) of the CL2 is a C; the amino acid at position 220 (EU numbering) in the H2H is a S and the amino acid at position 214 (EU numbering) of the CL2 is a S; the amino acids at positions 234, 235, and 237 (EU numbering) of the H2H are an A; the amino acid at position 354 (EU numbering) of the CH2H3 is a C; the amino acid at position 366 (EU numbering) of the CH2H3 is a W; and the amino acid at position 447 (EU numbering) of theCH2H3 is deleted, when numbered in accordance with H2 amino acid sequence of SEQ NO: 437 and L2 amino acid sequence of SEQ NO: 436.

[0226] In some embodiments, the bispecific antibody EIP0367 comprises a VH1 comprising the amino acid sequence of SEQ ID NO: 13, a VH2 comprising the amino acid sequence of SEQ ID NO: 2, a VL1 comprising the amino acid sequence of SEQ ID NO: 22, and a VL2 comprising the amino acid sequence of SEQ ID NO: 1.

[0227] In some embodiments, the bispecific antibody EIP0367 comprises a Hl comprising the amino acid sequence of SEQ ID NO: 122, a H2 comprising the amino acid sequence of SEQ ID NO: 120, a LI comprising the amino acid sequence of SEQ ID NO: 121, and a L2 comprising the amino acid sequence of SEQ ID NO: 119.

[0228] In addition to the specific complementarity determining regions recited above, the bispecific antibody EIP0377 comprises the following amino acids substitutions in the Hl and LI: the amino acid at position 39 (Kabat numbering) of the VH1 is a K and the amino acid at position 38 (Kabat numbering) of the VL1 is a D; the amino acid at position 147 (EU numbering) of the CHIHI is a D and the amino acid at position 145 (EU numbering) of the CHIHI is a S and the amino acid at position 131 (EU numbering) of the CL1 is a K; the amino acids at positions 234, 235, and 237 (EU numbering) in the H1H are an A; the amino acid at position 349 (EU numbering) of the CHlm is a C; the amino acid at position 366 (EU numbering) of the CHlm is a S; the amino acid at position 368 (EU numbering) of the CHlm is a A; the amino acid at position 407 (EU numbering) of CHlm is a V; and

[0229] the amino acid at position 447 (EU numbering) of the CHlm is deleted, when numbered in accordance with Hl amino acid sequence of SEQ NO: 439 and LI amino acid sequence of SEQ NO: 438.

[0230] In addition to the specific complementarity determining regions recited above, the bispecific antibody EIP0377 comprises the following amino acids substitutions in the H2 and L2: the amino acid at position 39 (Kabat numbering) of the VH2 is a D and the amino acid at position 38 (Kabat numbering) of the VL2 is a K; the amino acid at position 187 (EU numbering) of the CH2HI is a D and the amino acid at position 138 (EU numbering) of the CL2 is a K; the amino acid at position 170 (EU numbering) of the CH2HI is a C and the amino acid at position 162 (EU numbering) of the CL2 is a C; the amino acid at position 220 (EU numbering) in the H2H is a S and the amino acid at position 214 (EU numbering) of the CL2is a S; the amino acids at positions 234, 235, and 237 (EU numbering) of the H2H are an A; the amino acid at position 354 (EU numbering) of the CH2H3 is a C; the amino acid at position 366 (EU numbering) of the CH2H3 is a W; and the amino acid at position 447 (EU numbering) of the CH2H3 is deleted, when numbered in accordance with H2 amino acid sequence of SEQ NO: 437 and L2 amino acid sequence of SEQ NO: 436.

[0231] In some embodiments, the bispecific antibody EIP0377 comprises a VH1 comprising the amino acid sequence of SEQ ID NO: 13, a VH2 comprising the amino acid sequence of SEQ ID NO: 2, a VL1 comprising the amino acid sequence of SEQ ID NO: 22, and a VL2 comprising the amino acid sequence of SEQ ID NO: 1.

[0232] In some embodiments, the bispecific antibody EIP0377 comprises a Hl comprising the amino acid sequence of SEQ ID NO: 126, a H2 comprising the amino acid sequence of SEQ ID NO: 124, a LI comprising the amino acid sequence of SEQ ID NO: 125, and a L2 comprising the amino acid sequence of SEQ ID NO: 123.

[0233] In addition to the specific complementarity determining regions recited above, the bispecific antibody EIP0404 comprises the following amino acids substitutions in the Hl and LI: the amino acid at position 39 (Kabat numbering) of the VH1 is a D and the amino acid at position 38 (Kabat numbering) of the VL1 is a K; the amino acid at position 147 (EU numbering) of the CHIHI is a K and the amino acid at position 131 (EU numbering) of the CL1 is a D; the amino acid at position 185 (EU numbering) of the CHIHI is a E and the amino acid at position 137 (EU numbering) of the CL1 is a K; the amino acids at positions 234, 235, and 237 (EU numbering) in the H1H are an A; the amino acid at position 349 (EU numbering) of the CH1H3 is a C; the amino acid at position 366 (EU numbering) of the CHlm is a S; the amino acid at position 368 (EU numbering) of the CHlm is a A; the amino acid at position 407 (EU numbering) of CH1H3 is a V; and the amino acid at position 447 (EU numbering) of the CH1H3 is deleted, when numbered in accordance with Hl amino acid sequence of SEQ NO: 439 and LI amino acid sequence of SEQ NO: 438.

[0234] In addition to the specific complementarity determining regions recited above, the bispecific antibody EIP0404 comprises the following amino acids substitutions in the H2 and L2: the amino acid at position 39 (Kabat numbering) of the VH2 is a K and the amino acid at position 38 (Kabat numbering) of the VL2 is a D; the amino acid at position 147 (EU numbering) of the CH2HI is a D and the amino acid at position 180 (EU numbering) of theCL2 is a R; the amino acid at position 136 (EU numbering) of the CH2HI is a C and the amino acid at position 114 (EU numbering) of the CL2 is a C; the amino acid at position 220 (EU numbering) in the H2H is a S and the amino acid at position 214 (EU numbering) of the CL2 is a S; the amino acids at positions 234, 235, and 237 (EU numbering) of the H2H are an A; the amino acid at position 354 (EU numbering) of the CH2H3 is a C; the amino acid at position 366 (EU numbering) of the CH2H3 is a W; and the amino acid at position 447 (EU numbering) of the CH2H3 is deleted, when numbered in accordance with H2 amino acid sequence of SEQ NO: 437 and L2 amino acid sequence of SEQ NO: 436.

[0235] In some embodiments, the bispecific antibody EIP0404 comprises a VH1 comprising the amino acid sequence of SEQ ID NO: 13, a VH2 comprising the amino acid sequence of SEQ ID NO: 2, a VL1 comprising the amino acid sequence of SEQ ID NO: 24, and a VL2 comprising the amino acid sequence of SEQ ID NO: 1.

[0236] In some embodiments, the bispecific antibody EIP0404 comprises a Hl comprising the amino acid sequence of SEQ ID NO: 130, a H2 comprising the amino acid sequence of SEQ ID NO: 128, a LI comprising the amino acid sequence of SEQ ID NO: 129, and a L2 comprising the amino acid sequence of SEQ ID NO: 127.

[0237] In addition to the specific complementarity determining regions recited above, the bispecific antibody EIP0406 comprises the following amino acids substitutions in the Hl and LI: the amino acid at position 39 (Kabat numbering) of the VH1 is a K and the amino acid at position 38 (Kabat numbering) of the VL1 is a E; the amino acid at position 147 (EU numbering) of the CHIHI is a K and the amino acid at position 131 (EU numbering) of the CL1 is a D; the amino acid at position 185 (EU numbering) of the CHIHI is a E and the amino acid at position 137 (EU numbering) of the CL1 is a K; the amino acids at positions 234, 235, and 237 (EU numbering) in the H1H are an A; the amino acid at position 349 (EU numbering) of the CH1H3 is a C; the amino acid at position 366 (EU numbering) of the CH1H3 is a S; the amino acid at position 368 (EU numbering) of the CH1H3 is a A; the amino acid at position 407 (EU numbering) of CH1H3 is a V; and the amino acid at position 447 (EU numbering) of the CH1H3 is deleted, when numbered in accordance with Hl amino acid sequence of SEQ NO: 439 and LI amino acid sequence of SEQ NO: 438.

[0238] In addition to the specific complementarity determining regions recited above, the bispecific antibody EIP0406 comprises the following amino acids substitutions in the H2 andL2: the amino acid at position 39 (Kabat numbering) of the VH2 is a D and the amino acid at position 38 (Kabat numbering) of the VL2 is a K; the amino acid at position 187 (EU numbering) of the CH2HI is a D and the amino acid at position 138 (EU numbering) of the CL2 is a K; the amino acid at position 136 (EU numbering) of the CH2HI is a C and the amino acid at position 114 (EU numbering) of the CL2 is a C; the amino acid at position 220 (EU numbering) in the H2H is a S and the amino acid at position 214 (EU numbering) of the CL2 is a S; the amino acids at positions 234, 235, and 237 (EU numbering) of the H2H are an A; the amino acid at position 354 (EU numbering) of the CH2H3 is a C; the amino acid at position 366 (EU numbering) of the CH2H3 is a W; and the amino acid at position 447 (EU numbering) of the CH2H3 is deleted, when numbered in accordance with H2 amino acid sequence of SEQ NO: 437 and L2 amino acid sequence of SEQ NO: 436.

[0239] In some embodiments, the bispecific antibody EIP0406 comprises a VH1 comprising the amino acid sequence of SEQ ID NO: 13, a VH2 comprising the amino acid sequence of SEQ ID NO: 2, a VL1 comprising the amino acid sequence of SEQ ID NO: 24, and a VL2 comprising the amino acid sequence of SEQ ID NO: 1.

[0240] In some embodiments, the bispecific antibody EIP0406 comprises a Hl comprising the amino acid sequence of SEQ ID NO: 134, a H2 comprising the amino acid sequence of SEQ ID NO: 132, a LI comprising the amino acid sequence of SEQ ID NO: 133, and a L2 comprising the amino acid sequence of SEQ ID NO: 131.

[0241] In addition to the specific complementarity determining regions recited above, the bispecific antibody EIP0473 comprises the following amino acids substitutions in the Hl and LI: the amino acid at position 39 (Kabat numbering) of the VH1 is a K and the amino acid at position 38 (Kabat numbering) of the VL1 is a D; the amino acid at position 147 (EU numbering) of the CHIHI is a D and the amino acid at position 131 (EU numbering) of the CL1 is a K; the amino acid at position 185 (EU numbering) of the CHIHI is a D and the amino acid at position 137 (EU numbering) of the CL1 is a K; the amino acids at positions 234, 235, and 237 (EU numbering) in the H1H are an A; the amino acid at position 349 (EU numbering) of the CH1H3 is a C; the amino acid at position 366 (EU numbering) of the CHlm is a S; the amino acid at position 368 (EU numbering) of the CHlm is a A; the amino acid at position 407 (EU numbering) of CH1H3 is a V; and the amino acid at position 447 (EU numbering) ofthe CH1H3 is deleted, when numbered in accordance with Hl amino acid sequence of SEQ NO: 439 and LI amino acid sequence of SEQ NO: 438.

[0242] In addition to the specific complementarity determining regions recited above, the bispecific antibody EIP0473 comprises the following amino acids substitutions in the H2 and L2: the amino acid at position 39 (Kabat numbering) of the VH2 is a D and the amino acid at position 38 (Kabat numbering) of the VL2 is a K; the amino acid at position 187 (EU numbering) of the CH2HI is a D and the amino acid at position 138 (EU numbering) of the CL2 is a K; the amino acid at position 171 (EU numbering) of the CH2HI is a C and the amino acid at position 162 (EU numbering) of the CL2 is a C; the amino acid at position 220 (EU numbering) in the H2H is a S and the amino acid at position 214 (EU numbering) of the CL2 is a S; the amino acids at positions 234, 235, and 237 (EU numbering) of the H2H are an A; the amino acid at position 354 (EU numbering) of the CH2H3 is a C; the amino acid at position 366 (EU numbering) of the CH2H3 is a W; and the amino acid at position 447 (EU numbering) of the CH2H3 is deleted, when numbered in accordance with H2 amino acid sequence of SEQ NO: 437 and L2 amino acid sequence of SEQ NO: 436.

[0243] In some embodiments, the bispecific antibody EIP0473 comprises a VH1 comprising the amino acid sequence of SEQ ID NO: 13, a VH2 comprising the amino acid sequence of SEQ ID NO: 4, a VL1 comprising the amino acid sequence of SEQ ID NO: 22, and a VL2 comprising the amino acid sequence of SEQ ID NO: 3.

[0244] In some embodiments, the bispecific antibody EIP0473 comprises a Hl comprising the amino acid sequence of SEQ ID NO: 138, a H2 comprising the amino acid sequence of SEQ ID NO: 136, a LI comprising the amino acid sequence of SEQ ID NO: 137, and a L2 comprising the amino acid sequence of SEQ ID NO: 135.

[0245] In addition to the specific complementarity determining regions recited above, the bispecific antibody EIP0598 comprises the following amino acids substitutions in the Hl and LI: the amino acid at position 39 (Kabat numbering) of the VH1 is a K and the amino acid at position 38 (Kabat numbering) of the VL1 is a D; the amino acid at position 170 (EU numbering) of the CHI HI is a S and the amino acid at position 131 (EU numbering) of the CL1 is a D; the amino acid at position 173 (EU numbering) of the CHIHI is a C and the amino acid at position 162 (EU numbering) of the CL1 is a C; the amino acid at position 220 (EU numbering) of the H1H is a S and the amino acid at position 214 (EU numbering) of the CL1is an S; the amino acids at positions 234, 235, and 237 (EU numbering) in the H1H are an A; the amino acid at position 349 (EU numbering) of the CH1H3 is a C; the amino acid at position 366 (EU numbering) of the CH1H3 is a S; the amino acid at position 368 (EU numbering) of the CH1H3 is a A; the amino acid at position 407 (EU numbering) of CH1H3 is a V; and the amino acid at position 447 (EU numbering) of the CHlm is deleted, when numbered in accordance with Hl amino acid sequence of SEQ NO: 439 and LI amino acid sequence of SEQ NO: 438.

[0246] In addition to the specific complementarity determining regions recited above, the bispecific antibody EIP0598 comprises the following amino acids substitutions in the H2 and L2: the amino acid at position 39 (Kabat numbering) of the VH2 is a D and the amino acid at position 38 (Kabat numbering) of the VL2 is a K; the amino acid at position 147 (EU numbering) of the CH2HI is a D and the amino acid at position 180 (EU numbering) of the CL2 is a R; the amino acids at positions 234, 235, and 237 (EU numbering) of the H2H are an A; the amino acid at position 354 (EU numbering) of the CH2H3 is a C; the amino acid at position 366 (EU numbering) of the CH2H3 is a W; and the amino acid at position 447 (EU numbering) of the CH2H3 is deleted, when numbered in accordance with H2 amino acid sequence of SEQ NO: 437 and L2 amino acid sequence of SEQ NO: 436.

[0247] In some embodiments, the bispecific antibody EIP0598 comprises a VH1 comprising the amino acid sequence of SEQ ID NO: 13, a VH2 comprising the amino acid sequence of SEQ ID NO: 2, a VL1 comprising the amino acid sequence of SEQ ID NO: 22, and a VL2 comprising the amino acid sequence of SEQ ID NO: 1.

[0248] In some embodiments, the bispecific antibody EIP0598 comprises a Hl comprising the amino acid sequence of SEQ ID NO: 142, a H2 comprising the amino acid sequence of SEQ ID NO: 140, a LI comprising the amino acid sequence of SEQ ID NO: 141, and a L2 comprising the amino acid sequence of SEQ ID NO: 139.

[0249] Any one of the bispecific antibodies shown above in Table 7 can be further modified by substituting any one of the anti-CD3s antigen binding regions with any one of the anti- CD3s binding regions shown in Tables 7-9. For example, the anti-CD3s antigen binding regions of bispecific antibody “EIP0205” can be substituted with any one of the anti-CD3s binding regions shown in Tables 7-9 to produce the bispecific antibodies of the disclosure.Exemplary antibodies are shown in Table 8. The underlined sequences are CDR sequence according to Kabat and the bolded sequences are CDR sequences according to Chothia.Table 8. Exemplary Bispecific Antibodies that bind to CD3s and ULBP2 / 5 / 6

[0250] In some embodiments, exemplary, CD3s x ULBP2 / 5 / 6 bispecific antibodies of the disclosure include EIP0527, EIP0624, EIP0486, EIP0626, EIP0483, EIP0623, EIP0621, EIP0625, EIP0622, EIP0525.

[0251] Bispecific antibodies EIP0527, EIP0624, EIP0486, EIP0626, EIP0483, EIP0623, EIP0621, EIP0625, EIP0622, and EIP0525 comprise the following amino acids substitutionsin the Hl and LI: the amino acid at position 39 (Kabat numbering) of the VH1 is a K and the amino acid at position 38 (Kabat numbering) of the VL1 is a D;

[0252] the amino acid at position 147 (EU numbering) of the CHIHI is a K and the amino acid at position 131 (EU numbering) of the CL1 is a D; the amino acid at position 173 (EU numbering) of the CHIHI is a C and the amino acid at position 162 (EU numbering) of the CL1 is a C; the amino acid at position 220 (EU numbering) of the H1H is a S and the amino acid at position 214 (EU numbering) of the CL1 is a S; the amino acids at positions 234, 235, and 237 (EU numbering) in the H1H are an A; the amino acid at position 349 (EU numbering) of the CH1H3 is a C; the amino acid at position 366 (EU numbering) of the CHlm is a S; the amino acid at position 368 (EU numbering) of the CHlm is a A; the amino acid at position 407 (EU numbering) of CH1H3 is a V; and the amino acid at position 447 (EU numbering) of the CH1H3 is deleted, when numbered in accordance with Hl amino acid sequence of SEQ NO: 439 and LI amino acid sequence of SEQ NO: 438.

[0253] Bispecific antibodies EIP0527, EIP0624, EIP0486, EIP0626, EIP0483, EIP0623, EIP0621, EIP0625, EIP0622, and EIP0525 have a second antigen binding domain that binds ULBP2 / 5 / 6 comprising a VH2, comprising VH2CDRI having the amino acid sequence of SEQ ID NO: 5; a VH2CDR2 having the amino acid sequence of SEQ ID NO: 7; and a VH2CDR3 having the amino acid sequence of SEQ ID NO: 9; and a VL2, comprising a VL2CDRI having the amino acid sequence of SEQ ID NO: 10; a VL2CDR2 having the amino acid sequence of SEQ ID NO: 11; and a VL2CDR3 having the amino acid sequence of SEQ ID NO: 12.

[0254] Bispecific antibodies EIP0527, EIP0624, EIP0486, EIP0626, EIP0483, EIP0623, EIP0621, EIP0625, EIP0622, and EIP0525 comprise a VH2 comprising the amino acid sequence of SEQ ID NO: 2; and a VL2 comprising the amino acid sequence of SEQ ID NO: 1.

[0255] Bispecific antibodies EIP0527, EIP0624, EIP0486, EIP0626, EIP0483, EIP0623, EIP0621, EIP0625, EIP0622, and EIP0525 have a H2 comprising the amino acid sequence of SEQ ID NO: 68; and a L2 comprising the amino acid sequence of SEQ ID NO: 67.

[0256] In addition to the VH2, VL2, H2, L2 sequences and amino acid substitutions shown above, the bispecific antibody EIP0527 comprises a first antigen binding domain that binds CD3s comprising a VH1, comprising a VHICDRI having the amino acid sequence of SEQ ID NO: 29; a VH1CDR2 having the amino acid sequence of SEQ ID NO: 34; and a VH1CDR3having the amino acid sequence of SEQ ID NO: 37; and a VL1, comprising a VLICDRI having the amino acid sequence of SEQ ID NO: 42; a VL1CDR2 having the amino acid sequence of SEQ ID NO: 43; and a VL1CDR3 having the amino acid sequence of SEQ ID NO: 46.

[0257] In some embodiments, the bispecific antibody EIP0527 comprises a VH1 having the amino acid sequence of SEQ ID NO: 13 and a VL1 having the amino acid sequence of SEQ ID NO: 25. In some embodiments, the bispecific antibody EIP0527 comprises a Hl having the amino acid sequence of SEQ ID NO: 146 and a LI having the amino acid sequence of SEQ ID NO: 145.

[0258] In addition to the VH2, VL2, H2, L2 sequences and amino acid substitutions shown above, the bispecific antibody EIP0624 comprises a first antigen binding domain that binds CD3s comprising a VH1, comprising a VHICDRI having the amino acid sequence of SEQ ID NO: 29; a VH1CDR2 having the amino acid sequence of SEQ ID NO: 34; and a VH1CDR3 having the amino acid sequence of SEQ ID NO: 38; and a VL1, comprising a VLICDRI having the amino acid sequence of SEQ ID NO: 42; a VL1CDR2 having the amino acid sequence of SEQ ID NO: 43; and a VL1CDR3 having the amino acid sequence of SEQ ID NO: 47.

[0259] In some embodiments, the bispecific antibody EIP0624 comprises a VH1 having the amino acid sequence of SEQ ID NO: 15 and a VL1 having the amino acid sequence of SEQ ID NO: 26. In some embodiments, the bispecific antibody EIP0624 comprises a Hl having the amino acid sequence of SEQ ID NO: 150 and a LI having the amino acid sequence of SEQ ID NO: 149.

[0260] In addition to the VH2, VL2, H2, L2 sequences and amino acid substitutions shown above, the bispecific antibody EIP0486 comprises a first antigen binding domain that binds CD3s comprising a VH1, comprising a VHICDRI having the amino acid sequence of SEQ ID NO: 29; a VH1CDR2 having the amino acid sequence of SEQ ID NO: 34; and a VH1CDR3 having the amino acid sequence of SEQ ID NO: 37; and a VL1, comprising a VLICDRI having the amino acid sequence of SEQ ID NO: 42; a VL1CDR2 having the amino acid sequence of SEQ ID NO: 44; and a VL1CDR3 having the amino acid sequence of SEQ ID NO: 45.

[0261] In some embodiments, the bispecific antibody EIP0486 comprises a VH1 having the amino acid sequence of SEQ ID NO: 13 and a VL1 having the amino acid sequence of SEQ ID NO: 27. In some embodiments, the bispecific antibody EIP0486 comprises a Hl havingthe amino acid sequence of SEQ ID NO: 154 and a LI having the amino acid sequence of SEQ ID NO: 153.

[0262] In addition to the VH2, VL2, H2, L2 sequences and amino acid substitutions shown above, the bispecific antibody EIP0626 comprises a first antigen binding domain that binds CD3s comprising a VH1, comprising a VHICDRI having the amino acid sequence of SEQ ID NO: 29; a VH1CDR2 having the amino acid sequence of SEQ ID NO: 34; and a VH1CDR3 having the amino acid sequence of SEQ ID NO: 39; and a VL1, comprising a VLICDRI having the amino acid sequence of SEQ ID NO: 42; a VL1CDR2 having the amino acid sequence of SEQ ID NO: 43; and a VL1CDR3 having the amino acid sequence of SEQ ID NO: 47.

[0263] In some embodiments, the bispecific antibody EIP0626 comprises a VH1 having the amino acid sequence of SEQ ID NO: 16 and a VL1 having the amino acid sequence of SEQ ID NO: 26. In some embodiments, the bispecific antibody EIP0626 comprises a Hl having the amino acid sequence of SEQ ID NO: 158 and a LI having the amino acid sequence of SEQ ID NO: 157.

[0264] In addition to the VH2, VL2, H2, L2 sequences and amino acid substitutions shown above, the bispecific antibody EIP0483 comprises a first antigen binding domain that binds CD3s comprising a VH1, comprising a VHICDRI having the amino acid sequence of SEQ ID NO: 30; a VH1CDR2 having the amino acid sequence of SEQ ID NO: 34; and a VH1CDR3 having the amino acid sequence of SEQ ID NO: 37; and a VL1, comprising a VLICDRI having the amino acid sequence of SEQ ID NO: 42; a VL1CDR2 having the amino acid sequence of SEQ ID NO: 43; and a VL1CDR3 having the amino acid sequence of SEQ ID NO: 45.

[0265] In some embodiments, the bispecific antibody EIP0483 comprises a VH1 having the amino acid sequence of SEQ ID NO: 17 and a VL1 having the amino acid sequence of SEQ ID NO: 22. In some embodiments, the bispecific antibody EIP0483 comprises a Hl having the amino acid sequence of SEQ ID NO: 162 and a LI having the amino acid sequence of SEQ ID NO: 161.

[0266] In addition to the VH2, VL2, H2, L2 sequences and amino acid substitutions shown above, the bispecific antibody EIP0623 comprises a first antigen binding domain that binds CD3s comprising a VH1, comprising a VHICDRI having the amino acid sequence of SEQ ID NO: 29; a VH1CDR2 having the amino acid sequence of SEQ ID NO: 35; and a VH1CDR3 having the amino acid sequence of SEQ ID NO: 38; and a VL1, comprising a VLICDRI havingthe amino acid sequence of SEQ ID NO: 42; a VL1CDR2 having the amino acid sequence of SEQ ID NO: 43; and a VL1CDR3 having the amino acid sequence of SEQ ID NO: 47.

[0267] In some embodiments, the bispecific antibody EIP0623 comprises a VH1 having the amino acid sequence of SEQ ID NO: 18 and a VL1 having the amino acid sequence of SEQ ID NO: 26. In some embodiments, the bispecific antibody EIP0623 comprises a Hl having the amino acid sequence of SEQ ID NO: 166 and a LI having the amino acid sequence of SEQ ID NO: 165.

[0268] In addition to the VH2, VL2, H2, L2 sequences and amino acid substitutions shown above, the bispecific antibody EIP0621 comprises a first antigen binding domain that binds CD3s comprising a VH1, comprising a VHICDRI having the amino acid sequence of SEQ ID NO: 29; a VH1CDR2 having the amino acid sequence of SEQ ID NO: 34; and a VH1CDR3 having the amino acid sequence of SEQ ID NO: 40; and a VL1, comprising a VLICDRI having the amino acid sequence of SEQ ID NO: 42; a VL1CDR2 having the amino acid sequence of SEQ ID NO: 43; and a VL1CDR3 having the amino acid sequence of SEQ ID NO: 47.

[0269] In some embodiments, the bispecific antibody EIP0621 comprises a VH1 having the amino acid sequence of SEQ ID NO: 19 and a VL1 having the amino acid sequence of SEQ ID NO: 26. In some embodiments, the bispecific antibody EIP0621 comprises a Hl having the amino acid sequence of SEQ ID NO: 170 and a LI having the amino acid sequence of SEQ ID NO: 169.

[0270] In addition to the VH2, VL2, H2, L2 sequences and amino acid substitutions shown above, the bispecific antibody EIP0625 comprises a first antigen binding domain that binds CD3s comprising a VH1, comprising a VHICDRI having the amino acid sequence of SEQ ID NO: 29; a VH1CDR2 having the amino acid sequence of SEQ ID NO: 35; and a VH1CDR3 having the amino acid sequence of SEQ ID NO: 38; and a VL1, comprising a VLICDRI having the amino acid sequence of SEQ ID NO: 42; a VL1CDR2 having the amino acid sequence of SEQ ID NO: 43; and a VL1CDR3 having the amino acid sequence of SEQ ID NO: 45.

[0271] In some embodiments, the bispecific antibody EIP0625 comprises a VH1 having the amino acid sequence of SEQ ID NO: 18 and a VL1 having the amino acid sequence of SEQ ID NO: 22. In some embodiments, the bispecific antibody EIP0625 comprises a Hl having the amino acid sequence of SEQ ID NO: 174 and a LI having the amino acid sequence of SEQ ID NO: 173.

[0272] In addition to the VH2, VL2, H2, L2 sequences and amino acid substitutions shown above, the bispecific antibody EIP0622 comprises a first antigen binding domain that binds CD3s comprising a VH1, comprising a VHICDRI having the amino acid sequence of SEQ ID NO: 29; a VH1CDR2 having the amino acid sequence of SEQ ID NO: 34; and a VH1CDR3 having the amino acid sequence of SEQ ID NO: 41; and a VL1, comprising a VLICDRI having the amino acid sequence of SEQ ID NO: 42; a VL1CDR2 having the amino acid sequence of SEQ ID NO: 43; and a VL1CDR3 having the amino acid sequence of SEQ ID NO: 47.

[0273] In some embodiments, the bispecific antibody EIP0622 comprises a VH1 having the amino acid sequence of SEQ ID NO: 20 and a VL1 having the amino acid sequence of SEQ ID NO: 26. In some embodiments, the bispecific antibody EIP0622 comprises a Hl having the amino acid sequence of SEQ ID NO: 178 and a LI having the amino acid sequence of SEQ ID NO: 177.

[0274] In addition to the VH2, VL2, H2, L2 sequences and amino acid substitutions shown above, the bispecific antibody EIP0525 comprises a first antigen binding domain that binds CD3s comprising a VH1, comprising a VHICDRI having the amino acid sequence of SEQ ID NO: 31; a VH1CDR2 having the amino acid sequence of SEQ ID NO: 34; and a VH1CDR3 having the amino acid sequence of SEQ ID NO: 37; and a VL1, comprising a VLICDRI having the amino acid sequence of SEQ ID NO: 42; a VL1CDR2 having the amino acid sequence of SEQ ID NO: 43; and a VL1CDR3 having the amino acid sequence of SEQ ID NO: 45.

[0275] In some embodiments, the bispecific antibody EIP0525 comprises a VH1 having the amino acid sequence of SEQ ID NO: 21 and a VL1 having the amino acid sequence of SEQ ID NO: 22. In some embodiments, the bispecific antibody EIP0525 comprises a Hl having the amino acid sequence of SEQ ID NO: 182 and a LI having the amino acid sequence of SEQ ID NO: 181.

[0276] In some embodiments, exemplary, CD3s x ULBP2 / 5 / 6 bispecific antibodies of the disclosure include EIP0630, EIP0540, EIP0628, EIP0542, EIP0627, EIP0515, EIP0477, EIP0541, EIP0513, EIP0629.

[0277] Bispecific antibodies EIP0630, EIP0540, EIP0628, EIP0542, EIP0627, EIP0515, EIP0477, EIP0541, EIP0513, and EIP0629 have the following amino acids substitutions in the Hl and LI: the amino acid at position 39 (Kabat numbering) of the VH1 is a K and the amino acid at position 38 (Kabat numbering) of the VL1 is a D; the amino acid at position170 (EU numbering) of the CHIHI is a S and the amino acid at position 131 (EU numbering) of the CL1 is a D; the amino acid at position 173 (EU numbering) of the CHIHI is a C and the amino acid at position 162 (EU numbering) of the CL1 is a C; the amino acid at position 220 (EU numbering) of the H1H is a S and the amino acid at position 214 (EU numbering) of the CL1 is an S; the amino acids at positions 234, 235, and 237 (EU numbering) in the H1H are an A; the amino acid at position 349 (EU numbering) of the CHlm is a C; the amino acid at position 366 (EU numbering) of the CHlm is a S; the amino acid at position 368 (EU numbering) of the CH1H3 is a A; the amino acid at position 407 (EU numbering) of CH1H3 is a V; and the amino acid at position 447 (EU numbering) of the CH1H3 is deleted, when numbered in accordance with Hl amino acid sequence of SEQ NO: 439 and LI amino acid sequence of SEQ NO: 438.

[0278] Bispecific antibodies EIP0630, EIP0540, EIP0628, EIP0542, EIP0627, EIP0515, EIP0477, EIP0541, EIP0513, and EIP0629 have a second antigen binding domain that binds ULBP2 / 5 / 6 comprising a VH2, having VH2CDRI having the amino acid sequence of SEQ ID NO: 5; a VH2CDR2 comprising the amino acid sequence of SEQ ID NO: 7; and a VH2CDR3 having the amino acid sequence of SEQ ID NO: 9; and a VL2, having VL2CDRI having the amino acid sequence of SEQ ID NO: 10; a VL2CDR2 having the amino acid sequence of SEQ ID NO: 11; and a VL2CDR3 having the amino acid sequence of SEQ ID NO: 12.

[0279] Bispecific antibodies EIP0630, EIP0540, EIP0628, EIP0542, EIP0627, EIP0515, EIP0477, EIP0541, EIP0513, and EIP0629 have a VH2 having the amino acid sequence of SEQ ID NO: 2; and a VL2 having the amino acid sequence of SEQ ID NO: 1.

[0280] Bispecific antibodies EIP0630, EIP0540, EIP0628, EIP0542, EIP0627, EIP0515, EIP0477, EIP0541, EIP0513, and EIP0629 have a H2 having the amino acid sequence of SEQ ID NO: 140; and a L2 having the amino acid sequence of SEQ ID NO: 139.

[0281] In addition to the VH2, VL2, H2, L2 sequences and amino acid substitutions shown above, the bispecific antibody EIP0630 comprises a first antigen binding domain that binds CD3s comprising a VH1, comprising a VHICDRI having the amino acid sequence of SEQ ID NO: 29; a VH1CDR2 having the amino acid sequence of SEQ ID NO: 34; and a VH1CDR3 having the amino acid sequence of SEQ ID NO: 37; and a VL1, comprising a VLICDRI having the amino acid sequence of SEQ ID NO: 42; a VL1CDR2 having the amino acid sequence of SEQ ID NO: 43; and a VL1CDR3 having the amino acid sequence of SEQ ID NO: 46.

[0282] In some embodiments, the bispecific antibody EIP0630 comprises a VH1 having the amino acid sequence of SEQ ID NO: 13 and a VL1 having the amino acid sequence of SEQ ID NO: 25. In some embodiments, the bispecific antibody EIP0630 comprises a Hl having the amino acid sequence of SEQ ID NO: 186 and a LI having the amino acid sequence of SEQ ID NO: 185.

[0283] In addition to the VH2, VL2, H2, L2 sequences and amino acid substitutions shown above, the bispecific antibody EIP0540 comprises a first antigen binding domain that binds CD3s comprising a VH1, comprising a VHICDRI having the amino acid sequence of SEQ ID NO: 29; a VH1CDR2 having the amino acid sequence of SEQ ID NO: 34; and a VH1CDR3 having the amino acid sequence of SEQ ID NO: 38; and a VL1, comprising a VLICDRI having the amino acid sequence of SEQ ID NO: 42; a VL1CDR2 having the amino acid sequence of SEQ ID NO: 43; and a VL1CDR3 having the amino acid sequence of SEQ ID NO: 47.

[0284] In some embodiments, the bispecific antibody EIP0540 comprises a VH1 having the amino acid sequence of SEQ ID NO: 15 and a VL1 having the amino acid sequence of SEQ ID NO: 26. In some embodiments, the bispecific antibody EIP0540 comprises a Hl having the amino acid sequence of SEQ ID NO: 190 and a LI having the amino acid sequence of SEQ ID NO: 189.

[0285] In addition to the VH2, VL2, H2, L2 sequences and amino acid substitutions shown above, the bispecific antibody EIP0628 comprises a first antigen binding domain that binds CD3s comprising a VH1, comprising a VHICDRI having the amino acid sequence of SEQ ID NO: 29; a VH1CDR2 having the amino acid sequence of SEQ ID NO: 34; and a VH1CDR3 having the amino acid sequence of SEQ ID NO: 37; and a VL1, comprising a VLICDRI having the amino acid sequence of SEQ ID NO: 42; a VL1CDR2 having the amino acid sequence of SEQ ID NO: 44; and a VL1CDR3 having the amino acid sequence of SEQ ID NO: 45.

[0286] In some embodiments, the bispecific antibody EIP0628 comprises a VH1 having the amino acid sequence of SEQ ID NO: 13 and a VL1 having the amino acid sequence of SEQ ID NO: 27. In some embodiments, the bispecific antibody EIP0628 comprises a Hl having the amino acid sequence of SEQ ID NO: 194 and a LI having the amino acid sequence of SEQ ID NO: 193.

[0287] In addition to the VH2, VL2, H2, L2 sequences and amino acid substitutions shown above, the bispecific antibody EIP0542 comprises a first antigen binding domain that bindsCD3s comprising a VH1, comprising a VHICDRI having the amino acid sequence of SEQ ID NO: 29; a VH1CDR2 having the amino acid sequence of SEQ ID NO: 34; and a VH1CDR3 having the amino acid sequence of SEQ ID NO: 39; and a VL1, comprising a VLICDRI having the amino acid sequence of SEQ ID NO: 42; a VL1CDR2 having the amino acid sequence of SEQ ID NO: 43; and a VL1CDR3 having the amino acid sequence of SEQ ID NO: 47.

[0288] In some embodiments, the bispecific antibody EIP0542 comprises a VH1 having the amino acid sequence of SEQ ID NO: 16 and a VL1 having the amino acid sequence of SEQ ID NO: 26. In some embodiments, the bispecific antibody EIP0542 comprises a Hl having the amino acid sequence of SEQ ID NO: 198 and a LI having the amino acid sequence of SEQ ID NO: 197.

[0289] In addition to the VH2, VL2, H2, L2 sequences and amino acid substitutions shown above, the bispecific antibody EIP0627 comprises a first antigen binding domain that binds CD3s comprising a VH1, comprising a VHICDRI having the amino acid sequence of SEQ ID NO: 30; a VH1CDR2 having the amino acid sequence of SEQ ID NO: 34; and a VH1CDR3 having the amino acid sequence of SEQ ID NO: 37; and a VL1, comprising a VLICDRI having the amino acid sequence of SEQ ID NO: 42; a VL1CDR2 having the amino acid sequence of SEQ ID NO: 43; and a VL1CDR3 having the amino acid sequence of SEQ ID NO: 45.

[0290] In some embodiments, the bispecific antibody EIP0627 comprises a VH1 having the amino acid sequence of SEQ ID NO: 17 and a VL1 having the amino acid sequence of SEQ ID NO: 22. In some embodiments, the bispecific antibody EIP0627 comprises a Hl having the amino acid sequence of SEQ ID NO: 202 and a LI having the amino acid sequence of SEQ ID NO: 201.

[0291] In addition to the VH2, VL2, H2, L2 sequences and amino acid substitutions shown above, the bispecific antibody EIP0515 comprises a first antigen binding domain that binds CD3s comprising a VH1, comprising a VHICDRI having the amino acid sequence of SEQ ID NO: 29; a VH1CDR2 having the amino acid sequence of SEQ ID NO: 35; and a VH1CDR3 having the amino acid sequence of SEQ ID NO: 38; and a VL1, comprising a VLICDRI having the amino acid sequence of SEQ ID NO: 42; a VL1CDR2 having the amino acid sequence of SEQ ID NO: 43; and a VL1CDR3 having the amino acid sequence of SEQ ID NO: 47.

[0292] In some embodiments, the bispecific antibody EIP0515 comprises a VH1 having the amino acid sequence of SEQ ID NO: 18 and a VL1 having the amino acid sequence of SEQID NO: 26. In some embodiments, the bispecific antibody EIP0515 comprises a Hl having the amino acid sequence of SEQ ID NO: 206 and a LI having the amino acid sequence of SEQ ID NO: 205.

[0293] In addition to the VH2, VL2, H2, L2 sequences and amino acid substitutions shown above, the bispecific antibody EIP0477 comprises a first antigen binding domain that binds CD3s comprising a VH1, comprising a VHICDRI having the amino acid sequence of SEQ ID NO: 29; a VH1CDR2 having the amino acid sequence of SEQ ID NO: 34; and a VH1CDR3 having the amino acid sequence of SEQ ID NO: 40; and a VL1, comprising a VLICDRI having the amino acid sequence of SEQ ID NO: 42; a VL1CDR2 having the amino acid sequence of SEQ ID NO: 43; and a VL1CDR3 having the amino acid sequence of SEQ ID NO: 47.

[0294] In some embodiments, the bispecific antibody EIP0477 comprises a VH1 having the amino acid sequence of SEQ ID NO: 19 and a VL1 having the amino acid sequence of SEQ ID NO: 26. In some embodiments, the bispecific antibody EIP0477 comprises a Hl having the amino acid sequence of SEQ ID NO: 210 and a LI having the amino acid sequence of SEQ ID NO: 209.

[0295] In addition to the VH2, VL2, H2, L2 sequences and amino acid substitutions shown above, the bispecific antibody EIP0541 comprises a first antigen binding domain that binds CD3s comprising a VH1, comprising a VHICDRI having the amino acid sequence of SEQ ID NO: 29; a VH1CDR2 having the amino acid sequence of SEQ ID NO: 35; and a VH1CDR3 having the amino acid sequence of SEQ ID NO: 38; and a VL1, comprising a VLICDRI having the amino acid sequence of SEQ ID NO: 42; a VL1CDR2 having the amino acid sequence of SEQ ID NO: 43; and a VL1CDR3 having the amino acid sequence of SEQ ID NO: 45.

[0296] In some embodiments, the bispecific antibody EIP0541 comprises a VH1 having the amino acid sequence of SEQ ID NO: 18 and a VL1 having the amino acid sequence of SEQ ID NO: 22. In some embodiments, the bispecific antibody EIP0541 comprises a Hl having the amino acid sequence of SEQ ID NO: 214 and a LI having the amino acid sequence of SEQ ID NO: 213.

[0297] In addition to the VH2, VL2, H2, L2 sequences and amino acid substitutions shown above, the bispecific antibody EIP0513 comprises a first antigen binding domain that binds CD3s comprising a VH1, comprising a VHICDRI having the amino acid sequence of SEQ ID NO: 29; a VH1CDR2 having the amino acid sequence of SEQ ID NO: 34; and a VH1CDR3having the amino acid sequence of SEQ ID NO: 41; and a VL1, comprising a VLICDRI having the amino acid sequence of SEQ ID NO: 42; a VL1CDR2 having the amino acid sequence of SEQ ID NO: 43; and a VL1CDR3 having the amino acid sequence of SEQ ID NO: 47.

[0298] In some embodiments, the bispecific antibody EIP0513 comprises a VH1 having the amino acid sequence of SEQ ID NO: 20 and a VL1 having the amino acid sequence of SEQ ID NO: 26. In some embodiments, the bispecific antibody EIP0513 comprises a Hl having the amino acid sequence of SEQ ID NO: 218 and a LI having the amino acid sequence of SEQ ID NO: 217.

[0299] In addition to the VH2, VL2, H2, L2 sequences and amino acid substitutions shown above, the bispecific antibody EIP0629 comprises a first antigen binding domain that binds CD3s comprising a VH1, comprising a VHICDRI having the amino acid sequence of SEQ ID NO: 31; a VH1CDR2 having the amino acid sequence of SEQ ID NO: 34; and a VH1CDR3 having the amino acid sequence of SEQ ID NO: 37; and a VL1, comprising a VLICDRI having the amino acid sequence of SEQ ID NO: 42; a VL1CDR2 having the amino acid sequence of SEQ ID NO: 43; and a VL1CDR3 having the amino acid sequence of SEQ ID NO: 45.

[0300] In some embodiments, the bispecific antibody EIP0629 comprises a VH1 having the amino acid sequence of SEQ ID NO: 21 and a VL1 having the amino acid sequence of SEQ ID NO: 22. In some embodiments, the bispecific antibody EIP0629 comprises a Hl having the amino acid sequence of SEQ ID NO: 222 and a LI having the amino acid sequence of SEQ ID NO: 221.

[0301] In some embodiments, exemplary CD3s x ULBP2 / 5 / 6 bispecific antibodies of the present disclosure comprise an amino acid at position 446 (EU numbering) and / or at position 447 (EU numbering) of the CH1H3 and / or of the CH2H3. In some embodiments, wherein the exemplary bispecific antibodies comprise an amino acid at position 446 (EU numbering) of the CH1H3 and / or of the CH2H3, the amino acid at position 446 (EU numbering) is a G. In some embodiments, wherein the exemplary bispecific antibodies comprise an amino acid at position 446 (EU numbering) of the CHlm and / or of the CH2H3, the bispecific antibodies further comprise an amino acid at position 447 (EU numbering) of the CHlm and / or of the CH2H3. In some embodiments, wherein the exemplary bispecific antibodies comprise an amino acid at position 447 (EU numbering) of the CH1H3 and / or of the CH2H3, the amino acid at position 447 (EU numbering) is a K.

[0302] In some embodiments, exemplary CD3s x ULBP2 / 5 / 6 bispecific antibodies of the present disclosure comprise an amino acid at position 446 (EU numbering) of the CH1H3 or CH2H3. In some embodiments, the bispecific antibodies comprise an amino acid at position 446 (EU numbering) of the CHI H3 and CH2H3. In some embodiments, the bispecific antibodies comprise an amino acid at position 446 (EU numbering) of the CH1H3. In some embodiments, the bispecific antibodies comprise an amino acid at position 446 (EU numbering) of the CH2H3.

[0303] In some embodiments, wherein the bispecific antibodies comprise an amino acid at position 446 (EU numbering) of the CH1H3 and / or CH2H3, the amino acid at position 446 (EU numbering) is a G. In some embodiments, wherein the bispecific antibodies comprise an amino acid at position 446 (EU numbering) of the CH1H3, the amino acid at position 446 (EU numbering) is a G. In some embodiments, wherein the bispecific antibodies comprise an amino acid at position 446 (EU numbering) of the CH2H3, the amino acid at position 446 (EU numbering) is a G. In some embodiments, wherein the bispecific antibodies comprise an amino acid at position 446 (EU numbering) of the CH1H3 and CH2H3, the amino acid at position 446 (EU numbering) of the CH1H3 and CH2H3 is a G.

[0304] In some embodiments, exemplary CD3s x ULBP2 / 5 / 6 bispecific antibodies of the disclosure comprise an amino acid at position 447 (EU numbering) of the CH1H3 and / or of the CH2H3. In some embodiments, the bispecific antibodies comprise an amino acid at position 447 (EU numbering) of the CH1H3 or of the CH2H3. In some embodiments, the bispecific antibodies comprise an amino acid at position 447 (EU numbering) of the CH1H3 and of the CH2H3. In some embodiments, the bispecific antibodies comprise an amino acid at position 447 (EU numbering) of the CH1H3. In some embodiments, the bispecific antibodies comprise an amino acid at position 447 (EU numbering) of the CH2H3.

[0305] In some embodiments, wherein CD3s x ULBP2 / 5 / 6 bispecific antibodies comprise an amino acid at position 447 (EU numbering) of the CH1H3 and / or of the CH2H3, the amino acid at position 447 (EU numbering) is a K. In some embodiments, wherein the bispecific antibodies comprise an amino acid at position 447 (EU numbering) of the CH1H3, the amino acid at position 447 (EU numbering) is a K. In some embodiments, wherein the bispecific antibodies comprise an amino acid at position 447 (EU numbering) of the CH2H3, the amino acid at position 447 (EU numbering) is a K.Fusion Peptides

[0306] Provided herein is an antibody (e.g. monospecific antibody or bispecific antibody) that has a fusion peptide fused to the N-terminus or the C-terminus of the first heavy chain polypeptide or the second heavy chain polypeptide.

[0307] Critical to the initial T cell response is the capacity for T cells to detect foreign and mutated proteins through their T cell receptor. This response, often referred to as signal 1 of T cell activation, occurs when the T cell receptor engages a cell that displays a foreign or mutated protein fragment or antigen in a specific protein complex called the Major Histocompatibility Complex I (MHCI). The activation of the T cell receptor is by itself both activating and auto-regulatory to T cells. Strong binding of the TCR to an MHCI complex creates chronic activation of the TCR. This form of signal is associated with T cells that are reactive to self-antigens. T cells are programed to inactivate when they experience this form activation. T cells with TCR that bind weaker, but sufficient for activation, experience acute signaling with the potential to remain active and differentiate into memory T cells. This is emerging as important consideration in the design the T cell therapeutics.

[0308] T cell cytokine activation, often referred to signal 3, is important in T cell transitions, either from non-dividing to a state of rapid cell division or from one phenotypic state to another. T cell cytokine receptors bind to cytokines that are produced by immune and non- immune cells and depending on the cytokine and the state of the T cell at the time of receiving the cytokine signal can induce cell proliferation, can sustain vitality, or can induce differentiation of T cells into a specialized cell state appropriate for sustained activation or inactivation following infection.

[0309] One example is the transition that naive cells experience through cytokines which can induce naive T cells to proliferate and promote T cell differentiation into memory T cells. Exemplary cytokines include but are not limited to IL-2, IL-7, IL- 10, IL- 12, IL- 15, IL- 18 and IL-21.

[0310] Costimulatory receptor activation, referred to as signal 2 provides a context specific cell-to-cell reinforcement of T activation. The most recognized form of costimulation occurs when T cells interact with activated antigen presenting cells through the T cell costimulatoryreceptor CD28 with CD80 and CD86 ligands found on APCs. These interactions can “prime” specific T cells armed with T cell receptors responsive to pathogen or cancer proteins.

[0311] Less appreciated is costimulation induced at the site of infection and malignancies. This includes costimulation that acts through CD2 and NKG2D receptors responsive to ligands like CD58 and ULI 6 binding proteins (e.g. ULBP2 / 5 / 6) that are induced in immune cells and epithelial cells upon viral infection. These signals provide not only reinforcement of T activation, but confirmation that the T cell’s lethal effector activities are targeted with single cell accuracy. While many costimulatory receptors have been discovered, the importance of each receptor’s specific context and the impact of concurrent signaling of multiple costimulatory receptors remains largely unknown and an area to greatly advance our understanding of T cell biology and creating possibilities for novel tumor-targeted T cell therapeutic development.

[0312] Costimulatory ligands include but are not limited to CD48, CD58, CD86, TNFSF9, OX40L, 4-1BBL, GITL, CD70, CD80, MR1, TNFSF4, ICOSL or ICOSLG.

[0313] CD58 is advantageous over other costimulatory ligands in that it is the primary costimulatory pathway available at the tumor site as tumor infiltrating T lymphocytes often lose expression of other costimulatory receptors like CD28, or due to the low immunogenicity of tumor cells, tumor cells do not sufficiently activate T cell, thus limiting the potential of inducible costimulatory receptors like 41BB.

[0314] As described previously, the anti-CD3s antibodies of the disclosure induce varying levels of T cell receptor activation that confer alteration in T cell vitality and cytokine production. Accordingly, a fusion of the costimulatory ligand CD58 to the anti-CD3s bispecific antibody provides integrated costimulatory T cell activation for optimal T cell activation.

[0315] In some embodiments, the bispecific antibody has a peptide fused to the N-terminus of the first heavy chain polypeptide (Hl). In some embodiments, the bispecific antibody has a peptide fused to the C-terminus of the first heavy chain polypeptide (Hl). In some embodiments, the bispecific antibody has a polypeptide fused to the N-terminus of the second heavy chain polypeptide (H2). In some embodiments, the bispecific antibody has a peptide fused to the C-terminus of the second heavy chain polypeptide (H2). Exemplary peptides include but are not limited to IL-2, IL-7, IL- 10, IL- 12, IL- 15, IL- 18, IL-21 or portions thereof.Exemplary peptides include but are not limited to CD48, CD58, CD86, TNFSF9, OX40E, 4- 1BBE, GITE, CD70, CD80, MR1, TNFSF4, ICOSE, ICOSLG or portions thereof. Exemplary peptide sequences that are fused to the bispecific antibodies include but are not limited to those listed in Table 9 and Table 10.Table 9. Exemplary Fusion Peptide SequencesTable 10. Exemplary Fusion Peptide Sequences

[0316] In some embodiments the polypeptide is fused directly to the bispecific antibody. In some embodiments, the polypeptide is fused indirectly through a linker. In some embodiments, the bispecific antibody fused with a peptide comprises a linker sequence. Exemplary linker sequences include but are not limited to those listed in Table 11 and Table 12.Table 11. Exemplary Linker SequencesTable 12. Exemplary Linker SequencesBispecific antibody comprising a fusion peptide

[0317] In some embodiments, the present disclosure provides a bispecific antibody (e.g., a bispecific antibody targeting ULBP2 and CD3) that is fused to a peptide (e.g., a costimulatory CD58 peptide described herein). In some embodiments, a bispecific antibody described (e.g., a bispecific antibody targeting ULBP2 and CD3) herein comprises a peptide (e.g., a costimulatory CD58 peptide described herein) fused to the C-terminal of the heavy chain of the CD3 targeting arm. In some embodiments, a bispecific antibody described (e.g., a bispecific antibody targeting ULBP2 and CD3) herein comprises a peptide (e.g., a costimulatory CD58 peptide described herein) fused to the N-terminal of the heavy chain of the CD3 targeting arm. In some embodiments, a bispecific antibody described (e.g., a bispecific antibody targeting ULBP2 and CD3) herein comprises a peptide (e.g., a costimulatory CD58 peptide described herein) fused to the C-terminal of the light chain of the CD3 targeting arm. In some embodiments, a bispecific antibody described (e.g., a bispecific antibody targeting ULBP2 and CD3) herein comprises a peptide (e.g., acostimulatory CD58 peptide described herein) fused to the N-terminal of the light chain of the CD3 targeting arm. In some embodiments, a bispecific antibody described (e.g., a bispecific antibody targeting ULBP2 and CD3) herein comprises a peptide (e.g., a costimulatory CD58 peptide described herein) fused to the C-terminal of the heavy chain of the ULBP2 targeting arm. In some embodiments, a bispecific antibody described (e.g., a bispecific antibody targeting ULBP2 and CD3) herein comprises a peptide (e.g., a costimulatory CD58 peptide described herein) fused to the N-terminal of the heavy chain of the ULBP2 targeting arm. In some embodiments, a bispecific antibody described (e.g., a bispecific antibody targeting ULBP2 and CD3) herein comprises a peptide (e.g., a costimulatory CD58 peptide described herein) fused to the C-terminal of the light chain of the ULBP2 targeting arm. In some embodiments, a bispecific antibody described (e.g., a bispecific antibody targeting ULBP2 and CD3) herein comprises a peptide (e.g., a costimulatory CD58 peptide described herein) fused to the N-terminal of the light chain of the ULBP2 targeting arm. Table 13 sets forth exemplary bispecific antibodies targeting UBLP2 and CD3 that are fused to a CD58 peptide.

[0318] Table 13. Exemplary Bispecific Antibody fused to a peptide(When applicable: Italics - Variable region, Italics and underline - Kabat CDR definition, Italics and bold - Chothia CDR definition, Underline - CD58 or IL-7 fusion, Underline - cysteine mutation)Ill

[0319] In some embodiments, an exemplary CD3s x ULBP2 / 5 / 6 bispecific antibody of the disclosure includes EIP0820.

[0320] In some embodiments, bispecific antibody EIP0820 comprises the following amino acids substitutions in the Hl and LI: the amino acid at position 39 (Kabat numbering) of the VH1 is a K and the amino acid at position 38 (Kabat numbering) of the VL1 is a D; the amino acid at position 147 (EU numbering) of the CHIHI is a K and the amino acid at position 131 (EU numbering) of the CL1 is a D; the amino acid at position 173 (EU numbering) of the CHIHI is a C and the amino acid at position 162 (EU numbering) of the CL1 is a C; the amino acid at position 220 (EU numbering) of the H1H is a S and the amino acid at position 214 (EU numbering) of the CL1 is a S; the amino acids at positions 234, 235, and 237 (EU numbering) in the H1H are an A; the amino acid at position 349 (EU numbering) of the CH1H3 is a C; the amino acid at position 366 (EU numbering) of the CH1H3 is a S; the amino acid at position 368 (EU numbering) of the CH1H3 is a A; the amino acid at position 407 (EU numbering) of CH1H3 is a V; and the amino acid at position 447 (EU numbering) of the CH1H3 is deleted, when numbered in accordance with Hl amino acid sequence of SEQ NO: 439 and LI amino acid sequence of SEQ NO: 438.

[0321] In some embodiments, bispecific antibody EIP0820 has a second antigen binding domain that binds ULBP2 / 5 / 6 comprising a VH2, comprising VH2CDRI having the amino acid sequence of SEQ ID NO: 5; a VH2CDR2 having the amino acid sequence of SEQ ID NO: 7; and a VH2CDR3 having the amino acid sequence of SEQ ID NO: 9; and a VL2, comprising a VL2CDRI having the amino acid sequence of SEQ ID NO: 10; a VL2CDR2 having the amino acid sequence of SEQ ID NO: 11; and a VL2CDR3 having the amino acid sequence of SEQ ID NO: 12.

[0322] In some embodiments, bispecific antibody EIP0820 comprises a VH2 comprising the amino acid sequence of SEQ ID NO: 2; and a VL2 comprising the amino acid sequence of SEQ ID NO: 1.

[0323] In some embodiments, bispecific antibody EIP0820 comprises a VH2 comprising the amino acid sequence of SEQ ID NO: 629; and a VL2 comprising the amino acid sequence of SEQ ID NO: 1.

[0324] In some embodiments, bispecific antibody EIP0820 comprises a H2 comprising the amino acid sequence of SEQ ID NO: 621; and a L2 comprising the amino acid sequence of SEQ ID NO: 67.

[0325] In addition to the VH2, VL2, H2, L2 sequences and amino acid substitutions shown above, the bispecific antibody EIP0820 comprises a first antigen binding domain that binds CD3s comprising a VH1, comprising a VHICDRI having the amino acid sequence of SEQ ID NO: 30; a VH1CDR2 having the amino acid sequence of SEQ ID NO: 34; and a VH1CDR3 having the amino acid sequence of SEQ ID NO: 37; and a VL1, comprising a VLICDRI having the amino acid sequence of SEQ ID NO: 42; a VL1CDR2 having the amino acid sequence of SEQ ID NO: 43; and a VL1CDR3 having the amino acid sequence of SEQ ID NO: 45.

[0326] In some embodiments, the bispecific antibody EIP0820 comprises a VH1 having the amino acid sequence of SEQ ID NO: 17 and a VL1 having the amino acid sequence of SEQ ID NO: 22. In some embodiments, a CD58 peptide comprising the amino acid sequence of SEQ ID NO: 49 is fused to the C-terminal of the heavy chain targeting CD3 (Hl). Accordingly, in some embodiments, the bispecific antibody EIP0820 comprises a Hl having the amino acid sequence of SEQ ID NO: 622 and a LI having the amino acid sequence of SEQ ID NO: 69.

[0327] In some embodiments, an exemplary CD3s x ULBP2 / 5 / 6 bispecific antibody of the disclosure includes EIP0359.

[0328] In some embodiments, bispecific antibody EIP0359 has a second antigen binding domain that binds ULBP2 / 5 / 6 comprising a VH2, comprising VH2CDRI having the amino acid sequence of SEQ ID NO: 5; a VH2CDR2 having the amino acid sequence of SEQ ID NO: 7; and a VH2CDR3 having the amino acid sequence of SEQ ID NO: 9; and a VL2, comprising a VL2CDRI having the amino acid sequence of SEQ ID NO: 10; a VL2CDR2 having the amino acid sequence of SEQ ID NO: 11; and a VL2CDR3 having the amino acid sequence of SEQ ID NO: 12.

[0329] In some embodiments, bispecific antibody EIP0359 comprises a VH2 comprising the amino acid sequence of SEQ ID NO: 2; and a VL2 comprising the amino acid sequence of SEQ ID NO: 1.

[0330] In some embodiments, bispecific antibody EIP0359 comprises a H2 comprising the amino acid sequence of SEQ ID NO: 224; and a L2 comprising the amino acid sequence of SEQ ID NO: 223.

[0331] In addition to the VH2, VL2, H2, L2 sequences and amino acid substitutions shown above, the bispecific antibody EIP0359 comprises a first antigen binding domain that binds CD3s comprising a VH1, comprising a VHICDRI having the amino acid sequence of SEQ ID NO: 32; a VH1CDR2 having the amino acid sequence of SEQ ID NO: 36; and a VH1CDR3 having the amino acid sequence of SEQ ID NO: 37; and a VL1, comprising a VLICDRI having the amino acid sequence of SEQ ID NO: 42; a VL1CDR2 having the amino acid sequence of SEQ ID NO: 43; and a VL1CDR3 having the amino acid sequence of SEQ ID NO: 45.

[0332] In some embodiments, the bispecific antibody EIP0359 comprises a VH1 having the amino acid sequence of SEQ ID NO: 13 and a VL1 having the amino acid sequence of SEQ ID NO: 22. In some embodiments, a CD58 peptide comprising the amino acid sequence of SEQ ID NO: 49 is fused to the C-terminal of the heavy chain targeting CD3 (Hl). Accordingly, in some embodiments, the bispecific antibody EIP0359 comprises a Hl having the amino acid sequence of SEQ ID NO: 226 and a LI having the amino acid sequence of SEQ ID NO: 225.

[0333] In some embodiments, an exemplary CD3s x ULBP2 / 5 / 6 bispecific antibody of the disclosure includes EIP0566.

[0334] In some embodiments, bispecific antibody EIP0566 has a second antigen binding domain that binds ULBP2 / 5 / 6 comprising a VH2, comprising VH2CDRI having the amino acid sequence of SEQ ID NO: 5; a VH2CDR2 having the amino acid sequence of SEQ ID NO: 7; and a VH2CDR3 having the amino acid sequence of SEQ ID NO: 9; and a VL2, comprising a VL2CDRI having the amino acid sequence of SEQ ID NO: 10; a VL2CDR2 having the amino acid sequence of SEQ ID NO: 11; and a VL2CDR3 having the amino acid sequence of SEQ ID NO: 12. In some embodiments, bispecific antibody EIP0566 comprises a VH2 comprising the amino acid sequence of SEQ ID NO: 2; and a VL2 comprising the amino acid sequence of SEQ ID NO: 1. In some embodiments, bispecific antibody EIP0566 comprises a H2 comprising the amino acid sequence of SEQ ID NO: 228; and a L2 comprising the amino acid sequence of SEQ ID NO: 227.

[0335] In addition to the VH2, VL2, H2, L2 sequences and amino acid substitutions shown above, the bispecific antibody EIP0566 comprises a first antigen binding domain that binds CD3s comprising a VH1, comprising a VHICDRI having the amino acid sequence of SEQ ID NO: 32; a VH1CDR2 having the amino acid sequence of SEQ ID NO: 36; and a VH1CDR3 having the amino acid sequence of SEQ ID NO: 37; and a VL1, comprising a VLICDRI having the amino acid sequence of SEQ ID NO: 42; a VL1CDR2 having the amino acid sequence of SEQ ID NO: 43; and a VL1CDR3 having the amino acid sequence of SEQ ID NO: 45. In some embodiments, the bispecific antibody EIP0566 comprises a VH1 having the amino acid sequence of SEQ ID NO: 13 and a VL1 having the amino acid sequence of SEQ ID NO: 25. In some embodiments, a CD58 peptide comprising the amino acid sequence of SEQ ID NO: 49 is fused to the C-terminal of the heavy chain targeting CD3 (Hl). Accordingly, in some embodiments, the bispecific antibody EIP0566 comprises a Hl having the amino acid sequence of SEQ ID NO: 230 and a LI having the amino acid sequence of SEQ ID NO: 229.

[0336] In some embodiments, an exemplary CD3s x ULBP2 / 5 / 6 bispecific antibody of the disclosure includes EIP0634.

[0337] In some embodiments, bispecific antibody EIP0634 has a second antigen binding domain that binds ULBP2 / 5 / 6 comprising a VH2, comprising VH2CDRI having the amino acid sequence of SEQ ID NO: 5; a VH2CDR2 having the amino acid sequence of SEQ ID NO: 7; and a VH2CDR3 having the amino acid sequence of SEQ ID NO: 9; and a VL2, comprising a VL2CDRI having the amino acid sequence of SEQ ID NO: 10; a VL2CDR2 having the amino acid sequence of SEQ ID NO: 11; and a VL2CDR3 having the amino acid sequence of SEQ ID NO: 12. In some embodiments, bispecific antibody EIP0634 comprises a VH2 comprising the amino acid sequence of SEQ ID NO: 2; and a VL2 comprising the amino acid sequence of SEQ ID NO: 1. In some embodiments, bispecific antibody EIP0634 comprises a H2 comprising the amino acid sequence of SEQ ID NO: 232; and a L2 comprising the amino acid sequence of SEQ ID NO: 231.

[0338] In addition to the VH2, VL2, H2, L2 sequences and amino acid substitutions shown above, the bispecific antibody EIP0634 comprises a first antigen binding domain that binds CD3s comprising a VH1, comprising a VHICDRI having the amino acid sequence of SEQ ID NO: 32; a VH1CDR2 having the amino acid sequence of SEQ ID NO: 36; and a VH1CDR3 having the amino acid sequence of SEQ ID NO: 38; and a VL1, comprising a VLICDRI havingthe amino acid sequence of SEQ ID NO: 42; a VL1CDR2 having the amino acid sequence of SEQ ID NO: 43; and a VL1CDR3 having the amino acid sequence of SEQ ID NO: 47. In some embodiments, the bispecific antibody EIP0634 comprises a VH1 having the amino acid sequence of SEQ ID NO: 15 and a VL1 having the amino acid sequence of SEQ ID NO: 26. In some embodiments, a CD58 peptide comprising the amino acid sequence of SEQ ID NO: 49 is fused to the C-terminal of the heavy chain targeting CD3 (Hl). Accordingly, in some embodiments, the bispecific antibody EIP0634 comprises a Hl having the amino acid sequence of SEQ ID NO: 234 and a LI having the amino acid sequence of SEQ ID NO: 233.

[0339] In some embodiments, an exemplary CD3s x ULBP2 / 5 / 6 bispecific antibody of the disclosure includes EIP0562.

[0340] In some embodiments, bispecific antibody EIP0562 has a second antigen binding domain that binds ULBP2 / 5 / 6 comprising a VH2, comprising VH2CDRI having the amino acid sequence of SEQ ID NO: 5; a VH2CDR2 having the amino acid sequence of SEQ ID NO: 7; and a VH2CDR3 having the amino acid sequence of SEQ ID NO: 9; and a VL2, comprising a VL2CDRI having the amino acid sequence of SEQ ID NO: 10; a VL2CDR2 having the amino acid sequence of SEQ ID NO: 11; and a VL2CDR3 having the amino acid sequence of SEQ ID NO: 12. In some embodiments, bispecific antibody EIP0562 comprises a VH2 comprising the amino acid sequence of SEQ ID NO: 2; and a VL2 comprising the amino acid sequence of SEQ ID NO: 1. In some embodiments, bispecific antibody EIP0562 comprises a H2 comprising the amino acid sequence of SEQ ID NO: 236; and a L2 comprising the amino acid sequence of SEQ ID NO: 235.

[0341] In addition to the VH2, VL2, H2, L2 sequences and amino acid substitutions shown above, the bispecific antibody EIP0562 comprises a first antigen binding domain that binds CD3s comprising a VH1, comprising a VHICDRI having the amino acid sequence of SEQ ID NO: 32; a VH1CDR2 having the amino acid sequence of SEQ ID NO: 36; and a VH1CDR3 having the amino acid sequence of SEQ ID NO: 37; and a VL1, comprising a VLICDRI having the amino acid sequence of SEQ ID NO: 42; a VL1CDR2 having the amino acid sequence of SEQ ID NO: 44; and a VL1CDR3 having the amino acid sequence of SEQ ID NO: 45. In some embodiments, the bispecific antibody EIP0562 comprises a VH1 having the amino acid sequence of SEQ ID NO: 13 and a VL1 having the amino acid sequence of SEQ ID NO: 27. In some embodiments, a CD58 peptide comprising the amino acid sequence of SEQ ID NO:49 is fused to the C-terminal of the heavy chain targeting CD3 (Hl). Accordingly, in some embodiments, the bispecific antibody EIP0562 comprises a Hl having the amino acid sequence of SEQ ID NO: 238 and a LI having the amino acid sequence of SEQ ID NO: 237.

[0342] In some embodiments, an exemplary CD3s x ULBP2 / 5 / 6 bispecific antibody of the disclosure includes EIP0636.

[0343] In some embodiments, bispecific antibody EIP0636 has a second antigen binding domain that binds ULBP2 / 5 / 6 comprising a VH2, comprising VH2CDRI having the amino acid sequence of SEQ ID NO: 5; a VH2CDR2 having the amino acid sequence of SEQ ID NO: 7; and a VH2CDR3 having the amino acid sequence of SEQ ID NO: 9; and a VL2, comprising a VL2CDRI having the amino acid sequence of SEQ ID NO: 10; a VL2CDR2 having the amino acid sequence of SEQ ID NO: 11; and a VL2CDR3 having the amino acid sequence of SEQ ID NO: 12. In some embodiments, bispecific antibody EIP0636 comprises a VH2 comprising the amino acid sequence of SEQ ID NO: 2; and a VL2 comprising the amino acid sequence of SEQ ID NO: 1. In some embodiments, bispecific antibody EIP0636 comprises a H2 comprising the amino acid sequence of SEQ ID NO: 240; and a L2 comprising the amino acid sequence of SEQ ID NO: 239.

[0344] In addition to the VH2, VL2, H2, L2 sequences and amino acid substitutions shown above, the bispecific antibody EIP0636 comprises a first antigen binding domain that binds CD3s comprising a VH1, comprising a VHICDRI having the amino acid sequence of SEQ ID NO: 32; a VH1CDR2 having the amino acid sequence of SEQ ID NO: 36; and a VH1CDR3 having the amino acid sequence of SEQ ID NO: 39; and a VL1, comprising a VLICDRI having the amino acid sequence of SEQ ID NO: 42; a VL1CDR2 having the amino acid sequence of SEQ ID NO: 43; and a VL1CDR3 having the amino acid sequence of SEQ ID NO: 47. In some embodiments, the bispecific antibody EIP0636 comprises a VH1 having the amino acid sequence of SEQ ID NO: 16 and a VL1 having the amino acid sequence of SEQ ID NO: 26. In some embodiments, a CD58 peptide comprising the amino acid sequence of SEQ ID NO: 49 is fused to the C-terminal of the heavy chain targeting CD3 (Hl). Accordingly, in some embodiments, the bispecific antibody EIP0636 comprises a Hl having the amino acid sequence of SEQ ID NO: 242 and a LI having the amino acid sequence of SEQ ID NO: 241.

[0345] In some embodiments, an exemplary CD3s x ULBP2 / 5 / 6 bispecific antibody of the disclosure includes EIP0561.

[0346] In some embodiments, bispecific antibody EIP0561 has a second antigen binding domain that binds ULBP2 / 5 / 6 comprising a VH2, comprising VH2CDRI having the amino acid sequence of SEQ ID NO: 5; a VH2CDR2 having the amino acid sequence of SEQ ID NO: 7; and a VH2CDR3 having the amino acid sequence of SEQ ID NO: 9; and a VL2, comprising a VL2CDRI having the amino acid sequence of SEQ ID NO: 10; a VL2CDR2 having the amino acid sequence of SEQ ID NO: 11; and a VL2CDR3 having the amino acid sequence of SEQ ID NO: 12. In some embodiments, bispecific antibody EIP0561 comprises a VH2 comprising the amino acid sequence of SEQ ID NO: 2; and a VL2 comprising the amino acid sequence of SEQ ID NO. 1. In some embodiments, bispecific antibody EIP0561 comprises a H2 comprising the amino acid sequence of SEQ ID NO: 244; and a L2 comprising the amino acid sequence of SEQ ID NO: 243.

[0347] In addition to the VH2, VL2, H2, L2 sequences and amino acid substitutions shown above, the bispecific antibody EIP0561 comprises a first antigen binding domain that binds CD3s comprising a VH1, comprising a VHICDRI having the amino acid sequence of SEQ ID NO: 30; a VH1CDR2 having the amino acid sequence of SEQ ID NO: 34; and a VH1CDR3 having the amino acid sequence of SEQ ID NO: 37; and a VL1, comprising a VLICDRI having the amino acid sequence of SEQ ID NO: 42; a VL1CDR2 having the amino acid sequence of SEQ ID NO: 43; and a VL1CDR3 having the amino acid sequence of SEQ ID NO: 45. In some embodiments, the bispecific antibody EIP0561 comprises a VH1 having the amino acid sequence of SEQ ID NO: 17 and a VL1 having the amino acid sequence of SEQ ID NO: 22. In some embodiments, a CD58 peptide comprising the amino acid sequence of SEQ ID NO: 49 is fused to the C-terminal of the heavy chain targeting CD3 (Hl). Accordingly, in some embodiments, the bispecific antibody EIP0561 comprises a Hl having the amino acid sequence of SEQ ID NO: 246 and a LI having the amino acid sequence of SEQ ID NO: 245.

[0348] In some embodiments, an exemplary CD3s x ULBP2 / 5 / 6 bispecific antibody of the disclosure includes EIP0633.

[0349] In some embodiments, bispecific antibody EIP0633 has a second antigen binding domain that binds ULBP2 / 5 / 6 comprising a VH2, comprising VH2CDRI having the amino acid sequence of SEQ ID NO: 5; a VH2CDR2 having the amino acid sequence of SEQ ID NO: 7; and a VH2CDR3 having the amino acid sequence of SEQ ID NO: 9; and a VL2, comprising a VL2CDRI having the amino acid sequence of SEQ ID NO: 10; a VL2CDR2 having the aminoacid sequence of SEQ ID NO: 11; and a VL2CDR3 having the amino acid sequence of SEQ ID NO: 12. In some embodiments, bispecific antibody EIP0633 comprises a VH2 comprising the amino acid sequence of SEQ ID NO: 2; and a VL2 comprising the amino acid sequence of SEQ ID NO: 1. In some embodiments, bispecific antibody EIP0633 comprises a H2 comprising the amino acid sequence of SEQ ID NO: 248; and a L2 comprising the amino acid sequence of SEQ ID NO: 247.

[0350] In addition to the VH2, VL2, H2, L2 sequences and amino acid substitutions shown above, the bispecific antibody EIP0633 comprises a first antigen binding domain that binds CD3s comprising a VH1, comprising a VHICDRI having the amino acid sequence of SEQ ID NO: 29; a VH1CDR2 having the amino acid sequence of SEQ ID NO: 35; and a VH1CDR3 having the amino acid sequence of SEQ ID NO: 38; and a VL1, comprising a VLICDRI having the amino acid sequence of SEQ ID NO: 42; a VL1CDR2 having the amino acid sequence of SEQ ID NO: 43; and a VL1CDR3 having the amino acid sequence of SEQ ID NO: 47. In some embodiments, the bispecific antibody EIP0633 comprises a VH1 having the amino acid sequence of SEQ ID NO: 18 and a VL1 having the amino acid sequence of SEQ ID NO: 26. In some embodiments, a CD58 peptide comprising the amino acid sequence of SEQ ID NO: 49 is fused to the C-terminal of the heavy chain targeting CD3 (Hl). Accordingly, in some embodiments, the bispecific antibody EIP0633 comprises a Hl having the amino acid sequence of SEQ ID NO: 250 and a LI having the amino acid sequence of SEQ ID NO: 249.

[0351] In some embodiments, an exemplary CD3s x ULBP2 / 5 / 6 bispecific antibody of the disclosure includes EIP0631.

[0352] In some embodiments, bispecific antibody EIP0631 has a second antigen binding domain that binds ULBP2 / 5 / 6 comprising a VH2, comprising VH2CDRI having the amino acid sequence of SEQ ID NO: 5; a VH2CDR2 having the amino acid sequence of SEQ ID NO: 7; and a VH2CDR3 having the amino acid sequence of SEQ ID NO: 9; and a VL2, comprising a VL2CDRI having the amino acid sequence of SEQ ID NO: 10; a VL2CDR2 having the amino acid sequence of SEQ ID NO: 11; and a VL2CDR3 having the amino acid sequence of SEQ ID NO: 12. In some embodiments, bispecific antibody EIP0631 comprises a VH2 comprising the amino acid sequence of SEQ ID NO: 2; and a VL2 comprising the amino acid sequence of SEQ ID NO: 1. In some embodiments, bispecific antibody EIP0631 comprises a H2comprising the amino acid sequence of SEQ ID NO: 252; and a L2 comprising the amino acid sequence of SEQ ID NO: 251.

[0353] In addition to the VH2, VL2, H2, L2 sequences and amino acid substitutions shown above, the bispecific antibody EIP0631 comprises a first antigen binding domain that binds CD3s comprising a VH1, comprising a VHICDRI having the amino acid sequence of SEQ ID NO: 29; a VH1CDR2 having the amino acid sequence of SEQ ID NO: 34; and a VH1CDR3 having the amino acid sequence of SEQ ID NO: 40; and a VL1, comprising a VLICDRI having the amino acid sequence of SEQ ID NO: 42; a VL1CDR2 having the amino acid sequence of SEQ ID NO: 43; and a VL1CDR3 having the amino acid sequence of SEQ ID NO: 47. In some embodiments, the bispecific antibody EIP0631 comprises a VH1 having the amino acid sequence of SEQ ID NO: 19 and a VL1 having the amino acid sequence of SEQ ID NO: 26. In some embodiments, a CD58 peptide comprising the amino acid sequence of SEQ ID NO: 49 is fused to the C-terminal of the heavy chain targeting CD3 (Hl). Accordingly, in some embodiments, the bispecific antibody EIP0631 comprises a Hl having the amino acid sequence of SEQ ID NO: 254 and a LI having the amino acid sequence of SEQ ID NO: 253.

[0354] In some embodiments, an exemplary CD3s x ULBP2 / 5 / 6 bispecific antibody of the disclosure includes EIP0635.

[0355] In some embodiments, bispecific antibody EIP0635 has a second antigen binding domain that binds ULBP2 / 5 / 6 comprising a VH2, comprising VH2CDRI having the amino acid sequence of SEQ ID NO: 5; a VH2CDR2 having the amino acid sequence of SEQ ID NO: 7; and a VH2CDR3 having the amino acid sequence of SEQ ID NO: 9; and a VL2, comprising a VL2CDRI having the amino acid sequence of SEQ ID NO: 10; a VL2CDR2 having the amino acid sequence of SEQ ID NO: 11; and a VL2CDR3 having the amino acid sequence of SEQ ID NO: 12. In some embodiments, bispecific antibody EIP0635 comprises a VH2 comprising the amino acid sequence of SEQ ID NO: 2; and a VL2 comprising the amino acid sequence of SEQ ID NO: 1. In some embodiments, bispecific antibody EIP0635 comprises a H2 comprising the amino acid sequence of SEQ ID NO: 256; and a L2 comprising the amino acid sequence of SEQ ID NO: 255.

[0356] In addition to the VH2, VL2, H2, L2 sequences and amino acid substitutions shown above, the bispecific antibody EIP0635 comprises a first antigen binding domain that binds CD3s comprising a VH1, comprising a VHICDRI having the amino acid sequence of SEQ IDNO: 29; a VH1CDR2 having the amino acid sequence of SEQ ID NO: 35; and a VH1CDR3 having the amino acid sequence of SEQ ID NO: 38; and a VL1, comprising a VLICDRI having the amino acid sequence of SEQ ID NO: 42; a VL1CDR2 having the amino acid sequence of SEQ ID NO: 43; and a VL1CDR3 having the amino acid sequence of SEQ ID NO: 45. In some embodiments, the bispecific antibody EIP0635 comprises a VH1 having the amino acid sequence of SEQ ID NO: 18 and a VL1 having the amino acid sequence of SEQ ID NO: 22. In some embodiments, a CD58 peptide comprising the amino acid sequence of SEQ ID NO: 49 is fused to the C-terminal of the heavy chain targeting CD3 (Hl). Accordingly, in some embodiments, the bispecific antibody EIP0635 comprises a Hl having the amino acid sequence of SEQ ID NO: 258 and a LI having the amino acid sequence of SEQ ID NO: 257.

[0357] In some embodiments, an exemplary CD3s x ULBP2 / 5 / 6 bispecific antibody of the disclosure includes EIP0632.

[0358] In some embodiments, bispecific antibody EIP0632 has a second antigen binding domain that binds ULBP2 / 5 / 6 comprising a VH2, comprising VH2CDRI having the amino acid sequence of SEQ ID NO: 5; a VH2CDR2 having the amino acid sequence of SEQ ID NO: 7; and a VH2CDR3 having the amino acid sequence of SEQ ID NO: 9; and a VL2, comprising a VL2CDRI having the amino acid sequence of SEQ ID NO: 10; a VL2CDR2 having the amino acid sequence of SEQ ID NO: 11; and a VL2CDR3 having the amino acid sequence of SEQ ID NO: 12. In some embodiments, bispecific antibody EIP0632 comprises a VH2 comprising the amino acid sequence of SEQ ID NO: 2; and a VL2 comprising the amino acid sequence of SEQ ID NO: 1. In some embodiments, bispecific antibody EIP0632 comprises a H2 comprising the amino acid sequence of SEQ ID NO: 260; and a L2 comprising the amino acid sequence of SEQ ID NO: 259.

[0359] In addition to the VH2, VL2, H2, L2 sequences and amino acid substitutions shown above, the bispecific antibody EIP0632 comprises a first antigen binding domain that binds CD3s comprising a VH1, comprising a VHICDRI having the amino acid sequence of SEQ ID NO: 29; a VH1CDR2 having the amino acid sequence of SEQ ID NO: 34; and a VH1CDR3 having the amino acid sequence of SEQ ID NO: 41; and a VL1, comprising a VLICDRI having the amino acid sequence of SEQ ID NO: 42; a VL1CDR2 having the amino acid sequence of SEQ ID NO: 43; and a VL1CDR3 having the amino acid sequence of SEQ ID NO: 47. In some embodiments, the bispecific antibody EIP0632 comprises a VH1 having the amino acidsequence of SEQ ID NO: 20 and a VL1 having the amino acid sequence of SEQ ID NO: 26. In some embodiments, a CD58 peptide comprising the amino acid sequence of SEQ ID NO: 49 is fused to the C-terminal of the heavy chain targeting CD3 (Hl). Accordingly, in some embodiments, the bispecific antibody EIP0632 comprises a Hl having the amino acid sequence of SEQ ID NO: 262 and a LI having the amino acid sequence of SEQ ID NO: 261.

[0360] In some embodiments, an exemplary CD3s x ULBP2 / 5 / 6 bispecific antibody of the disclosure includes EIP0565.

[0361] In some embodiments, bispecific antibody EIP0565 has a second antigen binding domain that binds ULBP2 / 5 / 6 comprising a VH2, comprising VH2CDRI having the amino acid sequence of SEQ ID NO: 5; a VH2CDR2 having the amino acid sequence of SEQ ID NO: 7; and a VH2CDR3 having the amino acid sequence of SEQ ID NO: 9; and a VL2, comprising a VL2CDRI having the amino acid sequence of SEQ ID NO: 10; a VL2CDR2 having the amino acid sequence of SEQ ID NO: 11; and a VL2CDR3 having the amino acid sequence of SEQ ID NO: 12. In some embodiments, bispecific antibody EIP0565 comprises a VH2 comprising the amino acid sequence of SEQ ID NO: 2; and a VL2 comprising the amino acid sequence of SEQ ID NO: 1. In some embodiments, bispecific antibody EIP0565 comprises a H2 comprising the amino acid sequence of SEQ ID NO: 264; and a L2 comprising the amino acid sequence of SEQ ID NO: 263.

[0362] In addition to the VH2, VL2, H2, L2 sequences and amino acid substitutions shown above, the bispecific antibody EIP0565 comprises a first antigen binding domain that binds CD3s comprising a VH1, comprising a VHICDRI having the amino acid sequence of SEQ ID NO: 31; a VH1CDR2 having the amino acid sequence of SEQ ID NO: 34; and a VH1CDR3 having the amino acid sequence of SEQ ID NO: 37; and a VL1, comprising a VLICDRI having the amino acid sequence of SEQ ID NO: 42; a VL1CDR2 having the amino acid sequence of SEQ ID NO: 43; and a VL1CDR3 having the amino acid sequence of SEQ ID NO: 45. In some embodiments, the bispecific antibody EIP0565 comprises a VH1 having the amino acid sequence of SEQ ID NO: 21 and a VL1 having the amino acid sequence of SEQ ID NO: 22. In some embodiments, a CD58 peptide comprising the amino acid sequence of SEQ ID NO: 49 is fused to the C-terminal of the heavy chain targeting CD3 (Hl). Accordingly, in some embodiments, the bispecific antibody EIP0565 comprises a Hl having the amino acid sequence of SEQ ID NO: 266 and a LI having the amino acid sequence of SEQ ID NO: 265.

[0363] In some embodiments, an exemplary CD3s x ULBP2 / 5 / 6 bispecific antibody of the disclosure includes EIP0599.

[0364] In some embodiments, bispecific antibody EIP0599 has a second antigen binding domain that binds ULBP2 / 5 / 6 comprising a VH2, comprising VH2CDRI having the amino acid sequence of SEQ ID NO: 5; a VH2CDR2 having the amino acid sequence of SEQ ID NO: 7; and a VH2CDR3 having the amino acid sequence of SEQ ID NO: 9; and a VL2, comprising a VL2CDRI having the amino acid sequence of SEQ ID NO: 10; a VL2CDR2 having the amino acid sequence of SEQ ID NO: 11; and a VL2CDR3 having the amino acid sequence of SEQ ID NO: 12. In some embodiments, bispecific antibody EIP0599 comprises a VH2 comprising the amino acid sequence of SEQ ID NO: 2; and a VL2 comprising the amino acid sequence of SEQ ID NO: 1. In some embodiments, bispecific antibody EIP0599 comprises a H2 comprising the amino acid sequence of SEQ ID NO: 267; and a L2 comprising the amino acid sequence of SEQ ID NO: 330.

[0365] In addition to the VH2, VL2, H2, L2 sequences and amino acid substitutions shown above, the bispecific antibody EIP0599 comprises a first antigen binding domain that binds CD3s comprising a VH1, comprising a VHICDRI having the amino acid sequence of SEQ ID NO: 32; a VH1CDR2 having the amino acid sequence of SEQ ID NO: 36; and a VH1CDR3 having the amino acid sequence of SEQ ID NO: 37; and a VL1, comprising a VLICDRI having the amino acid sequence of SEQ ID NO: 42; a VL1CDR2 having the amino acid sequence of SEQ ID NO: 43; and a VL1CDR3 having the amino acid sequence of SEQ ID NO: 45. In some embodiments, the bispecific antibody EIP0599 comprises a VH1 having the amino acid sequence of SEQ ID NO: 13 and a VL1 having the amino acid sequence of SEQ ID NO: 22. In some embodiments, a CD58 peptide comprising the amino acid sequence of SEQ ID NO: 49 is fused to the C-terminal of the heavy chain targeting CD3 (Hl). Accordingly, in some embodiments, the bispecific antibody EIP0599 comprises a Hl having the amino acid sequence of SEQ ID NO: 269 and a LI having the amino acid sequence of SEQ ID NO: 268.

[0366] In some embodiments, an exemplary CD3s x ULBP2 / 5 / 6 bispecific antibody of the disclosure includes EIP0640.

[0367] In some embodiments, bispecific antibody EIP0640 has a second antigen binding domain that binds ULBP2 / 5 / 6 comprising a VH2, comprising VH2CDRI having the amino acid sequence of SEQ ID NO: 5; a VH2CDR2 having the amino acid sequence of SEQ ID NO: 7;and a VH2CDR3 having the amino acid sequence of SEQ ID NO: 9; and a VL2, comprising a VL2CDRI having the amino acid sequence of SEQ ID NO: 10; a VL2CDR2 having the amino acid sequence of SEQ ID NO: 11; and a VL2CDR3 having the amino acid sequence of SEQ ID NO: 12. In some embodiments, bispecific antibody EIP0640 comprises a VH2 comprising the amino acid sequence of SEQ ID NO: 2; and a VL2 comprising the amino acid sequence of SEQ ID NO: 1. In some embodiments, bispecific antibody EIP0640 comprises a H2 comprising the amino acid sequence of SEQ ID NO: 271; and a L2 comprising the amino acid sequence of SEQ ID NO: 270,

[0368] In addition to the VH2, VL2, H2, L2 sequences and amino acid substitutions shown above, the bispecific antibody EIP0640 comprises a first antigen binding domain that binds CD3s comprising a VH1, comprising a VHICDRI having the amino acid sequence of SEQ ID NO: 29; a VH1CDR2 having the amino acid sequence of SEQ ID NO: 34; and a VH1CDR3 having the amino acid sequence of SEQ ID NO: 37; and a VL1, comprising a VLICDRI having the amino acid sequence of SEQ ID NO: 42; a VL1CDR2 having the amino acid sequence of SEQ ID NO: 43; and a VL1CDR3 having the amino acid sequence of SEQ ID NO: 46. In some embodiments, the bispecific antibody EIP0640 comprises a VH1 having the amino acid sequence of SEQ ID NO: 13 and a VL1 having the amino acid sequence of SEQ ID NO: 25. In some embodiments, a CD58 peptide comprising the amino acid sequence of SEQ ID NO: 49 is fused to the C-terminal of the heavy chain targeting CD3 (Hl). Accordingly, in some embodiments, the bispecific antibody EIP0640 comprises a Hl having the amino acid sequence of SEQ ID NO: 273 and a LI having the amino acid sequence of SEQ ID NO: 272.

[0369] In some embodiments, an exemplary CD3s x ULBP2 / 5 / 6 bispecific antibody of the disclosure includes EIP0567.

[0370] In some embodiments, bispecific antibody EIP0567 has a second antigen binding domain that binds ULBP2 / 5 / 6 comprising a VH2, comprising VH2CDRI having the amino acid sequence of SEQ ID NO: 5; a VH2CDR2 having the amino acid sequence of SEQ ID NO: 7; and a VH2CDR3 having the amino acid sequence of SEQ ID NO: 9; and a VL2, comprising a VL2CDRI having the amino acid sequence of SEQ ID NO: 10; a VL2CDR2 having the amino acid sequence of SEQ ID NO: 11; and a VL2CDR3 having the amino acid sequence of SEQ ID NO: 12. In some embodiments, bispecific antibody EIP0567 comprises a VH2 comprising the amino acid sequence of SEQ ID NO: 2; and a VL2 comprising the amino acid sequenceof SEQ ID NO: 1. In some embodiments, bispecific antibody EIP0567 comprises a H2 comprising the amino acid sequence of SEQ ID NO: 275; and a L2 comprising the amino acid sequence of SEQ ID NO: 274,

[0371] In addition to the VH2, VL2, H2, L2 sequences and amino acid substitutions shown above, the bispecific antibody EIP0567 comprises a first antigen binding domain that binds CD3s comprising a VH1, comprising a VHICDRI having the amino acid sequence of SEQ ID NO: 29; a VH1CDR2 having the amino acid sequence of SEQ ID NO: 34; and a VH1CDR3 having the amino acid sequence of SEQ ID NO: 38; and a VL1, comprising a VLICDRI having the amino acid sequence of SEQ ID NO: 42; a VL1CDR2 having the amino acid sequence of SEQ ID NO: 43; and a VL1CDR3 having the amino acid sequence of SEQ ID NO: 47. In some embodiments, the bispecific antibody EIP0567 comprises a VH1 having the amino acid sequence of SEQ ID NO: 15 and a VL1 having the amino acid sequence of SEQ ID NO: 26. In some embodiments, a CD58 peptide comprising the amino acid sequence of SEQ ID NO: 49 is fused to the C-terminal of the heavy chain targeting CD3 (Hl). Accordingly, in some embodiments, the bispecific antibody EIP0567 comprises a Hl having the amino acid sequence of SEQ ID NO: 277 and a LI having the amino acid sequence of SEQ ID NO: 276.

[0372] In some embodiments, an exemplary CD3s x ULBP2 / 5 / 6 bispecific antibody of the disclosure includes EIP0638.

[0373] In some embodiments, bispecific antibody EIP0638 has a second antigen binding domain that binds ULBP2 / 5 / 6 comprising a VH2, comprising VH2CDRI having the amino acid sequence of SEQ ID NO: 5; a VH2CDR2 having the amino acid sequence of SEQ ID NO: 7; and a VH2CDR3 having the amino acid sequence of SEQ ID NO: 9; and a VL2, comprising a VL2CDRI having the amino acid sequence of SEQ ID NO: 10; a VL2CDR2 having the amino acid sequence of SEQ ID NO: 11; and a VL2CDR3 having the amino acid sequence of SEQ ID NO: 12. In some embodiments, bispecific antibody EIP0638 comprises a VH2 comprising the amino acid sequence of SEQ ID NO: 2; and a VL2 comprising the amino acid sequence of SEQ ID NO: 1. In some embodiments, bispecific antibody EIP0638 comprises a H2 comprising the amino acid sequence of SEQ ID NO: 279; and a L2 comprising the amino acid sequence of SEQ ID NO: 278.

[0374] In addition to the VH2, VL2, H2, L2 sequences and amino acid substitutions shown above, the bispecific antibody EIP0638 comprises a first antigen binding domain that bindsCD3s comprising a VH1, comprising a VHICDRI having the amino acid sequence of SEQ ID NO: 29; a VH1CDR2 having the amino acid sequence of SEQ ID NO: 34; and a VH1CDR3 having the amino acid sequence of SEQ ID NO: 37; and a VL1, comprising a VLICDRI having the amino acid sequence of SEQ ID NO: 42; a VL1CDR2 having the amino acid sequence of SEQ ID NO: 44; and a VL1CDR3 having the amino acid sequence of SEQ ID NO: 45. In some embodiments, the bispecific antibody EIP0638 comprises a VH1 having the amino acid sequence of SEQ ID NO: 13 and a VL1 having the amino acid sequence of SEQ ID NO: 27. In some embodiments, a CD58 peptide comprising the amino acid sequence of SEQ ID NO: 49 is fused to the C-terminal of the heavy chain targeting CD3 (Hl). Accordingly, in some embodiments, the bispecific antibody EIP0638 comprises a Hl having the amino acid sequence of SEQ ID NO: 281 and a LI having the amino acid sequence of SEQ ID NO: 280.

[0375] In some embodiments, an exemplary CD3s x ULBP2 / 5 / 6 bispecific antibody of the disclosure includes EIP0568.

[0376] In some embodiments, bispecific antibody EIP0568 has a second antigen binding domain that binds ULBP2 / 5 / 6 comprising a VH2, comprising VH2CDRI having the amino acid sequence of SEQ ID NO: 5; a VH2CDR2 having the amino acid sequence of SEQ ID NO: 7; and a VH2CDR3 having the amino acid sequence of SEQ ID NO: 9; and a VL2, comprising a VL2CDRI having the amino acid sequence of SEQ ID NO: 10; a VL2CDR2 having the amino acid sequence of SEQ ID NO: 11; and a VL2CDR3 having the amino acid sequence of SEQ ID NO: 12. In some embodiments, bispecific antibody EIP0568 comprises a VH2 comprising the amino acid sequence of SEQ ID NO: 2; and a VL2 comprising the amino acid sequence of SEQ ID NO: 1. In some embodiments, bispecific antibody EIP0568 comprises a H2 comprising the amino acid sequence of SEQ ID NO: 283; and a L2 comprising the amino acid sequence of SEQ ID NO: 282.

[0377] In addition to the VH2, VL2, H2, L2 sequences and amino acid substitutions shown above, the bispecific antibody EIP0568 comprises a first antigen binding domain that binds CD3s comprising a VH1, comprising a VHICDRI having the amino acid sequence of SEQ ID NO: 29; a VH1CDR2 having the amino acid sequence of SEQ ID NO: 34; and a VH1CDR3 having the amino acid sequence of SEQ ID NO: 39; and a VL1, comprising a VLICDRI having the amino acid sequence of SEQ ID NO: 42; a VL1CDR2 having the amino acid sequence of SEQ ID NO: 43; and a VL1CDR3 having the amino acid sequence of SEQ ID NO: 47. In someembodiments, the bispecific antibody EIP0568 comprises a VH1 having the amino acid sequence of SEQ ID NO: 16 and a VL1 having the amino acid sequence of SEQ ID NO: 26. In some embodiments, a CD58 peptide comprising the amino acid sequence of SEQ ID NO: 49 is fused to the C-terminal of the heavy chain targeting CD3 (Hl). Accordingly, in some embodiments, the bispecific antibody EIP0568 comprises a Hl having the amino acid sequence of SEQ ID NO: 285 and a LI having the amino acid sequence of SEQ ID NO: 284.

[0378] In some embodiments, an exemplary CD3s x ULBP2 / 5 / 6 bispecific antibody of the disclosure includes EIP0637.

[0379] In some embodiments, bispecific antibody EIP0637 has a second antigen binding domain that binds ULBP2 / 5 / 6 comprising a VH2, comprising VH2CDRI having the amino acid sequence of SEQ ID NO: 5; a VH2CDR2 having the amino acid sequence of SEQ ID NO: 7; and a VH2CDR3 having the amino acid sequence of SEQ ID NO: 9; and a VL2, comprising a VL2CDRI having the amino acid sequence of SEQ ID NO: 10; a VL2CDR2 having the amino acid sequence of SEQ ID NO: 11; and a VL2CDR3 having the amino acid sequence of SEQ ID NO: 12. In some embodiments, bispecific antibody EIP0637 comprises a VH2 comprising the amino acid sequence of SEQ ID NO: 2; and a VL2 comprising the amino acid sequence of SEQ ID NO: 1. In some embodiments, bispecific antibody EIP0637 comprises a H2 comprising the amino acid sequence of SEQ ID NO: 287; and a L2 comprising the amino acid sequence of SEQ ID NO: 286.

[0380] In addition to the VH2, VL2, H2, L2 sequences and amino acid substitutions shown above, the bispecific antibody EIP0637 comprises a first antigen binding domain that binds CD3s comprising a VH1, comprising a VHICDRI having the amino acid sequence of SEQ ID NO: 30; a VH1CDR2 having the amino acid sequence of SEQ ID NO: 34; and a VH1CDR3 having the amino acid sequence of SEQ ID NO: 37; and a VL1, comprising a VLICDRI having the amino acid sequence of SEQ ID NO: 42; a VL1CDR2 having the amino acid sequence of SEQ ID NO: 43; and a VL1CDR3 having the amino acid sequence of SEQ ID NO: 45. In some embodiments, the bispecific antibody EIP0637 comprises a VH1 having the amino acid sequence of SEQ ID NO: 17 and a VL1 having the amino acid sequence of SEQ ID NO: 22. In some embodiments, a CD58 peptide comprising the amino acid sequence of SEQ ID NO: 49 is fused to the C-terminal of the heavy chain targeting CD3 (Hl). Accordingly, in someembodiments, the bispecific antibody EIP0637 comprises a Hl having the amino acid sequence of SEQ ID NO: 289 and a LI having the amino acid sequence of SEQ ID NO: 288.

[0381] In some embodiments, an exemplary CD3s x ULBP2 / 5 / 6 bispecific antibody of the disclosure includes EIP0564.

[0382] In some embodiments, bispecific antibody EIP0564 has a second antigen binding domain that binds ULBP2 / 5 / 6 comprising a VH2, comprising VH2CDRI having the amino acid sequence of SEQ ID NO: 5; a VH2CDR2 having the amino acid sequence of SEQ ID NO: 7; and a VH2CDR3 having the amino acid sequence of SEQ ID NO: 9; and a VL2, comprising a VL2CDRI having the amino acid sequence of SEQ ID NO: 10; a VL2CDR2 having the amino acid sequence of SEQ ID NO: 11; and a VL2CDR3 having the amino acid sequence of SEQ ID NO: 12. In some embodiments, bispecific antibody EIP0564 comprises a VH2 comprising the amino acid sequence of SEQ ID NO: 2; and a VL2 comprising the amino acid sequence of SEQ ID NO: 1. In some embodiments, bispecific antibody EIP0564 comprises a H2 comprising the amino acid sequence of SEQ ID NO: 291; and a L2 comprising the amino acid sequence of SEQ ID NO: 290.

[0383] In addition to the VH2, VL2, H2, L2 sequences and amino acid substitutions shown above, the bispecific antibody EIP0564 comprises a first antigen binding domain that binds CD3s comprising a VH1, comprising a VHICDRI having the amino acid sequence of SEQ ID NO: 29; a VH1CDR2 having the amino acid sequence of SEQ ID NO: 35; and a VH1CDR3 having the amino acid sequence of SEQ ID NO: 38; and a VL1, comprising a VLICDRI having the amino acid sequence of SEQ ID NO: 42; a VL1CDR2 having the amino acid sequence of SEQ ID NO: 43; and a VL1CDR3 having the amino acid sequence of SEQ ID NO: 47. In some embodiments, the bispecific antibody EIP0564 comprises a VH1 having the amino acid sequence of SEQ ID NO: 18 and a VL1 having the amino acid sequence of SEQ ID NO: 26. In some embodiments, a CD58 peptide comprising the amino acid sequence of SEQ ID NO: 49 is fused to the C-terminal of the heavy chain targeting CD3 (Hl). Accordingly, in some embodiments, the bispecific antibody EIP0564 comprises a Hl having the amino acid sequence of SEQ ID NO: 293 and a LI having the amino acid sequence of SEQ ID NO: 292.

[0384] In some embodiments, an exemplary CD3s x ULBP2 / 5 / 6 bispecific antibody of the disclosure includes EIP0560.

[0385] In some embodiments, bispecific antibody EIP0560 has a second antigen binding domain that binds ULBP2 / 5 / 6 comprising a VH2, comprising VH2CDRI having the amino acid sequence of SEQ ID NO: 5; a VH2CDR2 having the amino acid sequence of SEQ ID NO: 7; and a VH2CDR3 having the amino acid sequence of SEQ ID NO: 9; and a VL2, comprising a VL2CDRI having the amino acid sequence of SEQ ID NO: 10; a VL2CDR2 having the amino acid sequence of SEQ ID NO: 11; and a VL2CDR3 having the amino acid sequence of SEQ ID NO: 12. In some embodiments, bispecific antibody EIP0560 comprises a VH2 comprising the amino acid sequence of SEQ ID NO: 2; and a VL2 comprising the amino acid sequence of SEQ ID NO. 1. In some embodiments, bispecific antibody EIP0560 comprises a H2 comprising the amino acid sequence of SEQ ID NO: 295; and a L2 comprising the amino acid sequence of SEQ ID NO: 294.

[0386] In addition to the VH2, VL2, H2, L2 sequences and amino acid substitutions shown above, the bispecific antibody EIP0560 comprises a first antigen binding domain that binds CD3s comprising a VH1, comprising a VHICDRI having the amino acid sequence of SEQ ID NO: 29; a VH1CDR2 having the amino acid sequence of SEQ ID NO: 34; and a VH1CDR3 having the amino acid sequence of SEQ ID NO: 40; and a VL1, comprising a VLICDRI having the amino acid sequence of SEQ ID NO: 42; a VL1CDR2 having the amino acid sequence of SEQ ID NO: 43; and a VL1CDR3 having the amino acid sequence of SEQ ID NO: 47. In some embodiments, the bispecific antibody EIP0560 comprises a VH1 having the amino acid sequence of SEQ ID NO: 19 and a VL1 having the amino acid sequence of SEQ ID NO: 26. In some embodiments, a CD58 peptide comprising the amino acid sequence of SEQ ID NO: 49 is fused to the C-terminal of the heavy chain targeting CD3 (Hl). Accordingly, in some embodiments, the bispecific antibody EIP0560 comprises a Hl having the amino acid sequence of SEQ ID NO: 297 and a LI having the amino acid sequence of SEQ ID NO: 296.

[0387] In some embodiments, an exemplary CD3s x ULBP2 / 5 / 6 bispecific antibody of the disclosure includes EIP0662.

[0388] In some embodiments, bispecific antibody EIP0662 has a second antigen binding domain that binds ULBP2 / 5 / 6 comprising a VH2, comprising VH2CDRI having the amino acid sequence of SEQ ID NO: 5; a VH2CDR2 having the amino acid sequence of SEQ ID NO: 7; and a VH2CDR3 having the amino acid sequence of SEQ ID NO: 9; and a VL2, comprising a VL2CDRI having the amino acid sequence of SEQ ID NO: 10; a VL2CDR2 having the aminoacid sequence of SEQ ID NO: 11; and a VL2CDR3 having the amino acid sequence of SEQ ID NO: 12. In some embodiments, bispecific antibody EIP0662 comprises a VH2 comprising the amino acid sequence of SEQ ID NO: 2; and a VL2 comprising the amino acid sequence of SEQ ID NO: 1. In some embodiments, bispecific antibody EIP0662 comprises a H2 comprising the amino acid sequence of SEQ ID NO: 299; and a L2 comprising the amino acid sequence of SEQ ID NO: 298.

[0389] In addition to the VH2, VL2, H2, L2 sequences and amino acid substitutions shown above, the bispecific antibody EIP0662 comprises a first antigen binding domain that binds CD3s comprising a VH1, comprising a VHICDRI having the amino acid sequence of SEQ ID NO: 29; a VH1CDR2 having the amino acid sequence of SEQ ID NO: 35; and a VH1CDR3 having the amino acid sequence of SEQ ID NO: 38; and a VL1, comprising a VLICDRI having the amino acid sequence of SEQ ID NO: 42; a VL1CDR2 having the amino acid sequence of SEQ ID NO: 43; and a VL1CDR3 having the amino acid sequence of SEQ ID NO: 45. In some embodiments, the bispecific antibody EIP0662 comprises a VH1 having the amino acid sequence of SEQ ID NO: 18 and a VL1 having the amino acid sequence of SEQ ID NO: 22. In some embodiments, a CD58 peptide comprising the amino acid sequence of SEQ ID NO: 49 is fused to the C-terminal of the heavy chain targeting CD3 (Hl). Accordingly, in some embodiments, the bispecific antibody EIP0662 comprises a Hl having the amino acid sequence of SEQ ID NO: 301 and a LI having the amino acid sequence of SEQ ID NO: 300.

[0390] In some embodiments, an exemplary CD3s x ULBP2 / 5 / 6 bispecific antibody of the disclosure includes EIP0563.

[0391] In some embodiments, bispecific antibody EIP0563 has a second antigen binding domain that binds ULBP2 / 5 / 6 comprising a VH2, comprising VH2CDRI having the amino acid sequence of SEQ ID NO: 5; a VH2CDR2 having the amino acid sequence of SEQ ID NO: 7; and a VH2CDR3 having the amino acid sequence of SEQ ID NO: 9; and a VL2, comprising a VL2CDRI having the amino acid sequence of SEQ ID NO: 10; a VL2CDR2 having the amino acid sequence of SEQ ID NO: 11; and a VL2CDR3 having the amino acid sequence of SEQ ID NO: 12. In some embodiments, bispecific antibody EIP0563 comprises a VH2 comprising the amino acid sequence of SEQ ID NO: 2; and a VL2 comprising the amino acid sequence of SEQ ID NO: 1. In some embodiments, bispecific antibody EIP0563 comprises a H2comprising the amino acid sequence of SEQ ID NO: 303; and a L2 comprising the amino acid sequence of SEQ ID NO: 302.

[0392] In addition to the VH2, VL2, H2, L2 sequences and amino acid substitutions shown above, the bispecific antibody EIP0563 comprises a first antigen binding domain that binds CD3s comprising a VH1, comprising a VHICDRI having the amino acid sequence of SEQ ID NO: 29; a VH1CDR2 having the amino acid sequence of SEQ ID NO: 34; and a VH1CDR3 having the amino acid sequence of SEQ ID NO: 41; and a VL1, comprising a VLICDRI having the amino acid sequence of SEQ ID NO: 42; a VL1CDR2 having the amino acid sequence of SEQ ID NO: 43; and a VL1CDR3 having the amino acid sequence of SEQ ID NO: 47. In some embodiments, the bispecific antibody EIP0563 comprises a VH1 having the amino acid sequence of SEQ ID NO: 20 and a VL1 having the amino acid sequence of SEQ ID NO: 26. In some embodiments, a CD58 peptide comprising the amino acid sequence of SEQ ID NO: 49 is fused to the C-terminal of the heavy chain targeting CD3 (Hl). Accordingly, in some embodiments, the bispecific antibody EIP0563 comprises a Hl having the amino acid sequence of SEQ ID NO: 305 and a LI having the amino acid sequence of SEQ ID NO: 304.

[0393] In some embodiments, an exemplary CD3s x ULBP2 / 5 / 6 bispecific antibody of the disclosure includes EIP0639.

[0394] In some embodiments, bispecific antibody EIP0639 has a second antigen binding domain that binds ULBP2 / 5 / 6 comprising a VH2, comprising VH2CDRI having the amino acid sequence of SEQ ID NO: 5; a VH2CDR2 having the amino acid sequence of SEQ ID NO: 7; and a VH2CDR3 having the amino acid sequence of SEQ ID NO: 9; and a VL2, comprising a VL2CDRI having the amino acid sequence of SEQ ID NO: 10; a VL2CDR2 having the amino acid sequence of SEQ ID NO: 11; and a VL2CDR3 having the amino acid sequence of SEQ ID NO: 12. In some embodiments, bispecific antibody EIP0639 comprises a VH2 comprising the amino acid sequence of SEQ ID NO: 2; and a VL2 comprising the amino acid sequence of SEQ ID NO: 1. In some embodiments, bispecific antibody EIP0639 comprises a H2 comprising the amino acid sequence of SEQ ID NO: 307; and a L2 comprising the amino acid sequence of SEQ ID NO: 306.

[0395] In addition to the VH2, VL2, H2, L2 sequences and amino acid substitutions shown above, the bispecific antibody EIP0639 comprises a first antigen binding domain that binds CD3s comprising a VH1, comprising a VHICDRI having the amino acid sequence of SEQ IDNO: 31; a VH1CDR2 having the amino acid sequence of SEQ ID NO: 34; and a VH1CDR3 having the amino acid sequence of SEQ ID NO: 37; and a VL1, comprising a VLICDRI having the amino acid sequence of SEQ ID NO: 42; a VL1CDR2 having the amino acid sequence of SEQ ID NO: 43; and a VL1CDR3 having the amino acid sequence of SEQ ID NO: 45. In some embodiments, the bispecific antibody EIP0639 comprises a VH1 having the amino acid sequence of SEQ ID NO: 21 and a VL1 having the amino acid sequence of SEQ ID NO: 22. In some embodiments, a CD58 peptide comprising the amino acid sequence of SEQ ID NO: 49 is fused to the C-terminal of the heavy chain targeting CD3 (Hl). Accordingly, in some embodiments, the bispecific antibody EIP0639 comprises a Hl having the amino acid sequence of SEQ ID NO: 309 and a LI having the amino acid sequence of SEQ ID NO: 308.

[0396] In some embodiments, an exemplary CD3s x ULBP2 / 5 / 6 bispecific antibody of the disclosure includes EIP0547.

[0397] In some embodiments, bispecific antibody EIP0547 has a second antigen binding domain that binds ULBP2 / 5 / 6 comprising a VH2, comprising VH2CDRI having the amino acid sequence of SEQ ID NO: 5; a VH2CDR2 having the amino acid sequence of SEQ ID NO: 7; and a VH2CDR3 having the amino acid sequence of SEQ ID NO: 9; and a VL2, comprising a VL2CDRI having the amino acid sequence of SEQ ID NO: 10; a VL2CDR2 having the amino acid sequence of SEQ ID NO: 11; and a VL2CDR3 having the amino acid sequence of SEQ ID NO: 12. In some embodiments, bispecific antibody EIP0547 comprises a VH2 comprising the amino acid sequence of SEQ ID NO: 2; and a VL2 comprising the amino acid sequence of SEQ ID NO: 1. In some embodiments, bispecific antibody EIP0547 comprises a H2 comprising the amino acid sequence of SEQ ID NO: 311; and a L2 comprising the amino acid sequence of SEQ ID NO: 310.

[0398] In addition to the VH2, VL2, H2, L2 sequences and amino acid substitutions shown above, the bispecific antibody EIP0547 comprises a first antigen binding domain that binds CD3s comprising a VH1, comprising a VHICDRI having the amino acid sequence of SEQ ID NO: 29; a VH1CDR2 having the amino acid sequence of SEQ ID NO: 34; and a VH1CDR3 having the amino acid sequence of SEQ ID NO: 37; and a VL1, comprising a VLICDRI having the amino acid sequence of SEQ ID NO: 42; a VL1CDR2 having the amino acid sequence of SEQ ID NO: 43; and a VL1CDR3 having the amino acid sequence of SEQ ID NO: 45. In some embodiments, the bispecific antibody EIP0547 comprises a VH1 having the amino acidsequence of SEQ ID NO: 13 and a VL1 having the amino acid sequence of SEQ ID NO: 22. In some embodiments, a CD58 peptide comprising the amino acid sequence of SEQ ID NO: 49 is fused to the C-terminal of the heavy chain targeting CD3 (Hl). Accordingly, in some embodiments, the bispecific antibody EIP0547 comprises a Hl having the amino acid sequence of SEQ ID NO: 313 and a LI having the amino acid sequence of SEQ ID NO: 312.

[0399] In some embodiments, an exemplary CD3s x ULBP2 / 5 / 6 bispecific antibody of the disclosure includes EIP0641.

[0400] In some embodiments, bispecific antibody EIP0641 has a second antigen binding domain that binds ULBP2 / 5 / 6 comprising a VH2, comprising VH2CDRI having the amino acid sequence of SEQ ID NO: 5; a VH2CDR2 having the amino acid sequence of SEQ ID NO: 7; and a VH2CDR3 having the amino acid sequence of SEQ ID NO: 9; and a VL2, comprising a VL2CDRI having the amino acid sequence of SEQ ID NO: 10; a VL2CDR2 having the amino acid sequence of SEQ ID NO: 11; and a VL2CDR3 having the amino acid sequence of SEQ ID NO: 12. In some embodiments, bispecific antibody EIP0641 comprises a VH2 comprising the amino acid sequence of SEQ ID NO: 2; and a VL2 comprising the amino acid sequence of SEQ ID NO: 1. In some embodiments, bispecific antibody EIP0641 comprises a H2 comprising the amino acid sequence of SEQ ID NO: 315; and a L2 comprising the amino acid sequence of SEQ ID NO: 314.

[0401] In addition to the VH2, VL2, H2, L2 sequences and amino acid substitutions shown above, the bispecific antibody EIP0641 comprises a first antigen binding domain that binds CD3s comprising a VH1, comprising a VHICDRI having the amino acid sequence of SEQ ID NO: 29; a VH1CDR2 having the amino acid sequence of SEQ ID NO: 34; and a VH1CDR3 having the amino acid sequence of SEQ ID NO: 37; and a VL1, comprising a VLICDRI having the amino acid sequence of SEQ ID NO: 42; a VL1CDR2 having the amino acid sequence of SEQ ID NO: 43; and a VL1CDR3 having the amino acid sequence of SEQ ID NO: 45. In some embodiments, the bispecific antibody EIP0641 comprises a VH1 having the amino acid sequence of SEQ ID NO: 13 and a VL1 having the amino acid sequence of SEQ ID NO: 22. In some embodiments, a CD58 peptide comprising the amino acid sequence of SEQ ID NO: 49 is fused to the C-terminal of the heavy chain targeting CD3 (Hl). Accordingly, in some embodiments, the bispecific antibody EIP0641 comprises a Hl having the amino acid sequence of SEQ ID NO: 317 and a LI having the amino acid sequence of SEQ ID NO: 316.

[0402] In some embodiments, an exemplary CD3s x ULBP2 / 5 / 6 bispecific antibody of the disclosure includes EIP0360.

[0403] In some embodiments, bispecific antibody EIP0360 has a second antigen binding domain that binds ULBP2 / 5 / 6 comprising a VH2, comprising VH2CDRI having the amino acid sequence of SEQ ID NO: 5; a VH2CDR2 having the amino acid sequence of SEQ ID NO: 7; and a VH2CDR3 having the amino acid sequence of SEQ ID NO: 9; and a VL2, comprising a VL2CDRI having the amino acid sequence of SEQ ID NO: 10; a VL2CDR2 having the amino acid sequence of SEQ ID NO: 11; and a VL2CDR3 having the amino acid sequence of SEQ ID NO: 12. In some embodiments, bispecific antibody EIP0360 comprises a VH2 comprising the amino acid sequence of SEQ ID NO: 2; and a VL2 comprising the amino acid sequence of SEQ ID NO: 1. In some embodiments, bispecific antibody EIP0360 comprises a H2 comprising the amino acid sequence of SEQ ID NO: 319; and a L2 comprising the amino acid sequence of SEQ ID NO: 318.

[0404] In addition to the VH2, VL2, H2, L2 sequences and amino acid substitutions shown above, the bispecific antibody EIP0360 comprises a first antigen binding domain that binds CD3s comprising a VH1, comprising a VHICDRI having the amino acid sequence of SEQ ID NO: 29; a VH1CDR2 having the amino acid sequence of SEQ ID NO: 34; and a VH1CDR3 having the amino acid sequence of SEQ ID NO: 37; and a VL1, comprising a VLICDRI having the amino acid sequence of SEQ ID NO: 42; a VL1CDR2 having the amino acid sequence of SEQ ID NO: 43; and a VL1CDR3 having the amino acid sequence of SEQ ID NO: 45.

[0405] In some embodiments, the bispecific antibody EIP0360 comprises a VH1 having the amino acid sequence of SEQ ID NO: 13 and a VL1 having the amino acid sequence of SEQ ID NO: 22. In some embodiments, a CD58 peptide comprising the amino acid sequence of SEQ ID NO: 50 is fused to the C-terminal of the heavy chain targeting CD3 (Hl). Accordingly, in some embodiments, the bispecific antibody EIP0360 comprises a Hl having the amino acid sequence of SEQ ID NO: 321 and a LI having the amino acid sequence of SEQ ID NO: 320.

[0406] In some embodiments, an exemplary CD3s x ULBP2 / 5 / 6 bispecific antibody of the disclosure includes EIP0363.

[0407] In some embodiments, bispecific antibody EIP0363 has a second antigen binding domain that binds ULBP2 / 5 / 6 comprising a VH2, comprising VH2CDRI having the amino acidsequence of SEQ ID NO: 5; a VH2CDR2 having the amino acid sequence of SEQ ID NO: 7; and a VH2CDR3 having the amino acid sequence of SEQ ID NO: 9; and a VL2, comprising a VL2CDRI having the amino acid sequence of SEQ ID NO: 10; a VL2CDR2 having the amino acid sequence of SEQ ID NO: 11; and a VL2CDR3 having the amino acid sequence of SEQ ID NO: 12.

[0408] In some embodiments, bispecific antibody EIP0363 comprises a VH2 comprising the amino acid sequence of SEQ ID NO: 2; and a VL2 comprising the amino acid sequence of SEQ ID NO: 1.

[0409] In some embodiments, bispecific antibody EIP0363 comprises a H2 comprising the amino acid sequence of SEQ ID NO: 323; and a L2 comprising the amino acid sequence of SEQ ID NO: 322.

[0410] In addition to the VH2, VL2, H2, L2 sequences and amino acid substitutions shown above, the bispecific antibody EIP0363 comprises a first antigen binding domain that binds CD3s comprising a VH1, comprising a VHICDRI having the amino acid sequence of SEQ ID NO: 32; a VH1CDR2 having the amino acid sequence of SEQ ID NO: 36; and a VH1CDR3 having the amino acid sequence of SEQ ID NO: 37; and a VL1, comprising a VLICDRI having the amino acid sequence of SEQ ID NO: 42; a VL1CDR2 having the amino acid sequence of SEQ ID NO: 43; and a VL1CDR3 having the amino acid sequence of SEQ ID NO: 45.

[0411] In some embodiments, the bispecific antibody EIP0363 comprises a VH1 having the amino acid sequence of SEQ ID NO: 13 and a VL1 having the amino acid sequence of SEQ ID NO: 22. In some embodiments, a IL-7 peptide is fused to the C-terminal of the heavy chain targeting CD3 (Hl). Accordingly, in some embodiments, the bispecific antibody EIP0363 comprises a Hl having the amino acid sequence of SEQ ID NO: 325 and a LI having the amino acid sequence of SEQ ID NO: 324.Methods of Use

[0412] Any of the bispecific antibodies of the disclosure may be used in therapeutic methods. In one aspect, bispecific antibody may be for use as a medicament is provided. In further aspects, an antibody for use in treating or delaying progression of a cell proliferative disorder (e.g., cancer). In certain embodiments, an antibody for use in a method of treatment is provided. In certain embodiments, the disclosure provides an antibody for use in a method oftreating an individual having a cell proliferative disorder comprising administering to the individual an effective amount of the antibody. In one such embodiment, the method further comprises administering to the individual an effective amount of at least one additional therapeutic agent, for example, as described below. In further embodiments, the disclosure provides an antibody for use in enhancing immune function in an individual having a cell proliferative disorder. In certain embodiments, the disclosure provides an antibody for use in a method of enhancing immune function in an individual having a cell proliferative disorder comprising administering to the individual an effective of the antibody to activate effector cells (e.g., T cells, e.g., CD8+ and / or CD4+ T cells), expand (increase) an effector cell population, reduce a target cell population, and / or kill a target cell (e.g., target tumor cell). An "individual" according to any of the above embodiments may be a human.

[0413] In a further aspect, the disclosure provides for the use of antibodies of the disclosure in the manufacture or preparation of a medicament. In one embodiment, the medicament is for treatment of a cell proliferative disorder (e.g., cancer, such as squamous cancer, adenocarcinoma, or metastatic cancer). In a further embodiment, the medicament is for use in a method of treating a cell proliferative disorder or an autoimmune disorder comprising administering to an individual having a cell proliferative disorder or an autoimmune disorder an effective amount of the medicament. In one such embodiment, the method further comprises administering to the individual an effective amount of at least one additional therapeutic agent, for example, as described below. In a further embodiment, the medicament is for activating effector cells (e.g., T cells, e.g., CD8+ and / or CD4+ T cells), expanding (increasing) an effector cell population, reducing a target cell (e.g., a cell expressing ULBP2) population, and / or killing target cells (e.g., target tumor cells) in the individual. In a further embodiment, the medicament is for use in a method of enhancing immune function in an individual having a cell proliferative disorder or an autoimmune disorder comprising administering to the individual an amount effective of the medicament to activate effector cells (e.g., T cells, e.g., CD8+ and / or CD4+ T cells), expand (increase) an effector cell population, reduce a target cell (e.g. , a cell expressing ULBP2) population, and / or kill a target cell (e.g., target tumor cell). An "individual" according to any of the above embodiments may be a human.

[0414] In a further aspect, the disclosure provides a method for treating a cell proliferative disorder (e.g., cancer). In one embodiment, the method comprises administering to an individual having such a cell proliferative disorder an effective amount of a bispecific antibody. In one such embodiment, the method further comprises administering to the individual an effective amount of at least one additional therapeutic agent, for example, as described below. An "individual" according to any of the above embodiments may be a human. In a further aspect, the disclosure provides a method for enhancing immune function in an individual having a cell proliferative disorder or an autoimmune disorder in an individual having a cell proliferative disorder or an autoimmune disorder. In one embodiment, the method comprises administering to the individual an effective amount of a bispecific antibody to activate effector cells (e.g., T cells, e.g., CD8+ and / or CD4+ T cells), expand (increase) an effector cell population, reduce a target cell (e.g., a cell expressing ULBP2) population, and / or kill a target cell (e.g., target tumor cell).

[0415] The method further comprises comparing a level of ULBP2 expression in the cancer sample to a level of ULBP2 expression in healthy / control / reference tissue to determine if the level of ULBP2 expression in the cancer sample is higher. If the level of ULBP2 expression is higher in the cancer sample, the subject receives a ULBP2 targeting therapeutic. In some embodiments, the ULBP2 targeting therapeutic is one or more of the antibodies (e.g., a bispecific antibody targeting ULBP2 and CD3) provided herein. In some embodiments, any method for measuring the level of ULBP2 can be employed. In some embodiments, this is any amount greater than a negative amount in a staining assay. In some embodiments, this is any amount above a level present in surrounding healthy / control / reference tissue or corresponding tissue from a healthy / control / reference subject. In some embodiments, high levels of expression of ULBP2 is defined in comparison to an expression level of ULBP2 in a non-cancer sample.

[0416] In some embodiments, the expression level of ULBP2 in the cancer sample is at least 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9% or 1.0% higher than the expression level of ULBP2 in the non-cancer sample. In some embodiments, the expression level of ULBP2 in the cancer sample is at least 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9% or 10% higher than the expression level of ULBP2 in the non-cancer sample. In some embodiments, the expression level of ULBP2 in the cancer sample is at least 15%, 20%, 25%, 30%, 35%, 40%,45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 125%, 150%, 175%, 200%, 225%, 250%, 275%, 300%, 325%, 350%, 375%, 400%, 425%, 450%, 475% or 500% higher than the expression level of ULBP2 in the non-cancer sample. In some embodiments, the expression level of ULBP2 in the cancer sample is at least 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 11-fold, 12-fold, 13-fold, 14-fold, 15-fold, 16-fold, 17- fold, 18-fold, 19-fold or 20-fold higher than the expression level of ULBP2 in the non-cancer sample.

[0417] The method further comprises comparing a level of TROP2, NECTIN4, KRT5, KRT6A, SERPINB3, SERPINB4, and / or HER2 expression in the cancer sample to a level of TROP2, NECTIN4, KRT5, KRT6A, SERPINB3, SERPINB4, and / or HER2 expression in healthy / control / reference tissue to determine if the level of TROP2, NECTIN4, KRT5, KRT6A, SERPINB3, SERPINB4, and / or HER2 expression in the cancer sample is higher. If the level of TROP2, NECTIN4, KRT5, KRT6A, SERPINB3, SERPINB4, and / or HER2 expression is higher in the cancer sample, the subject receives a ULBP2 targeting therapeutic. In some embodiments, the ULBP2 targeting therapeutic is one or more of the antibodies provided herein. In some embodiments, any method for measuring the level of TROP2, NECTIN4, KRT5, KRT6A, SERPINB3, SERPINB4, and / or HER2 can be employed.

[0418] In some embodiments, the healthy / control / reference sample is a sample from a normal tissue. In some embodiments, the normal tissue is a tissue that is an adjacent tissue to the cancer in the subject. For example, when assaying for expression via staining, the levels of the protein are above those understood to be “negative” to one of skill in the art for the particular assay. Exemplary assays include but are not limited to RNA based assays, FACS, and IHC, each with their appropriate levels of positive and negative results. Any method of detecting the level of a protein in a sample is contemplated. One skilled in the art can select a suitable method depending on the type of sample being analyzed and the identity and number of proteins being detected. Nonlimiting exemplary such methods include immunohistochemistry, ELISA, Western blotting, multiplex analyte detection (using, for example, Luminex technology), mass spectrometry, etc. Similarly, any method of detecting the level of an mRNA in a sample is contemplated. One skilled in the art can select a suitable method depending on the type of sample being analyzed and the identity and number ofmRNAs being detected. Nonlimiting exemplary such methods include RT-PCR, quantitative RT-PCR and microarray-based methods, etc.

[0419] A ULBP2-positive cancer according to any of the above embodiments may be a basal squamous bladder cancer or lung cancer. In some embodiments, an ULBP2-positive cancer is a cancer that receives an anti-ULBP2 immunohistochemistry (IHC) or in situ hybridization (ISH) score greater than “0,” which corresponds to very weak or no staining in >90% of tumor cells. In another embodiment, a ULBP2-positive cancer expresses ULBP2 at a 1+, 2+ or 3+ level. In some embodiments, a ULBP2-positive cancer is a cancer that expresses ULBP2 according to a reverse-transcriptase PCR (RT-PCR) assay that detects ULBP2 mRNA. In some embodiments, the RT-PCR is quantitative RT-PCR.

[0420] In a further aspect, the disclosure provides pharmaceutical formulations comprising any of the bispecific antibodies provided herein, e.g., for use in any of the above therapeutic methods. In one embodiment, a pharmaceutical formulation comprises any of the bispecific antibodies provided herein and a pharmaceutically acceptable carrier. In another embodiment, a pharmaceutical formulation comprises any of the bispecific antibodies provided herein and at least one additional therapeutic agent, for example, as described herein.

[0421] Antibodies of the disclosure can be used either alone or in combination with other agents in a therapy. For instance, an antibody of the disclosure may be co-administered with at least one additional therapeutic agent. In certain embodiments, an additional therapeutic agent is a chemotherapeutic agent, growth inhibitory agent, cytotoxic agent, agent used in radiation therapy, anti-angiogenesis agent, apoptotic agent, anti-tubulin agent, or other agent, such as a epidermal growth factor receptor (EGFR) antagonist (e.g., a tyrosine kinase inhibitor), HER1 / EGFR inhibitor (e.g., erlotinib (Tarceva™), platelet derived growth factor inhibitor (e.g., Gleevec™ (Imatinib Mesylate)), a COX-2 inhibitor (e.g., celecoxib), interferon, cytokine, antibody other than the anti-CD3 antibody of the disclosure, such as an antibody that bind to one or more of the following targets ErbB2, ErbB3, ErbB4, PDGFR- beta, BlyS, APRIL, BCMA VEGF, or VEGF receptor(s), TRAIL / Apo2, PD-1 (e.g. Nivolumab, Pembrolizumab, Cemiplimab), PD-L1 (Atezolizumab, Avelumab, Durvalumab), PD-L2, or another bioactive or organic chemical agent. In some embodiments, the disclosure provides a method wherein the additional therapeutic agent is a glucocorticoid. In one embodiment, the glucocorticoid is dexamethasone.

[0422] In some aspects, the additional therapeutic agent is a checkpoint inhibitor. The term “inhibition” or “inhibitor” includes a reduction in a certain parameter, e.g., an activity, of a given molecule, e.g., an immune checkpoint inhibitor. For example, inhibition of an activity, e.g., an activity of, e.g., PD-1, PD-L1, CTLA-4, TIM-3, CEACAM (e.g., CEACAM-1, CEACAM-3 and / or CEACAM-5), LAG-3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 or TGFR beta, of at least 5%, 10%, 20%, 30%, 40% or more is included by this term. The level of inhibition need not be 100%.

[0423] In some aspects, the checkpoint inhibitor is a PD-1 inhibitor. In some aspects, the PD- 1 inhibitor is an anti-PDl antibody. In some aspects, the PD-1 inhibitor is an anti PD-1 monoclonal antibody. Exemplary anti-PD-1 monoclonal antibodies include, but are not limited to cemiplimab (Libtayo), nivolumab (Opdivo), pembrolizumab (Keytruda). In some aspects, the checkpoint inhibitor is a PD-L1 inhibitor. Exemplary PD-L1 inhibitors include but are not limited to avelumab (Bavencio), durvalumab (Imfinzi) and atezolizumab (Tecentriq).

[0424] Such combination therapies noted above encompass combined administration (where two or more therapeutic agents are included in the same or separate formulations), and separate administration, in which case, administration of the antibody of the disclosure can occur prior to, simultaneously, and / or following, administration of the additional therapeutic agent or agents. In one embodiment, administration of the bispecific antibody and administration of an additional therapeutic agent occur within about one month, or within about one, two or three weeks, or within about one, two, three, four, five, or six days, of each other. Bispecific antibodies of the disclosure can also be used in combination with radiation therapy.

[0425] In some aspects, the additional therapeutic agent is a chimeric antigen receptor (CAR) T cell therapy. In some embodiments, the CAR-T cell therapy specifically binds CD 19. Exemplary CAR-T cell therapies that specifically bind CD 19 include but are not limited to BREYANZI® (lisocabtagene maraleucel), TECARTUS™ (brexucabtagene autoleucel), KYMRIAH™ (tisagenlecleucel), YESCARTA™ (axicabtagene ciloleucel), ABECMA® (idecabtagene vicleucel), or CARVYKTI™ (ciltacabtagene autoleucel).

[0426] An antibody of the disclosure (and / or any additional therapeutic agent) can be administered by any suitable means, including parenteral, intrapulmonary, and intranasal,and, if desired for local treatment, intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. In some embodiments, the antibody is administered by subcutaneous administration. In some embodiments, an anti-CD3s antibody administered by subcutaneous injection exhibits a less toxic response in a patient than the same anti-CD3s antibody administered by intravenous injection. Dosing can be by any suitable route, for example, by injections, such as intravenous or subcutaneous injections, depending in part on whether the administration is brief or chronic. Various dosing schedules including but not limited to single or multiple administrations over various time-points, bolus administration, and pulse infusion are contemplated herein.

[0427] Antibodies of the disclosure would be formulated, dosed, and administered in a fashion consistent with good medical practice. Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners. The antibody need not be, but is optionally formulated with one or more agents currently used to prevent or treat the disorder in question. The effective amount of such other agents depends on the amount of antibody present in the formulation, the type of disorder or treatment, and other factors discussed above. These are generally used in the same dosages and with administration routes as described herein, or about from 1 to 99% of the dosages described herein, or in any dosage and by any route that is empirically / clinically determined to be appropriate.

[0428] For the prevention or treatment of disease, the appropriate dosage of an antibody of the disclosure (when used alone or in combination with one or more other additional therapeutic agents) will depend on the type of disease to be treated, the type of antibody, the severity and course of the disease, whether the antibody is administered for preventive or therapeutic purposes, previous therapy, the patient's clinical history and response to the antibody, and the discretion of the attending physician. The antibody is suitably administered to the patient at one time or over a series of treatments.

[0429] As a general proposition, the therapeutically effective amount of the bispecific antibody administered to human will be in the range of about 0.01 to about 100 mg / kg ofpatient body weight whether by one or more administrations. In some embodiments, the antibody used is about 0.01 to about 45 mg / kg, about 0.01 to about 40 mg kg, about 0.01 to about 35 mg / kg, about 0.01 to about 30 mg / kg, about 0.01 to about 25 mg / kg, about 0.01 to about 20 mg / kg, about 0.01 to about 15 mg kg, about 0.01 to about 10 mg / kg, about 0.01 to about 5 mg / kg, or about 0.01 to about 1 mg / kg administered daily, for example. In one embodiment, a bispecific antibody described herein is administered to a human at a dose of about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg or about 1400 mg on day 1 of 21 -day cycles. The dose may be administered as a single dose or as multiple doses (e.g., 2 or 3 doses), such as infusions. For repeated administrations over several days or longer, depending on the condition, the treatment would generally be sustained until a desired suppression of disease symptoms occurs. One exemplary dosage of the antibody would be in the range from about 0.05 mg / kg to about 10 mg / kg. Thus, one or more doses of about 0.5 mg / kg, 2.0 mg / kg, 4.0 mg kg, or 10 mg / kg (or any combination thereof) may be administered to the patient. Such doses may be administered intermittently, for example, every week or every three weeks (e.g., such that the patient receives from about two to about twenty, or, for example, about six doses of the bispecific antibody). An initial higher loading dose, followed by one or more lower doses may be administered. The progress of this therapy is easily monitored by conventional techniques and assays.

[0430] In some embodiments, the methods may further comprise an additional therapy. The additional therapy may be radiation therapy, surgery, chemotherapy, gene therapy, DMA therapy, viral therapy, RNA therapy, immunotherapy, bone marrow transplantation, nanotherapy, monoclonal antibody therapy, or a combination of the foregoing. The additional therapy may be in the form of adjuvant or neoadjuvant therapy. In some embodiments, the additional therapy is the administration of small molecule enzymatic inhibitor or anti- metastatic agent. In some embodiments, the additional therapy is the administration of sideeffect limiting agents (e.g., agents intended to lessen the occurrence and / or severity of side effects of treatment, such as anti-nausea agents, etc.). In some embodiments, the additional therapy is radiation therapy. In some embodiments, the additional therapy is surgery. In some embodiments, the additional therapy is a combination of radiation therapy and surgery. Insome embodiments, the additional therapy is gamma irradiation. In some embodiments, the additional therapy may be a separate administration of one or more of the therapeutic agents described above.

[0431] It will be appreciated that administration of therapeutic entities in accordance with the disclosure will be administered with suitable carriers, excipients, and other agents that are incorporated into formulations to provide improved transfer, delivery, tolerance, and the like. A multitude of appropriate formulations can be found in the formulary known to all pharmaceutical chemists: Remington's Pharmaceutical Sciences (15th ed, Mack Publishing Company, Easton, PA (1975)), particularly Chapter 87 by Blaug, Seymour, therein. These formulations include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids, lipid (cationic or anionic) containing vesicles (such as Lipofectin™), DNA conjugates, anhydrous absorption pastes, oil-in-water and water-in-oil emulsions, emulsions carbowax (polyethylene glycols of various molecular weights), semi-solid gels, and semi-solid mixtures containing carbowax. Any of the foregoing mixtures may be appropriate in treatments and therapies in accordance with the present disclosure, provided that the active ingredient in the formulation is not inactivated by the formulation and the formulation is physiologically compatible and tolerable with the route of administration. See also Baldrick P. “Pharmaceutical excipient development: the need for preclinical guidance.” Regul. Toxicol Pharmacol. 32(2):210-8 (2000), Wang W. “Lyophilization and development of solid protein pharmaceuticals.” Int. J. Pharm. 203(1-2): 1-60 (2000), Charman WN “Lipids, lipophilic drugs, and oral drug delivery-some emerging concepts.” J Pharm Sci. 89(8):967-78 (2000), Powell et al. “Compendium of excipients for parenteral formulations” PDA J Pharm Sci Technol. 52:238-311 (1998) and the citations therein for additional information related to formulations, excipients and carriers well known to pharmaceutical chemists.

[0432] Therapeutic formulations of the disclosure, which include an antibody of the disclosure, are used to treat or alleviate a symptom associated with a cancer, such as, by way of non-limiting example, leukemias, lymphomas, breast cancer, colon cancer, ovarian cancer, bladder cancer, prostate cancer, glioma, lung & bronchial cancer, colorectal cancer, pancreatic cancer, esophageal cancer, liver cancer, urinary bladder cancer, kidney and renal pelvis cancer, oral cavity & pharynx cancer, uterine corpus cancer, and / or melanoma The present disclosure also provides methods of treating or alleviating a symptom associated witha cancer. A therapeutic regimen is carried out by identifying a subject, e.g. , a human patient suffering from (or at risk of developing) a cancer, using standard methods.

[0433] Efficaciousness of treatment is determined in association with any known method for diagnosing or treating the particular immune-related disorder. Alleviation of one or more symptoms of the immune-related disorder indicates that the antibody confers a clinical benefit.

[0434] Methods for the screening of antibodies that possess the desired specificity include, but are not limited to, enzyme linked immunosorbent assay (ELISA) and other immunologically mediated techniques known within the art.

[0435] Antibodies directed against a target such as CD3s, ULBP2, or a combination thereof (or a fragment thereof), may be used in methods known within the art relating to the localization and / or quantitation of these targets, e.g., for use in measuring levels of these targets within appropriate physiological samples, for use in diagnostic methods, for use in imaging the protein, and the like). In a given embodiment, antibodies specific any of these targets, or derivative, fragment, analog or homolog thereof, that contain the antibody derived antigen binding domain, are utilized as pharmacologically active compounds (referred to hereinafter as “Therapeutics”).

[0436] An antibody of the disclosure can be used to isolate a particular target using standard techniques, such as immunoaffinity, chromatography or immunoprecipitation. Antibodies of the disclosure (or a fragment thereof) can be used diagnostically to monitor protein levels in tissue as part of a clinical testing procedure, e.g. , to determine the efficacy of a given treatment regimen. Detection can be facilitated by coupling (z.e., physically linking) the antibody to a detectable substance. Examples of detectable substances include various enzymes, prosthetic groups, fluorescent materials, luminescent materials, bioluminescent materials, and radioactive materials. Examples of suitable enzymes include horseradish peroxidase, alkaline phosphatase, P-galactosidase, or acetylcholinesterase; examples of suitable prosthetic group complexes include streptavidin / biotin and avidin / biotin; examples of suitable fluorescent materials include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride or phycoerythrin; an example of a luminescent material includes luminol; examples of bioluminescent materials includeluciferase, luciferin, and aequorin, and examples of suitable radioactive material include125I,1311,35S or3H.

[0437] Antibodies of the disclosure, including polyclonal, monoclonal, humanized and fully human antibodies, may be used as therapeutic agents. Such agents will generally be employed to treat or prevent a disease or pathology associated with aberrant expression or activation of a given target in a subject. An antibody preparation, preferably one having high specificity and high affinity for its target antigen, is administered to the subject and will generally have an effect due to its binding with the target. Administration of the antibody may abrogate or inhibit or interfere with the signaling function of the target. Administration of the antibody may abrogate or inhibit or interfere with the binding of the target with an endogenous ligand to which it naturally binds.

[0438] A therapeutically effective amount of an antibody of the disclosure relates generally to the amount needed to achieve a therapeutic objective. As noted above, this may be a binding interaction between the antibody and its target antigen that, in certain cases, interferes with the functioning of the target. The amount required to be administered will furthermore depend on the binding affinity of the antibody for its specific antigen, and will also depend on the rate at which an administered antibody is depleted from the free volume other subject to which it is administered. Common ranges for therapeutically effective dosing of an antibody or antibody fragment of the disclosure may be, by way of nonlimiting example, from about 0.1 mg / kg body weight to about 50 mg / kg body weight. Common dosing frequencies may range, for example, from twice daily to once a week.

[0439] Antibodies or a fragment thereof of the disclosure can be administered for the treatment of a variety of diseases and disorders in the form of pharmaceutical compositions. Principles and considerations involved in preparing such compositions, as well as guidance in the choice of components are provided, for example, in Remington: The Science And Practice Of Pharmacy 19th ed. (Alfonso R. Gennaro, et al., editors) Mack Pub. Co., Easton, Pa.: 1995; Drug Absorption Enhancement: Concepts, Possibilities, Limitations, And Trends, Harwood Academic Publishers, Langhorne, Pa., 1994; and Peptide And Protein Drug Delivery (Advances In Parenteral Sciences, Vol. 4), 1991, M. Dekker, New York.

[0440] Where antibody fragments are used, the smallest inhibitory fragment that specifically binds to the binding domain of the target protein is preferred. For example, based upon thevariable-region sequences of an antibody, peptide molecules can be designed that retain the ability to bind the target protein sequence. Such peptides can be synthesized chemically and / or produced by recombinant DNA technology. (See, e.g., Marasco et al., Proc. Natl. Acad. Sci. USA, 90: 7889-7893 (1993)). The formulation can also contain more than one active compound as necessary for the particular indication being treated, preferably those with complementary activities that do not adversely affect each other. Alternatively, or in addition, the composition can comprise an agent that enhances its function, such as, for example, a cytotoxic agent, cytokine, chemotherapeutic agent, or growth-inhibitory agent. Such molecules are suitably present in combination in amounts that are effective for the purpose intended.

[0441] The active ingredients can also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly-(methylmethacrylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles, and nanocapsules) or in macroemulsions.

[0442] The formulations to be used for in vivo administration must be sterile. This is readily accomplished by filtration through sterile filtration membranes.

[0443] Sustained-release preparations can be prepared. Suitable examples of sustained- release preparations include semipermeable matrices of solid hydrophobic polymers containing the antibody, which matrices are in the form of shaped articles, e.g., films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)), polylactides (U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid and y ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPOT ™ (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(-)-3-hydroxybutyric acid. While polymers such as ethylenevinyl acetate and lactic acid-glycolic acid enable release of molecules for over 100 days, certain hydrogels release proteins for shorter time periods.

[0444] An antibody according to the disclosure can be used as an agent for detecting the presence of a given target (or a protein fragment thereof) in a sample. In some embodiments,the antibody contains a detectable label. Antibodies are polyclonal, or more preferably, monoclonal. An intact antibody, or a fragment thereof (e.g., Fab, scFv, or F(ab)2) is used. The term “labeled”, with regard to the probe or antibody, is intended to encompass direct labeling of the probe or antibody by coupling (z.e., physically linking) a detectable substance to the probe or antibody, as well as indirect labeling of the probe or antibody by reactivity with another reagent that is directly labeled. Examples of indirect labeling include detection of a primary antibody using a fluorescently-labeled secondary antibody and end-labeling of a DNA probe with biotin such that it can be detected with fluorescently-labeled streptavidin. The term “biological sample” is intended to include tissues, cells and biological fluids isolated from a subject, as well as tissues, cells and fluids present within a subject. Included within the usage of the term “biological sample”, therefore, is blood and a fraction or component of blood including blood serum, blood plasma, or lymph. That is, the detection method of the disclosure can be used to detect an analyte mRNA, protein, or genomic DNA in a biological sample in vitro as well as in vivo. For example, in vitro techniques for detection of an analyte mRNA include Northern hybridizations and in situ hybridizations. In vitro techniques for detection of an analyte protein include enzyme linked immunosorbent assays (ELISAs), Western blots, immunoprecipitations, and immunofluorescence. In vitro techniques for detection of an analyte genomic DNA include Southern hybridizations. Procedures for conducting immunoassays are described, for example in “ELISA: Theory and Practice: Methods in Molecular Biology”, Vol. 42, J. R. Crowther (Ed.) Human Press, Totowa, NJ, 1995; “Immunoassay”, E. Diamandis and T. Christopoulus, Academic Press, Inc., San Diego, CA, 1996; and “Practice and Theory of Enzyme Immunoassays”, P. Tijssen, Elsevier Science Publishers, Amsterdam, 1985. Furthermore, in vivo techniques for detection of an analyte protein include introducing into a subject a labeled anti- analyte protein antibody. For example, the antibody can be labeled with a radioactive marker whose presence and location in a subject can be detected by standard imaging techniques.In Some embodiments of this disclosure provide a method of treating a squamous cell cancer in a subject, the method comprising administering to the subject an anti-ULBP2 antibody (e.g., a bispecific antibody that binds ULBP2 and CD3) provided herein in combination with a chemotherapy, a radiotherapy, and / or an immune checkpoint inhibitor. Any suitable chemotherapy can be used in the methods described herein, including but not limited to atopoisomerase inhibitor, an anthracycline doxorubicin, a DNA break inducing antibiotic, a pyrimidine antagonist, or a platinum alkylating agent. Any suitable radiotherapy can be used in the methods described herein, including but not limited to 3D conformal radiation therapy (3DCRT), image-guided radiation therapy (IGRT), intensity modulated radiation therapy (IMRT), volumetric modulated arc therapy (VMAT), brachytherapy, intraoperative radiation therapy (IORT), stereotactic radiosurgery (SRS), proton therapy, MRI linear accelerator, and / or stereotactic body radiation therapy (SBRT). Any suitable immune checkpoint inhibitor can be used in the methods described herein, including but not limited to avelumab, durvalumab, atezolizumab, pembrolizumab, nivolumab, atezolizumab, ipilimumab, or tremelimumab.

[0445] Squamous cell cancers (SCCs) are malignancies caused by squamous cells, a subtype of epithelial cell found in the skin and mucous membranes. SCCs are commonly associated with skin cancer, but can develop in any organ lined by squamous cells, including but not limited to the bladder, lungs, esophagus, cervix, anus, vulva, penis, thymus, thyroid, and mouth (e.g., in head and neck squamous cell cancer, or oropharyngeal squamous cell cancer). In some embodiments, the disclosure provides a method of treating a bladder squamous cell cancer in a subject, the method comprising administering to the subject an anti-ULBP2 antibody (e.g., a bispecific antibody that binds ULBP2 and CD3) provided herein. In some embodiments, the disclosure provides a method of treating a lung squamous cell cancer in a subject, the method comprising administering to the subject an anti-ULBP2 antibody (e.g., a bispecific antibody that binds ULBP2 and CD3) provided herein. In some embodiments, the disclosure provides a method of treating an esophageal squamous cell cancer in a subject, the method comprising administering to the subject an anti-ULBP2 antibody (e.g., a bispecific antibody that binds ULBP2 and CD3) provided herein. In some embodiments, the disclosure provides a method of treating a head and neck squamous cell cancer in a subject, the method comprising administering to the subject an anti-ULBP2 antibody (e.g., a bispecific antibody that binds ULBP2 and CD3) provided herein. In some embodiments, the disclosure provides a method of treating a cervical squamous cell cancer in a subject, the method comprising administering to the subject an anti-ULBP2 antibody (e.g., a bispecific antibody that binds ULBP2 and CD3) provided herein. In some embodiments, the disclosure provides a method of treating a skin squamous cell cancer in a subject, the method comprising administering tothe subject an anti-ULBP2 antibody (e.g., a bispecific antibody that binds ULBP2 and CD3) provided herein. In some embodiments, the disclosure provides a method of treating a thymic squamous cell cancer in a subject, the method comprising administering to the subject an anti- ULBP2 antibody (e.g., a bispecific antibody that binds ULBP2 and CD3) provided herein. In some embodiments, the disclosure provides a method of treating an anal squamous cell cancer in a subject, the method comprising administering to the subject an anti-ULBP2 antibody (e.g., a bispecific antibody that binds ULBP2 and CD3) provided herein. In some embodiments, the disclosure provides a method of treating a vulva squamous cell cancer in a subject, the method comprising administering to the subject an anti-ULBP2 antibody (e.g., a bispecific antibody that binds ULBP2 and CD3) provided herein. In some embodiments, the disclosure provides a method of treating a penile squamous cell cancer in a subject, the method comprising administering to the subject an anti-ULBP2 antibody (e.g., a bispecific antibody that binds ULBP2 and CD3) provided herein. In some embodiments, the disclosure provides a method of treating an adrenocortical squamous cell cancer in a subject, the method comprising administering to the subject an anti-ULBP2 antibody (e.g., a bispecific antibody that binds ULBP2 and CD3) provided herein. In some embodiments, the disclosure provides a method of treating a squamous cell cancer in a subject, the method comprising administering an anti-ULBP2 antibody provided herein and a chemotherapy agent, a radiation therapy, and / or an immune checkpoint inhibitor.

[0446] In some embodiments, this disclosure provides a method of treating an adeno carcinoma in a subject, the method comprising administering to the subject an anti-ULBP2 antibody (e.g., a bispecific antibody that binds ULBP2 and CD3) provided herein in combination with a chemotherapy, a radio therapy, and / or an immune checkpoint inhibitor. In some embodiments, the adenocarcinoma is lung adenocarcinoma, pancreatic adenocarcinoma, esophageal adenocarcinoma, bladder adenocarcinoma, or colon adenocarcinoma. In some embodiments, a subject having cancer (squamous cell cancer or adenocarcinoma) has increases level of ULBP2 expression level in the cancer cells relative to a non-cancerous cell. In some embodiments, ULBP2 expression level is well correlated with the portion of squamous cell cancer in the cancer tissue. In some embodiments, an adenocarcinoma has increases ULBP2 expression when the cancer has an EGFR activating mutation or an EGFR copy number alteration (e.g., increased EGFP copy numbers). EGRFactivating mutations are generally know, for example as described by Gazdar, Oncogene. 2009 Aug; 28(Suppl 1): S24-S31. Accordingly, the present disclosure provides methods for treating an adenocarcinoma with an EGFR activating mutation an EGFR copy number alteration (e.g., increased EGFR copy numbers), the method comprising administering to the subject an anti-ULBP2 antibody (e.g., a bispecific antibody that binds ULBP2 and CD3) provided herein in combination with a chemotherapy or a radiotherapy. In some embodiments, a subject having a cancer (e.g., adenocarcinoma) with an EGFR activating mutation an EGFR copy number alteration (e.g., increased EGFR copy numbers) has previously been treated using a tyrosine kinase inhibitors (TKI) (e.g., Osimertinib), however, the TKI treatment does not decrease ULBP2 expression level in the cancer. In some embodiments, a subject having a cancer (e.g., adenocarcinoma) with an EGFR activating mutation an EGFR copy number alteration (e.g., increased EGFR copy numbers) has previously been treated using a tyrosine kinase inhibitors (TKI) (e.g., Osimertinib) has relapsed cancer after remission. In some embodiments, administration of an anti-ULBP2 antibody (e.g., a bispecific antibody that binds ULBP2 and CD3) provided herein) decreases ULBP2 expression level in a cancer with an EGFR activating mutation an EGFR copy number alteration (e.g., increased EGFR copy numbers) and the combination therapy with a chemotherapy, radio therapy, and / or immune checkpoint inhibitor improves the efficacy of the anti-ULBP2 antibody (e.g., a bispecific antibody that binds ULBP2 and CD3).

[0447] In some embodiments, the disclosure provides a method of treating a metastatic cancer in a subject, the method comprising administering to the subject an anti-ULBP2 antibody (e.g., a bispecific antibody that binds ULBP2 and CD3) provided herein in combination with a chemotherapy, a radio therapy, and / or an immune checkpoint inhibitor. Metastatic cancers are caused by tumors that have spread from their original site (non-primary tumors) to other parts of the body. Non-primary tumors can metastasize via the bloodstream or lymphatic system. Metastatic cancers are typically more advanced and often harder to treat, as they can invade organs such as the lungs, liver, bones, or brain. Among squamous cell cancers, metastatic squamous cell carcinoma of the lung and cervical squamous cell carcinoma are especially prevalent.

[0448] Non-primary tumors (metastatic tumors) are identified based on their cellular characteristics and location relative to the putative primary tumor. Methods to identify non-primary tumors include histopathology, immunohistochemistry, imaging e.g., CT, MRI, or PET scans), genomic profiling (e.g., DNA sequencing), and medical history. In some embodiments, metastatic cancer having non-primary tumors have a similar ULBP2 expression level as their primary tumor cells. In some embodiments, administration of an anti- ULBP2 antibody (e.g., a bispecific antibody that binds ULBP2 and CD3 provided herein) decreases ULBP2 expression level in a non-primary metastatic cancer and the combination therapy with a chemotherapy, radio therapy, and / or immune checkpoint inhibitor improves the efficacy of the anti-ULBP2 antibody (e.g., a bispecific antibody that binds ULBP2 and CD3). In some embodiments, the disclosure provides a method of treating a metastatic cancer in a subject, the method comprising administering to the subject an anti-ULBP2 antibody provided herein and a chemotherapy agent, a radiation therapy and / or an immune checkpoint inhibitor.Pharmaceutical Compositions

[0449] The antibodies of the disclosure (also referred to herein as “active compounds”), and derivatives, fragments, analogs and homologs thereof, can be incorporated into pharmaceutical compositions suitable for administration. Such compositions typically comprise the antibody and a pharmaceutically acceptable carrier. As used herein, the term “pharmaceutically acceptable carrier” is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. Suitable carriers are described in the most recent edition of Remington’s Pharmaceutical Sciences, a standard reference text in the field, which is incorporated herein by reference. Preferred examples of such carriers or diluents include, but are not limited to, water, saline, ringer’s solutions, dextrose solution, and 5% human serum albumin. Liposomes and non-aqueous vehicles such as fixed oils may also be used. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the compositions is contemplated. Supplementary active compounds can also be incorporated into the compositions.

[0450] A pharmaceutical composition of the disclosure is formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral,e.g., intravenous, intradermal, subcutaneous, oral e.g., inhalation), transdermal (z.e., topical), transmucosal, and rectal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid (EDTA); buffers such as acetates, citrates or phosphates, and agents for the adjustment of tonicity such as sodium chloride or dextrose. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.

[0451] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, N J.) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringeability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as manitol, sorbitol, sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum mono stearate and gelatin.

[0452] Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation are vacuum drying and freeze-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

[0453] Oral compositions generally include an inert diluent or an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and / or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or com starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

[0454] For administration by inhalation, the compounds are delivered in the form of an aerosol spray from pressured container or dispenser which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.

[0455] Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art.

[0456] The compounds can also be prepared in the form of suppositories (e.g., with conventional suppository bases such as cocoa butter and other glycerides) or retention enemas for rectal delivery.

[0457] In one embodiment, the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, poly anhydrides, poly glycolic acid, collagen, poly orthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811.

[0458] It is especially advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the disclosure are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active compound for the treatment of individuals.

[0459] The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

[0460] The disclosure will be further described in the following examples, which do not limit the scope of the disclosure described in the claims.Definitions

[0461] Unless otherwise defined, scientific and technical terms used in connection with the present disclosure shall have the meanings that are commonly understood by those of ordinary skill in the art. Further, unless otherwise required by context, singular terms shall includepluralities and plural terms shall include the singular. Generally, nomenclatures utilized in connection with, and techniques of, cell and tissue culture, molecular biology, and protein and oligo- or polynucleotide chemistry and hybridization described herein are those well- known and commonly used in the art. Standard techniques are used for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (e.g., electroporation, lipofection). Enzymatic reactions and purification techniques are performed according to manufacturer's specifications or as commonly accomplished in the art or as described herein. The foregoing techniques and procedures are generally performed according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification. See e.g., Sambrook et al. Molecular Cloning: A Laboratory Manual (2d ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (1989)). The nomenclatures utilized in connection with, and the laboratory procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those well-known and commonly used in the art. Standard techniques are used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, and delivery, and treatment of patients.

[0462] As utilized in accordance with the present disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings:

[0463] The term “ULBP2-positive cancer” refers to a cancer comprising cells that express ULBP2 on their surface. In some embodiments, expression of ULBP2 on the cell surface is determined, for example, using antibodies to ULBP2 in a method such as immunohistochemistry, LACS, etc. Alternatively, ULBP2 mRNA expression is considered to correlate to ULBP2 expression on the cell surface and can be determined by a method selected from in situ hybridization and RT-PCR (including quantitative RT-PCR). The term “ULBP2-positive cell” refers to a cell that expresses ULBP2 on its surface. The terms “cancer” and “cancerous” refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth / proliferation. Examples of cancer include, but are not limited to, carcinoma, lymphoma (e.g., Hodgkin's and non-Hodgkin's lymphoma), blastoma, sarcoma, and leukemia. More particular examples of such cancers include squamous cell cancer, small-cell lung cancer, non-small cell lung cancer, adenocarcinoma ofthe lung, squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastrointestinal cancer, pancreatic cancer, glioma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer (including triple negative (ER- / PR- / Her2-) breast cancer), colon cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney cancer, liver cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, leukemia and other lymphoproliferative disorders, and various types of head and neck cancer

[0464] The phrase “reference sample”, “reference cell”, or “reference tissue”, denote a sample with at least one known characteristic that can be used as a comparison to a sample with at least one unknown characteristic. In some embodiments, a reference sample can be used as a positive or negative indicator. A reference sample can be used to establish a level of protein and / or mRNA that is present in, for example, healthy tissue, in contrast to a level of protein and / or mRNA present in the sample with unknown characteristics. In some embodiments, the reference sample comes from the same subject, but is from a different part of the subject than that being tested. In some embodiments, the reference sample is from a tissue area surrounding or adjacent to the cancer. In some embodiments, the reference sample is not from the subject being tested, but is a sample from a subject known to have, or not to have, a disorder in question (for example, a particular cancer or ULBP2 related disorder). In some embodiments, the reference sample is from the same subject, but from a point in time before the subject developed cancer. In some embodiments, the reference sample is from a benign cancer sample (for example, benign breast cancer sample), from the same or a different subject. When a negative reference sample is used for comparison, the level of expression or amount of the molecule in question in the negative reference sample will indicate a level at which one of skill in the art will appreciate, given the present disclosure, that there is no and / or a low level of the molecule. When a positive reference sample is used for comparison, the level of expression or amount of the molecule in question in the positive reference sample will indicate a level at which one of skill in the art will appreciate, given the present disclosure, that there is a level of the molecule.

[0465] The term “disease” or “disorder” as used herein refers to a condition where treatment is needed and / or desired.

[0466] The term “tumor cell”, “cancer cell”, “cancer”, “tumor”, and / or “neoplasm”, unless otherwise designated, are used herein interchangeably and refer to a cell (or cells) exhibiting an uncontrolled growth and / or abnormal increased cell survival and / or inhibition of apoptosis which interferes with the normal functioning of bodily organs and systems. Included in this definition are benign and malignant cancers, polyps, hyperplasia, as well as dormant tumors or micrometastases. The terms “cancer” and “tumor” encompass solid and hematological / lymphatic cancers and also encompass malignant, pre-malignant, and benign growth, such as dysplasia. Also, included in this definition are cells having abnormal proliferation that is not impeded (e g immune evasion and immune escape mechanisms) by the immune system (e.g. virus infected cells). Exemplary tumor cells include, but are not limited to: basal cell carcinoma, biliary tract cancer; bladder cancer; bone cancer; brain and central nervous system cancer; breast cancer; cancer of the peritoneum; cervical cancer; choriocarcinoma; colon and rectum cancer; connective tissue cancer; cancer of the digestive system; endometrial cancer; esophageal cancer; eye cancer; cancer of the head and neck; gastric cancer (including gastrointestinal cancer); glioblastoma; hepatic carcinoma; hepatoma; intra-epithelial neoplasm; kidney or renal cancer; larynx cancer; leukemia; liver cancer; lung cancer e.g., small-cell lung cancer, non- small cell lung cancer, adenocarcinoma of the lung, and squamous carcinoma of the lung); melanoma; myeloma; neuroblastoma; oral cavity cancer (lip, tongue, mouth, and pharynx); ovarian cancer; pancreatic cancer; prostate cancer; retinoblastoma; rhabdomyosarcoma; rectal cancer; cancer of the respiratory system; salivary gland carcinoma; sarcoma; skin cancer; squamous cell cancer; stomach cancer; testicular cancer; thyroid cancer; uterine or endometrial cancer; cancer of the urinary system; vulval cancer; lymphoma including Hodgkin's and non-Hodgkin's lymphoma, as well as B- cell lymphoma (including low grade / follicular non-Hodgkin's lymphoma (NHL); small lymphocytic (SL) NHL; intermediate grade / follicular NHL; intermediate grade diffuse NHL; high grade immunoblastic NHL; high grade lymphoblastic NHL; high grade small noncleaved cell NHL; bulky disease NHL; mantle cell lymphoma; AIDS-related lymphoma; and Waldenstrom's Macroglobulinemia; chronic lymphocytic leukemia (CLL); acute lymphoblastic leukemia (ALL); Hairy cell leukemia; chronic myeloblastic leukemia; as well as other carcinomas and sarcomas; and post-transplant lymphoproliferative disorder (PTLD),as well as abnormal vascular proliferation associated with phakomatoses, edema (such as that associated with brain tumors), and Meigs' syndrome.

[0467] In some embodiments, the term cancer can encompass: a lung cancer, a breast cancer, a head and neck cancer, an ovarian cancer, and / or an endometrial cancer. When desired, the difference between a “cancer” and a “cancer cell” can be denoted by the use of the explicit use of the phrase “cancer cell”; however, the term “cancer” will encompass concepts such as the subject having cancer, and multicellular tumors, as well as single cancer cells.

[0468] An “increase or decrease” refers to a statistically significant increase or decrease respectively. As will be clear to the skilled person, “modulating” can also involve effecting a change (which can either be an increase or a decrease) in affinity, avidity, specificity and / or selectivity of a target or antigen, for one or more of its ligands, binding partners, partners for association into a homomultimeric or heteromultimeric form, or substrates; effecting a change (which can either be an increase or a decrease) in the sensitivity of the target or antigen for one or more conditions in the medium or surroundings in which the target or antigen is present (such as pH, ion strength, the presence of co-factors, etc.), compared to the same conditions but without the presence of an antibody, bispecific or multispecific polypeptide agent. This can be determined in any suitable manner and / or using any suitable assay known per se or described herein, depending on the target involved.

[0469] As used herein, “an immune response” is meant to encompass cellular and / or humoral immune responses that are sufficient to inhibit or prevent onset or ameliorate the symptoms of disease (for example, cancer or cancer metastasis). “An immune response” can encompass aspects of both the innate and adaptive immune systems.

[0470] As used herein, “treatment” is an approach for obtaining beneficial or desired clinical results. “Treatment” as used herein, covers any administration or application of a therapeutic for disease in a mammal, including a human. For purposes of this disclosure, beneficial or desired clinical results include, but are not limited to, any one or more of: alleviation of one or more symptoms, diminishment of extent of disease, preventing or delaying spread (for example, metastasis, for example metastasis to the lung or to the lymph node) of disease, preventing or delaying recurrence of disease, delay or slowing of disease progression, amelioration of the disease state, inhibiting the disease or progression of the disease, inhibiting or slowing the disease or its progression, arresting its development, and remission(whether partial or total). Also encompassed by “treatment” is a reduction of pathological consequence of a proliferative disease. The methods provided herein contemplate any one or more of these aspects of treatment. In-line with the above, the term treatment does not require one-hundred percent removal of all aspects of the disorder.

[0471] “Ameliorating” means a lessening or improvement of one or more symptoms as compared to not administering an anti-ULBP2 antibody. “Ameliorating” also includes shortening or reduction in duration of a symptom.

[0472] The term “biological sample” means a quantity of a substance from a living thing or formerly living thing. Such substances include, but are not limited to, blood, (for example, whole blood), plasma, serum, urine, amniotic fluid, synovial fluid, endothelial cells, leukocytes, monocytes, other cells, organs, tissues, bone marrow, lymph nodes and spleen.

[0473] The term “control” refers to a composition known to not contain an analyte (“negative control”) or to contain analyte (“positive control”). A positive control can comprise a known concentration of analyte. “Control,” “positive control,” and “calibrator” may be used interchangeably herein to refer to a composition comprising a known concentration of analyte. A “positive control” can be used to establish assay performance characteristics and is a useful indicator of the integrity of reagents (for example, analytes).

[0474] ‘ ‘Predetermined cutoff’ and “predetermined level” refer generally to an assay cutoff value that is used to assess diagnostic / prognostic / therapeutic efficacy results by comparing the assay results against the predetermined cutoff / level, where the predetermined cutoff / level already has been linked or associated with various clinical parameters (for example, severity of disease, progression / nonprogression / improvement, etc.). While the present disclosure may provide exemplary predetermined levels, it is well-known that cutoff values may vary depending on the nature of the immunoassay (for example, antibodies employed, etc.). It further is well within the skill of one of ordinary skill in the art to adapt the disclosure herein for other immunoassays to obtain immunoas say- specific cutoff values for those other immunoassays based on this disclosure. Whereas the precise value of the predetermined cutoff / level may vary between assays, correlations as described herein (if any) may be generally applicable.

[0475] The terms “inhibition” or “inhibit” refer to a decrease or cessation of any phenotypic characteristic or to the decrease or cessation in the incidence, degree, or likelihood of thatcharacteristic. To “reduce” or “inhibit” is to decrease, reduce or arrest an activity, function, and / or amount as compared to a reference. In some embodiments, by “reduce” or “inhibit” is meant the ability to cause an overall decrease of 20% or greater. In some embodiments, by “reduce” or “inhibit” is meant the ability to cause an overall decrease of 50% or greater. In some embodiments, by “reduce” or “inhibit” is meant the ability to cause an overall decrease of 75%, 85%, 90%, 95%, or greater. In some embodiments, the amount noted above is inhibited or decreased over a period of time, relative to a control dose (such as a placebo) over the same period of time.

[0476] As used herein, “delaying development of a disease” means to defer, hinder, slow, retard, stabilize, suppress and / or postpone development of the disease (such as cancer). This delay can be of varying lengths of time, depending on the history of the disease and / or individual being treated. As is evident to one skilled in the art, a sufficient or significant delay can, in effect, encompass prevention, in that the individual does not develop the disease. For example, a late stage cancer, such as development of metastasis, may be delayed.

[0477] “Preventing,” as used herein, includes providing prophylaxis with respect to the occurrence or recurrence of a disease in a subject that may be predisposed to the disease but has not yet been diagnosed with the disease. Unless otherwise specified, the terms “reduce”, “inhibit”, or “prevent” do not denote or require complete prevention over all time.

[0478] As used herein, to “suppress” a function or activity is to reduce the function or activity when compared to otherwise same conditions except for a condition or parameter of interest, or alternatively, as compared to another condition. For example, an antibody which suppresses tumor growth reduces the rate of growth of the tumor compared to the rate of growth of the tumor in the absence of the antibody.

[0479] The term "antibody binding region" refers to a region of the antigen, which comprises the epitope to which the antibody binds. An antibody binding region may be determined by epitope binning using biolayer interferometry, by alanine scan, or by domain shuffle assays (using antigen constructs in which regions of the antigen are exchanged with that of another species and determining whether the antibody still binds to the antigen or not). The amino acids within the antibody binding region that are involved in the interaction with the antibody may be determined by hydrogen / deuterium exchange mass spectrometry and / or by crystallography of the antibody bound to its antigen.

[0480] As used herein, the term “antibody” refers to immunoglobulin molecules and immunologically active portions of immunoglobulin (Ig) molecules, i.e., molecules that contain an antigen binding site that specifically binds (immunoreacts with) an antigen. By “specifically bind” or “immunoreacts with” or “immunospecifically bind” is meant that the antibody reacts with one or more antigenic determinants of the desired antigen and does not react with other polypeptides or binds at much lower affinity (Ka > 10'6). Antibodies include, but are not limited to, polyclonal, monoclonal, chimeric, dAb (domain antibody), single chain, Fab, Fab’ and F(ab')2 fragments, scFvs, and a Fab expression library.

[0481] The basic antibody structural unit is known to comprise a tetramer. Each tetramer is composed of two identical pairs of polypeptide chains, each pair having one “light” (about 25 kDa) and one “heavy” chain (about 50-70 kDa). The amino-terminal portion of each chain includes a variable region of about 100 to 110 or more amino acids primarily responsible for antigen recognition. The carboxy-terminal portion of each chain defines a constant region primarily responsible for effector function. In general, antibody molecules obtained from humans relate to any of the classes IgG, IgM, IgA, IgE and IgD, which differ from one another by the nature of the heavy chain present in the molecule. Certain classes have subclasses as well, such as IgGi, IgG2, IgG4 and others. Furthermore, in humans, the light chain may be a kappa chain or a lambda chain.

[0482] The term “monoclonal antibody” (MAb) or “monoclonal antibody composition”, as used herein, refers to a population of antibody molecules that contain only one molecular species of antibody molecule consisting of a unique light chain gene product and a unique heavy chain gene product. In particular, the complementarity determining regions (CDRs) of the monoclonal antibody are identical in all the molecules of the population. MAbs contain an antigen binding site capable of immunoreacting with a particular epitope of the antigen characterized by a unique binding affinity for it.

[0483] The term “antigen binding region” or “antigen-binding site” or “binding portion” refers to the part of the immunoglobulin molecule that participates in antigen binding. The antigen binding site is formed by amino acid residues of the N-terminal variable (“V”) regions of the heavy (“H”) and light (“L”) chains. Three highly divergent stretches within the V regions of the heavy and light chains, referred to as “hypervariable regions,” are interposed between more conserved flanking stretches known as “framework regions,” or “FRs”. Thus,the term “FR” refers to amino acid sequences which are naturally found between, and adjacent to, hypervariable regions in immunoglobulins. In an antibody molecule, the three hypervariable regions of a light chain and the three hypervariable regions of a heavy chain are disposed relative to each other in three dimensional space to form an antigen-binding surface. The antigen-binding surface is complementary to the three-dimensional surface of a bound antigen, and the three hypervariable regions of each of the heavy and light chains are referred to as “complementarity-determining regions,” or “CDRs.” Various methods are known in the art for numbering the amino acids sequences of antibodies and identification of the complementary determining regions. For example, the Kabat numbering system (See Kabat, E.A., et al., Sequences of Protein of immunological interest, Fifth Edition, US Department of Health and Human Services, US Government Printing Office (1991)) or the IMGT numbering system (See IMGT®, the international ImMunoGeneTics information system®. Available online: http: / / www.imgt.org / ). The IMGT numbering system is routinely used and accepted as a reliable and accurate system in the art to determine amino acid positions in coding sequences, alignment of alleles, and to easily compare sequences in immunoglobulin (IG) and T-cell receptor (TR) from all vertebrate species. The accuracy and the consistency of the IMGT data are based on IMGT-ONTOLOGY, the first, and so far unique, ontology for immunogenetics and immunoinformatics (See Lefranc. M.P. et al., Biomolecules, 2014 Dec; 4(4), 1102-1139). IMGT tools and databases run against IMGT reference directories built from a large repository of sequences. In the IMGT system the IG V-DOMAIN and IG C-DOMAIN are delimited taking into account the exon delimitation, whenever appropriate. Therefore, the availability of more sequences to the IMGT database, the IMGT exon numbering system can be and “is used” by those skilled in the art reliably to determine amino acid positions in coding sequences and for alignment of alleles. Additionally, correspondences between the IMGT unique numbering with other numberings (i.e., Kabat) are available in the IMGT Scientific chart (See Lefranc. M.P. et al., Biomolecules, 2014 Dec; 4(4), 1102-1139).

[0484] The term "hypervariable region" or “variable region” refers to the amino acid residues of an antibod...

Claims

CLAIMSWhat is claimed is:

1. A method of decreasing a population of cancer cells in a subject having cancer, the method comprising administering to the subject: a) an anti-ULBP2 antibody or antigen binding fragment thereof, and b) a chemotherapy agent, a radiation therapy, and / or an immune checkpoint inhibitor, wherein the plurality of cancer cells express ULI 6 binding protein 2 (ULBP2).

2. The method of claim 1, wherein the method results in a decrease of about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90% in the number of ULBP2 expressing cancer cells in the subject relative to the number of ULBP2 expressing cancer cells in the subject prior to the administration of the anti-ULBP2 antibody or antigen binding fragment thereof and the chemotherapy agent and / or the radiation therapy.

3. The method of any one of claims 1-2, wherein the anti-ULBP2 antibody or antigen binding fragment thereof and the chemotherapy agent, radiation therapy, and / or an immune checkpoint inhibitor are administered sequentially.

4. The method of any one of claims 1-3, wherein the anti-ULBP2 antibody or antigen binding fragment thereof and the chemotherapy agent, radiation therapy, and / or an immune checkpoint inhibitor are administered concurrently.

5. The method of any one of claims 1-4, wherein the cancer is a squamous cancer.

6. The method of claim 5, wherein the squamous cancer is a basal squamous cancer.

7. The method of any one of claims 1-6, wherein the subject has a bladder cancer, a lung cancer, a head and neck cancer, a cervical cancer, esophageal cancer, anal cancer, vulvar cancer, penile cancer, thymic cancer, skin cancer cell, or adrenocortical cancer.

8. The method of any one of claims 1-3, wherein the cancer is an adenocarcinoma.

9. The method of claim 8, wherein the adenocarcinoma is lung adenocarcinoma, pancreatic adenocarcinoma, bladder adenocarcinoma, esophageal adenocarcinoma, or colon adenocarcinoma.

10. The method of any one of claims 1-9, wherein the subject has an EGFR activating mutation or an EGFR copy number alteration.

11. The method of claim 10, wherein the subject is previously treated with a tyrosine kinase inhibitors (TKI).

12. The method of claim 11, wherein the TKI is Osimertinib.

13. The method of claim 11 or 12, wherein the TKI does not decrease ULBP2 expression level in the cancer.

14. The method of any one of claims 11-13, wherein the subject previously received TKI has relapsed cancer after TKI treatment.

15. The method of any one of claims 1-3, wherein the cancer is a metastatic cancer.

16. The method of claim 15, wherein the subject with metastatic cancer has non-primary lesions in the liver, lung, bone, brain, or lymph node originated from a primary cancer.

17. The method of claim 15 or 16, wherein the primary cancer is a squamous cancer or an adenocarcinoma.

18. the method of claim 17, wherein the primary cancer is a squamous cancer comprising a bladder cancer, a lung cancer, a head and neck cancer, a cervical cancer, esophageal cancer, anal cancer, vulvar cancer, penile cancer, thymic cancer, skin cancer cell, or adrenocortical cancer.

19. The method of claim 17, wherein the primary cancer is an adenocarcinoma including lung adenocarcinoma, pancreatic adenocarcinoma, bladder adenocarcinoma, esophageal adenocarcinoma, or colon adenocarcinoma.

20. The method of any one of claims 1-19, wherein the subject has been previously administered immune checkpoint inhibitor.

21. The method of any one of claims 1-20, wherein the immune checkpoint inhibitor is an PD1 / PDL1 inhibitor or a CTLA4 inhibitor.

22. The method of any one of claims 1-21, wherein the immune checkpoint inhibitor is avelumab, durvalumab, atezolizumab, pembrolizumab, nivolumab, atezolizumab, ipilimumab, or tremelimumab.

23. The method of any one of claims 20-22, wherein the immune checkpoint inhibitor does not decrease ULBP2 expression level in the cancer.

24. The method of any one of claims 1-23, wherein the anti-ULBP2 antibody or fragment thereof comprises: a) a complementarity determining region 1 (VH2CDRI) comprising the amino acid sequence of SEQ ID NO: 428; a complementarity determining region 2 (VH2CDR2) comprising the amino acid sequence of SEQ ID NO: 430; a complementarity determining region 3 (VH2CDR3) comprising the amino acid sequence of SEQ ID NO: 432; a complementarity determining region 1 (VL2CDRI) comprising the amino acid sequence of SEQ ID NO: 433; a complementarity determining region 2 (VL2CDR2) comprising the amino acid sequence of SEQ ID NO: 434; and acomplementarity determining region 3 (VL2CDR3) comprising the amino acid sequence of SEQ ID NO: 435; or b) a complementarity determining region 1 (VH2CDRI) comprising the amino acid sequence of SEQ ID NO: 5; a complementarity determining region 2 (VH2CDR2) comprising the amino acid sequence of SEQ ID NO: 7; a complementarity determining region 3 (VH2CDR3) comprising the amino acid sequence of SEQ ID NO: 9; a complementarity determining region 1 (VL2CDRI) comprising the amino acid sequence of SEQ ID NO: 10; a complementarity determining region 2 (VL2CDR2) comprising the amino acid sequence of SEQ ID NO: 11; and a complementarity determining region 3 (VL2CDR3) comprising the amino acid sequence of SEQ ID NO: 12.

25. The method of any one of claims 1-24, wherein the anti-ULBP2 antibody or fragment thereof is a bispecific antibody that specifically binds ULBP2 and CD3 or wherein the anti-ULBP2 antibody or fragment thereof is a bispecific antibody that specifically binds ULBP2 and PD1.

26. The method of claim 24 or 25, wherein a CD58 polypeptide or a fragment thereof is fused to the C-terminus of a heavy chain polypeptide of the bispecific antibody.

27. The method of claim 26, wherein the CD58 comprises the amino acid sequence of SEQ ID NO: 49.

28. The method of any one of claims 1-27, wherein the chemotherapy agent is selected from the group consisting of a topoisomerase inhibitor, an anthracycline doxorubicin, a DNA break inducing antibiotic, a pyrimidine antagonist, and a platinum alkylating agent.

29. The method of any one of claims 1-28, wherein the radiation therapy is selected from the group consisting of 3D conformal radiation therapy (3DCRT), image-guided radiation therapy (IGRT), intensity modulated radiation therapy (IMRT), volumetric modulated arc therapy (VMAT), brachytherapy, intraoperative radiation therapy (IORT),stereotactic radiosurgery (SRS), proton therapy, MRI linear accelerator, and / or stereotactic body radiation therapy (SBRT).

30. A method for identifying a human subject having a cancer that is suitable for therapy with an anti-UL16 binding protein 2 (ULBP2) antibody or antigen binding fragment thereof comprising the steps of: a) obtaining a biological sample a human subject having a cancer; b) detecting the expression levels of ULBP2; c) comparing the detected expression level of ULBP2 with a control level of ULBP2 expression; and d) identifying the subject as a responder when the detected expression level of ULBP2 is greater than the control level of ULBP2 expression.

31. The method of claim 30, further comprising: e) administering an anti-ULBP2 antibody or fragment thereof in an amount sufficient to alleviate a symptom of the cancer when the subject is identified as a responder.

32. A method for treating a human subject having a cancer comprising the steps of: a) obtaining a biological sample from a human subject having a cancer; b) detecting the expression levels of ULBP2; c) comparing the detected expression level of ULBP2 with a control level of ULBP2 expression; d) identifying the subject as a responder when the detected expression level of ULBP2 is greater than the control level of ULBP2 expression; and e) administering an anti-ULBP2 antibody or fragment thereof in an amount sufficient to alleviate a symptom of the cancer when the subject is identified as a responder.

33. The method of any one of claims 30-32, wherein the anti-ULBP2 antibody or fragment thereof comprises:a) a complementarity determining region 1 (VH2CDRI) comprising the amino acid sequence of SEQ ID NO: 428; a complementarity determining region 2 (VH2CDR2) comprising the amino acid sequence of SEQ ID NO: 430; a complementarity determining region 3 (VH2CDR3) comprising the amino acid sequence of SEQ ID NO: 432; a complementarity determining region 1 (VL2CDRI) comprising the amino acid sequence of SEQ ID NO: 433; a complementarity determining region 2 (VL2CDR2) comprising the amino acid sequence of SEQ ID NO: 434; and a complementarity determining region 3 (VL2CDR3) comprising the amino acid sequence of SEQ ID NO: 435; or b) a complementarity determining region 1 (VH2CDRI) comprising the amino acid sequence of SEQ ID NO: 5; a complementarity determining region 2 (VH2CDR2) comprising the amino acid sequence of SEQ ID NO: 7; a complementarity determining region 3 (VH2CDR3) comprising the amino acid sequence of SEQ ID NO: 9; a complementarity determining region 1 (VL2CDRI) comprising the amino acid sequence of SEQ ID NO: 10; a complementarity determining region 2 (VL2CDR2) comprising the amino acid sequence of SEQ ID NO: 11; and a complementarity determining region 3 (VL2CDR3) comprising the amino acid sequence of SEQ ID NO: 12.

34. The method of any one of claims 30-33, wherein the anti-ULBP2 antibody or fragment thereof is a bispecific antibody that specifically binds ULBP2 and CD3.

35. The method of any claim 34, wherein a CD58 polypeptide or a fragment thereof is fused to the C-terminus of a heavy chain polypeptide of the bispecific antibody.

36. The method of claim 35, wherein the CD58 comprises the amino acid sequence of SEQ ID NO: 49 or 50.

37. The method of any one of claims 30-36, wherein the cancer is a squamous cancer.

38. The method of claim 37, wherein the squamous cancer is a basal squamous cancer.

39. The method of claim 37 or 38, wherein the subject has a bladder cancer, a lung cancer, a head and neck cancer, a cervical cancer, esophageal cancer, anal cancer, vulvar cancer, penile cancer, thymic cancer, skin cancer cell, or adrenocortical cancer.

40. The method of any one of claims 30-36, wherein the cancer is an adenocarcinoma.

41. The method of claim 40, wherein the adenocarcinoma is lung adenocarcinoma, pancreatic adenocarcinoma, bladder adenocarcinoma, esophageal adenocarcinoma, or colon adenocarcinoma.

42. The method of any one of claims 30-41, wherein the subject has an EGFR activating mutation or an EGFR copy number alteration.

43. The method of any one of claims 30-36, wherein the cancer is a metastatic cancer.

44. The method of claim 43, wherein the subject with metastatic cancer has non-primary lesions in the liver, lung, bone, brain, or lymph node originated from a primary cancer.

45. The method of claim 43 or 44, wherein the primary cancer is a squamous cancer or an adenocarcinoma.

46. the method of claim 45, wherein the primary cancer is a squamous cancer comprising a bladder cancer, a lung cancer, a head and neck cancer, a cervical cancer, esophageal cancer, anal cancer, vulvar cancer, penile cancer, thymic cancer, skin cancer cell, or adrenocortical cancer.

47. The method of claim 46, wherein the primary cancer is an adenocarcinoma including lung adenocarcinoma, pancreatic adenocarcinoma, bladder adenocarcinoma, esophageal adenocarcinoma, or colon adenocarcinoma.

48. The method of any one of claims 30-47, wherein the subject is simultaneously administered or previously administered with a therapeutically effective amount of a therapeutic agent.

49. The method of claim 48, wherein the therapeutic agent is a chemotherapy agent selected from the group consisting of a topoisomerase inhibitor, an anthracycline doxorubicin, a DNA break inducing antibiotic, a pyrimidine antagonist, and a platinum alkylating agent.

50. The method of claim 48, wherein the therapeutic agent is a radiation therapy selected from the group consisting of 3D conformal radiation therapy (3DCRT), image- guided radiation therapy (IGRT), intensity modulated radiation therapy (IMRT), volumetric modulated arc therapy (VMAT), brachytherapy, intraoperative radiation therapy (IORT), stereotactic radiosurgery (SRS), proton therapy, MRI linear accelerator, and / or stereotactic body radiation therapy (SBRT).

51. The method of claim 48, wherein the therapeutic agent is a CAR-T cell therapy, an immune checkpoint inhibitor, a co-stimulatory ligand or a cytokine.

52. The method of any one of claims 25-29 or 34-51, wherein the bispecific antibody comprises an anti-ULBP2 antibody or antigen binding fragment thereof comprising a light chain variable region (VL2) that comprises the amino acid sequence of SEQ ID NO: 1, and a heavy chain variable region (VH2) that comprises the amino acid sequence of SEQ ID NO: 629.

53. The method of any one of claims 25-29 or 34-52, wherein the anti-ULBP2 antibody or antigen binding fragment thereof comprises a light chain (L2) that comprising the amino acid sequence of SEQ ID NO: 67, or a heavy chain (H2) that comprising the amino acid sequence of SEQ ID NO: 621.

54. The method of any one of claims 25-29 or 34-53, wherein the bispecific antibody comprises an anti-CD3 antibody or antigen binding fragment thereof comprising a light chain variable region (VL1) that comprises the amino acid sequence of SEQ ID NO: 22, and a heavy chain variable region (VH1) that comprises the amino acid sequence of SEQ ID NO: 17.

55. The method of any one of claims 25-29 or 24-54, wherein the CD58 polypeptide or a fragment thereof is fused to the C-terminus of a heavy chain of the anti-CD3 antibody or antigen fragment thereof of the bispecific antibody.

56. The method of any one of claims 25-29 or 24-55, wherein the anti-CD3 antibody or antigen binding fragment thereof comprises a light chain (LI) comprising the amino acid sequence of SEQ ID NOL 69, and a heavy chain fused to the CD58 polypeptide (Hl) comprising the amino acid sequence of SEQ ID NO: 622.

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