Methods of treating advanced solid tumors with b7-h4 antibody-drug conjugates

Abstract

Methods for using anti-B7-H4 antibody-drug conjugates for the treatment of cancers, such as, e.g., B7-H4-associated solid tumors and breast cancer (e.g, ovarian cancer, primary peritoneal cancer, fallopian tube cancer, breast cancer, endometrial carcinoma, lung cancer, cholangiocarcinoma, gallbladder carcinoma, and head and neck carcinoma), are provided.

Description

METHODS OF TREATING ADVANCED SOLID TUMORS WITH B7-H4 ANTIBODY-DRUG CONJUGATESCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This patent application claims priority benefits of U.S. Provisional Application No. 63 / 588,617 filed on October 6, 2023, U.S. Provisional Application No. 63 / 557,108 filed on February 23, 2024, and U.S. Provisional Application No. 63 / 662,576 filed on June 21, 2024, the content of each of which is incorporated herein by reference in their entirety.REFERENCE TO AN ELECTRONIC SEQUENCE LISTING

[0002] The content of the electronic sequence listing (761682010840seqlist.xml; Size: 94,573 bytes; and Date of Creation: October 1, 2024) is herein incorporated by reference in its entirety.FIELD OF THE INVENTION

[0003] The present invention relates to methods of treating a solid tumor, such as e.g. , locally advanced or metastatic solid tumors (e.g., ovarian cancer, primary peritoneal cancer, fallopian tube cancer, breast cancer, endometrial carcinoma, lung cancer, cholangiocarcinoma, gallbladder carcinoma, and head and neck carcinoma) with a B7-H4 antibody drug conjugate (B7-H4-ADC).BACKGROUND

[0004] B7-H4 is a member of the B7 family of immune checkpoint ligands whose expression is elevated on a variety of solid tumors, in particular breast and ovarian tumors (Leong et al., 2015, Mol Pharm 72, 1717-1729). Similar to B7-H1 / PD-L1, B7-H4 has been shown to negatively regulate T cell function and targeted killing of B7-H4-expressing tumor cells may relieve this inhibitory signal (Dangaj et al., 2013, Cancer Res 73, 4820-4829;Prasad et al., 2003, Immunity 18, 863-873; Sica et al., 2003, Immunity 18, 849-861; Zang et al., 2003, Proc Natl Acad Sci U S A 100, 10388-10392).

[0005] B7-H4 (also known as B7X; B7H4; B7S1; B7h.5; VCTN1; PRO1291; GenBankAccession No Q7Z7D3) is an immune regulatory molecule that shares homology with other B7 family members, including PD-L1. Human B7-H4 is encoded by VTCN1. It is a type I transmembrane protein comprised of both IgV and IgC ectodomains. While B7-H4expression in healthy tissues is relatively limited at the protein level, B7-H4 is expressed in several solid tumors such as gynecological carcinomas of the breast, ovary, and endometrium. Expression of B7-H4 in tumors tends to correlate with poor prognosis. The receptor for B7-H4 is unknown, but it is believed to be expressed on T cells. B7-H4 is believed to directly inhibit T cell activity.

[0006] Cancer remains to be one of the deadliest threats to human health. In the U.S., cancer affects nearly 1.3 million new patients each year, and is the second leading cause of death after heart disease, accounting for approximately 1 in 4 deaths. It is also predicted that cancer may surpass cardiovascular diseases as the number one cause of death within 5 years. Solid tumors are responsible for most of those deaths. Although there have been significant advances in the medical treatment of certain cancers, the overall 5-year survival rate for all cancers has improved only by about 10% in the past 20 years. Cancers, or malignant tumors, metastasize and grow rapidly in an uncontrolled manner, making timely detection and treatment extremely difficult.

[0007] Lung cancer remains the leading cause of death from cancer in the United States, with over 155,000 deaths estimated in 2017. Treatments with curative intent for patients with early-stage disease include surgery, chemotherapy, radiation therapy, or a combined modality approach. However, a majority of patients are diagnosed with advanced stage disease, which is usually incurable. Non-small cell lung cancer (NSCLC) represents up to 80% of all lung cancers. Within the subtypes of NSCLC, squamous cell carcinoma (SCC / NSCLC) represents approximately 30% of NSCLC. Systemic therapies used in the metastatic setting for SCC / NSCLC have shown limited benefit and are primarily aimed at prolonging survival and maintaining the quality of life for as long as possible, while minimizing side effects due to treatment. First line treatment for patients with SCC / NSCLC whose tumors do not express high levels of PD-L1 include a platinum-based chemotherapy doublet that does not contain pemetrexed, anti-VEGF antibody, or an anti-EGFR antibody necitumumab in combination with gemcitabine and cisplatin. Patients with at least 50% tumor cell staining for PD-L1 are offered first-line treatment with the anti-PD-1 inhibitor pembrolizumab. Patients who progress on an initial combination chemotherapy regimen may receive an anti-PD-1 or PD- L1 antibody, and combination chemotherapy is considered for patients whose disease has progressed after receiving PD-1 / L1 inhibitors. New classes of therapy are urgently needed that can provide meaningful benefit to SCC / NSCLC patients.

[0008] Breast cancers are classified on the basis of three protein expression markers: estrogen receptor (ER), progesterone receptor (PgR), and the overexpression of the growth factor receptor HER2 / neu. Hormonal therapies, including tamoxifen and aromatase inhibitors, can be effective in treating tumors that express the hormone receptors ER and PgR. HER2-directed therapies are useful for tumors that express HER2 / neu; these tumors are the only class of breast cancer that is currently eligible for monoclonal antibody therapy. For these patients, unconjugated antibodies, such as Herceptin or Peijeta, are generally used in combination with chemotherapy.

[0009] Ovarian cancers are classified on the basis of the origin cell types. Ovarian epithelial carcinoma, is the most common type of ovarian cancer, representing approximately 90% of ovarian cancers. It includes serous, endometrioid, and clear cell tumors. Less common ovarian epithelial tumors are mucinous and malignant Brenner tumors. Epithelial ovarian cancers develop from the epithelium, a layer of cells that covers the ovary. Poorly differentiated epithelial ovarian cancer is defined as high grade serous ovarian carcinoma (HGSOC) and it includes fallopian tube and primary peritoneal epithelial serous tumors. HGSOC is treated by cytotoxic therapy, including platinum chemotherapy regimens and taxanes. Targeted agents, such as PARP inhibitors, are used in the treatment and maintenance setting. Immunotherapy is a topic of current research in ovarian cancer. In some cases, the antibody bevacizumab, though still a topic of active research, is used to treat advanced cancer along with chemotherapy. Relapsed platinum resistant and refractory HGSOC is an area of high unmet medical need.

[0010] Cholangiocarcinoma, also known as bile duct cancer, is a disease in which malignant (cancer) cells form in the bile ducts. Bile duct cancer can be intrahepatic or extrahepatic. Risk factors for cholangiocarcinoma include primary sclerosing cholangitis, ulcerative colitis, cirrhosis, hepatitis C, hepatitis B, infection with certain liver flukes, and some congenital liver malformations. Cholangiocarcinoma is typically incurable at diagnosis.

[0011] Endometrial cancer is a cancer that arises from the endometrium. It is the result of abnormal growth of cells that have the ability to invade or spread to other parts of the body. Endometrial cancer is associated with obesity, excessive estrogen exposure, high blood pressure and diabetes. It is the third most common cause of death in cancers which only affect women, behind ovarian and cervical cancer.

[0012] Fallopian tube cancer, also known as tubal cancer, develops in the fallopian tubes that connect the ovaries and the uterus. It is more common for cancer to spread, or metastasize, from other parts of the body, such as the ovaries or endometrium, than for cancer to actually originate in the fallopian tubes. To date, little is known regarding what causes fallopian tube cancer, but genetics are suspected to play a role.

[0013] Peritoneal cancer is also known as serous surface papillary carcinoma, primary peritoneal carcinoma, extra-ovarian serous carcinoma, primary serous papillary carcinoma, and psammomacarcinoma. It develops in the peritoneum, a thin layer of tissue lining the abdomen that is made of epithelial cells. The causes of peritoneal cancer are unclear. Peritoneal cancer can be hard to detect in the early stages. The median survival of primary peritoneal carcinomas is usually shorter by 2-6 months time when compared with serous ovarian cancer.

[0014] Gallbladder cancer is an abnormal growth of cells that begins in the gallbladder. If diagnosed early enough, it can be treated by removing the gallbladder, part of the liver and associated lymph nodes. Most often it is found after symptoms such as abdominal pain, jaundice and vomiting occur, by which time it has spread to other organs such as the liver. The outlook is poor for recovery if the cancer is found after symptoms have started to occur, with a 5-year survival rate of close to 3%.

[0015] There is clearly a significant need for effective treatments for solid tumors, particularly locally advanced or metastatic solid tumors, and breast cancer, particularly latestage breast cancer. The present invention meets the need for improved treatment of solid tumors, such as, e.g., locally advanced or metastatic solid tumors (e.g., ovarian cancer, lung cancer, cholangiocarcinoma and endometrial cancer), and breast cancer by providing a highly specific and effective anti-B7-H4-antibody-drug conjugate. The present invention also meets the need for improved treatment of solid tumors, such as, e.g., locally advanced or metastatic solid tumors (e.g. peritoneal cancer, fallopian tube cancer, gallbladder cancer) by providing a highly specific and effective anti-B7-H4-antibody-drug conjugate.

[0016] All references cited herein, including patent applications, patent publications, and scientific literature, are herein incorporated by reference in their entirety, as if each individual reference were specifically and individually indicated to be incorporated by reference.BRIEF SUMMARY OF THE INVENTION

[0017] In certain aspects, provided herein is a method of treating a solid tumor in an individual, comprising administering to the individual a B7-H4 antibody-drug conjugate (B7- H4-ADC) twice every three weeks (2Q3W), wherein the B7-H4-ADC comprises an anti-B7- H4 antibody conjugated to a vcMMAE (valine-citruline-monomethyl auristatin E), wherein the anti-B7-H4 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region of the anti-B7-H4 antibody comprises the three complementarity determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or antigen-binding fragment thereof comprises the three CDRs of SEQ ID NO: 12; wherein the vcMMAE comprises the structure:or a pharmaceutically acceptable salt thereof.

[0018] In certain asepcts, provided herein is a method of treating a solid tumor in an individual, comprising administering to the individual a B7-H4-ADC once every three weeks (Q3W), wherein the B7-H4-ADC comprises an anti-B7-H4 antibody conjugated to a vcMMAE (valine-citruline-monomethyl auristatin E), wherein the anti-B7-H4 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region of the anti-B7-H4 antibody comprises the three complementarity determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or antigen-binding fragment thereof comprises the three CDRs of SEQ ID NO: 12; wherein the vcMMAE comprises the structure:or a pharmaceutically acceptable salt thereof.

[0019] In some embodiments, the B7-H4-ADC is administered at a dose of about 0.75 mg / kg to about 1.5 mg / kg, according to the individual’s body weight. In some embodiments, the B7-H4-ADC is administered at a dose of about 0.75 mg / kg, about 1.0 mg / kg, about 1.25 mg / kg, or about 1.5 mg / kg, according to the individual’s body weight.

[0020] In some embodiments, the B7-H4-ADC is administered at a dose of about 0.25 mg / kg / week to about 1.60 mg / kg / week, according to the individual’s body weight.

[0021] In some embodiments, the B7-H4-ADC is administered at a dose of about 0.56 mg / kg / week, 0.67 mg / kg / week, 0.83 mg / kg / week, 1.00 mg / kg / week, 1.17 mg / kg / week, 1.33 mg / kg / week, 1.50 mg / kg / week, or about 1.60 mg / kg / week, according to the individual’s body weight.

[0022] In some embodiments, the B7-H4-ADC is administered at a dose of about 0.25 mg / kg / week, 0.33 mg / kg / week, about 0.42 mg / kg / week, about 0.50 mg / kg / week, 0.58 mg / kg / week, 0.67 mg / kg / week, about 0.75 mg / kg / week, or about 0.80 mg / kg / week, according to the individual’s body weight.

[0023] In some embodiments, the individual’s body weight is an actual body weight. In some embodiments, the individual’s body weight is an adjusted ideal body weight.

[0024] In some embodiments, the B7-H4-ADC is administered on day 1 and day 8 of the three-week period. In some embodiments, the B7-H4-ADC is administered at least four times.

[0025] In some embodiments, the B7-H4-ADC is administered on day 1 of the three- week period. In some embodiments, the B7-H4-ADC is administered at least twice.

[0026] In certain aspects, provided herein is a method of treating a solid tumor in an individual, comprising administering to the individual a B7-H4-ADC twice every four weeks (2Q4W), wherein the B7-H4-ADC comprises an anti-B7-H4 antibody conjugated to a vcMMAE (valine-citruline-monomethyl auristatin E), wherein the anti-B7-H4 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region of the anti-B7-H4 antibody comprises the three complementarity determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or antigen-binding fragment thereof comprises the three CDRs of SEQ ID NO: 12; wherein the vcMMAE comprises the structure:or a pharmaceutically acceptable salt thereof.

[0027] In certain aspects, provided herein is a method of treating a solid tumor in an individual, comprising administering to the individual a B7-H4-ADC three times every four weeks (3Q4W), wherein the B7-H4-ADC comprises an anti-B7-H4 antibody conjugated to a vcMMAE (valine-citruline-monomethyl auristatin E), wherein the anti-B7-H4 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region of the anti-B7-H4 antibody comprises the three complementarity determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or antigen-binding fragment thereof comprises the three CDRs of SEQ ID NO: 12; wherein the vcMMAE comprises the structure:or a pharmaceutically acceptable salt thereof.

[0028] In some embodiments, the B7-H4-ADC is administered at a dose of about 1.25 mg / kg to about 2.0 mg / kg, according to the individual’s body weight. In some embodiments, the B7-H4-ADC is administered at a dose of about 1.25 mg / kg, about 1.5 mg / kg, about 1.75 mg / kg, or about 2.0 mg / kg, according to the individual’s body weight.

[0029] In some embodiments, the B7-H4-ADC is administered at a dose of about 0.38 mg / kg / week to about 1.80 mg / kg / week, according to the individual’s body weight.

[0030] In some embodiments, the B7-H4-ADC is administered at a dose of about 0.38 mg / kg / week, about 0.50 mg / kg / week, about 0.63 mg / kg / week, about 0.75 mg / kg / week, about 0.88 mg / kg / week, about 1.00 mg / kg / week, 1.13 mg / kg / week, or about 1.20 mg / kg / week, according to the individual’s body weight.

[0031] In some embodiments, the B7-H4-ADC is administered at a dose of about 0.56 mg / kg / week, about 0.75 mg / kg / week, about 0.94 mg / kg / week, about 1.13 mg / kg / week, about 1.31 mg / kg / week, about 1.50 mg / kg / week, about 1.69 mg / kg / week, or about 1.80 mg / kg / week, according to the individual’s body weight.

[0032] In some embodiments, the individual’s body weight is an actual body weight. In some embodiments, the individual’s body weight is an adjusted ideal body weight.

[0033] In some embodiments, the B7-H4-ADC is administered on day 1 and day 15 of the four-week period. In some embodiments, the B7-H4-ADC is administered at least four times.

[0034] In some embodiments, the B7-H4-ADC is administered on day 1, day 8, and day 15 of the four-week period. In some embodiments, the B7-H4-ADC is administered at least six times.

[0035] In some embodiments, the B7-H4-ADC is administered intravenously (IV).

[0036] In some embodiments, the solid tumor is an advanced solid tumor. In some embodiments, the solid tumor is selected from the group consisting of ovarian cancer, primary peritoneal cancer, fallopian tube cancer, breast cancer, endometrial carcinoma, lung cancer, cholangiocarcinoma, gallbladder carcinoma, and head and neck carcinoma. In some embodiments, the ovarian cancer is a high-grade serous ovarian cancer (HGSOC). In some embodiments, the breast cancer is a HER2-negative / HR-positive breast cancer. In some embodiments, the breast cancer is triple negative breast cancer (TNBC). In some embodiments, the TNBC is locally advanced unresectable or metastatic TNBC. In some embodiments, the lung cancer is a non-small cell lung cancer (NSCLC). In some embodiments, the NSCLC is a squamous cell lung cancer or an adenocarcinoma. In some embodiments, the head and neck carcinoma is an adenoid cystic carcinoma (ACC).

[0037] In some embodiments, the method provided herein further comprises determining the expression level of B7-H4 in the solid tumor. In some embodiments, the expression level is determined by immunohistochemistry (IHC). In some embodiments, greater than 25% of the solid tumor has an IHC intensity score of 1 to 3. In some embodiments, greater than 25% of cells of the solid tumor express B7-H4. In some embodiments, greater than 50% of cells of the solid tumor express B7-H4.

[0038] In some embodiments, such treatment results in one or more therapeutic effects selected from the group consisting of size of a tumor derived from the cancer, duration of response, progression-free survival, and overall survival. In some embodiments, such treatment results in at least about 15% reduction in tumor size in the individual. In some embodiments, such treatment results in a durable response. In some embodiments, the durable response lasts for at least up to 67 weeks. In some embodiments, such treatment results in one or more therapeutic effects in the individual improving after administration of the B7-H4-ADC relative to a baseline.

[0039] In some embodiments, the individual exhibits progression-free survival of at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about eighteen months, at least about two years, at least about three years, at least about four years, or at least about five years after administration of the B7-H4- ADC.

[0040] In some embodiments, the individual exhibits overall survival of at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about eighteen months, at least about two years, at least about three years, at least about four years, or at least about five years after administration of the B7-H4-ADC.

[0041] In some embodiments, the duration of response to the B7-H4-ADC is at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about eighteen months, at least about two years, at least about three years, at least about four years, or at least about five years after administration of the B7-H4- ADC.

[0042] In some embodiments, the anti-B7-H4 antibody comprises heavy chain variable region (VH)-complementarity determining region (CDR) 1 , VH-CDR2, VH-CDR3 and light chain variable region (VL)-CDRl, VL-CDR2, and VL-CDR3 sequences of SEQ ID NOs: 5- 10, respectively. In some embodiments, the anti-B7-H4 antibody comprises a heavy chain variable region (HCVR) having at least 95% identity to SEQ ID NO: 11, and a light chain variable region (LCVR) having at least 95% identity to SEQ ID NO: 12. In some embodiments, the B7-H4-ADC comprises an anti-B7-H4 antibody conjugated to a vcMMAE (valine-citruline-monomethyl auristatin E), wherein the anti-B7-H4 antibody comprises a heavy chain variable region (HCVR) having at least 95% identity to SEQ ID NO: 11, and a light chain variable region (LCVR) having at least 95% identity to SEQ ID NO: 12. In some embodiments, the heavy chain variable region has at least 98% identity to SEQ ID NO: 11 and the light chain variable region has at least 98% identity to SEQ ID NO: 12. In some embodiments, the heavy chain variable region has at least 99% identity to SEQ ID NO: 11 and the light chain variable region has at least 99% identity to SEQ ID NO: 12. In some embodiments, the heavy chain variable region comprises the sequence of SEQ ID NO: 11 and the light chain variable region comprises the sequence of SEQ ID NO: 12.

[0043] In some embodiments, the B7-H4-ADC comprises the structure:wherein Ab is the anti-B7-H4 antibody, and wherein p is a vcMMAE to antibody ratio.

[0044] In some embodiments, the B7-H4-ADC comprises the structure:wherein Ab is the anti-B7-H4 antibody, and wherein p is a vcMMAE to antibody ratio.

[0045] In some embodiments, p is about 1 to about 8. In some embodiments, p is about 4.

[0046] In some embodiments, the anti-B7-H4 antibody is a fully human antibody.

[0047] In some embodiments, the anti-B7-H4 antibody is a IgGl monoclonal antibody.

[0048] In some embodiments, the B7-H4-ADC is within a heterogeneous population ofB7-H4-ADCs, wherein the anti-B7-H4 antibodies comprised within the heterogeneous population of B7-H4-ADCs exhibit variable post-translational modifications.

[0049] In some embodiments, within at least 50%, 60%, 70%, 80%, 90%, or 95% of the anti-B7-H4 antibodies comprised within the heterogeneous population of B7-H4-ADCs:(i) the C-terminal lysine residues are removed from both heavy chains;(ii) the N-terminal glutamine of each heavy chain cyclized to pyroglutamic acid; and / or(iii) the consensus glycosylation site at Asn300 of each heavy chain occupied predominantly with biantennary, core fucosylated glycans without terminal galactose residues.

[0050] In some embodiments, the B7-H4-ADC is administered as a monotherapy.

[0051] In some embodiments, the method provided herein further comprises administering to the individual about 400 mg pembrolizumab once every 6 weeks (Q6W). In some embodiments, the method provided herein further comprises administering to the individual about 200 mg pembrolizumab once every 3 weeks (Q3W). In some embodiments, the pembrolizumab is administered starting day 1. In some embodiments, the pembrolizumab is administered intravenously (IV).BRIEF DESCRIPTION OF THE DRAWINGS

[0052] FIG. 1 is a Phase 1 B7-H4-ADC clinical study design. AiBW is adjusted ideal body weight. TNBC is triple negative breast cancer.

[0053] FIG. 2A is a waterfall plot demonstrating the change from baseline in the sum of diameters (SoD) in a target lesion size. Each bar represents an individual given a specific dose for the 2Q3W schedule. FIG. 2B is a spider diagram showing the change from baseline in tumor size over weeks. Each line represents an individual given a specific dose for the 2Q3W schedule. The bars or lines labeled with an asterisk indicate ongoing treatment. The upper dashed line indicates a 20% increase in SoD, and the lower dashed line indicates a 30% reduction in SoD.

[0054] FIG. 3A is a waterfall plot demonstrating the change from baseline in the sum of diameters (SoD) in a target lesion size. Each bar represents an individual given a specific dose for the 2Q4W schedule. FIG. 3B is a spider diagram showing the change from baseline in tumor size over weeks. Each line represents an individual given a specific dose for the 2Q4W schedule. The bars or lines labeled with an asterisk indicate ongoing treatment. Theupper dashed line indicates a 20% increase in SoD, and the lower dashed line indicates a 30% reduction in SoD.

[0055] FIG. 4 shows a stacked bar chart quantifying the prevalence of B7-H4 expression in tumor sections acquired from individuals diagnosed with the indicated cancer. Each bar is categorized by immunohistochemistry staining intensity scores of 1 to 3. For prevalence calculations, tumors were considered positive if staining was observed on greater than 25% of tumor cells.

[0056] FIG. 5 shows a waterfall plot demonstrating the change from baseline in the sum of diameters (SoD) in a target lesion size for tumors from triple negative breast cancer. Each bar represents an individual given a specific dose for the 2Q3W or 2Q4W schedule. Each bar is labeled with CR (complete response), PR (partial response), SD (stable disease), or PD (progressive disease). Bars 1-7, 9, 10, 12, and 34 are labeled “PD”; bars 8, 11, and 13-29 are labeled “SD”; bars 30-33 and 35-38 are labeled “PR”; and bar 39 is labeled “CR.” The bars labeled with a triangle indicate ongoing treatment. The upper dashed line indicates a 20% increase in SoD, and the lower dashed line indicates a 30% reduction in SoD.

[0057] FIG. 6 shows a waterfall plot demonstrating the change from baseline in the sum of diameters (SoD) in a target lesion size for tumors from HR+ Her2- breast cancer. Each bar represents an individual given a specific dose for the 2Q3W or 2Q4W schedule. Each bar is labeled with PR (partial response), SD (stable disease), or PD (progressive disease). Bars 1-8, 10, 12, and 13 are labeled “PD”; bars 9, 11, 14-18, and 20 are labeled “SD”; and bars 19 and 21-24 are “PR.” The bars labeled with a triangle indicate ongoing treatment. The upper dashed line indicates a 20% increase in SoD, and the lower dashed line indicates a 30% reduction in SoD.DETAILED DESCRIPTION

[0058] So that the invention may be more readily understood, certain technical and scientific terms are specifically defined below. Unless specifically defined elsewhere in this document, all other technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this invention belongs.I. Definitions

[0059] As used herein, including the appended claims, the singular forms of words such as “a,” “an,” and “the,” include their corresponding plural references unless the context clearly dictates otherwise.

[0060] An “antibody-drug conjugate” or “ADC” refers to an antibody conjugated to a cytotoxic agent or cytostatic agent. Typically, antibody-drug conjugates bind to a target antigen (e.g., B7-H4) on a cell surface, followed by internalization of the antibody-drug conjugate into the cell and subsequent release of the drug into the cell. In certain exemplary embodiments, an antibody-drug conjugate is a B7-H4-ADC.

[0061] A “polypeptide” or “polypeptide chain” is a polymer of amino acid residues joined by peptide bonds, whether produced naturally or synthetically. Polypeptides of less than about 10 amino acid residues are commonly referred to as “peptides.”

[0062] A “protein” is a macromolecule comprising one or more polypeptide chains. A protein may also comprise non-peptidic components, such as carbohydrate groups.Carbohydrates and other non-peptidic substituents may be added to a protein by the cell in which the protein is produced, and will vary with the type of cell. Proteins are defined herein in terms of their amino acid backbone structures. Substituents such as carbohydrate groups are generally not specified, but may be present nonetheless.

[0063] The terms “amino-terminal” and “carboxy -terminal” denote positions within polypeptides. Where the context allows, these terms are used with reference to a particular sequence or portion of a polypeptide to denote proximity or relative position. For example, a certain sequence positioned carboxy-terminal to a reference sequence within a polypeptide is located proximal to the carboxy terminus of the reference sequence, but is not necessarily at the carboxy terminus of the complete polypeptide.

[0064] For purposes of classifying amino acids substitutions as conservative or nonconservative, the following amino acid substitutions are considered conservative substitutions: serine substituted by threonine, alanine, or asparagine; threonine substituted by proline or serine; asparagine substituted by aspartic acid, histidine, or serine; aspartic acid substituted by glutamic acid or asparagine; glutamic acid substituted by glutamine, lysine, or aspartic acid; glutamine substituted by arginine, lysine, or glutamic acid; histidine substituted by tyrosine or asparagine; arginine substituted by lysine or glutamine; methionine substituted by isoleucine, leucine or valine; isoleucine substituted by leucine, valine, or methionine;leucine substituted by valine, isoleucine, or methionine; phenylalanine substituted by tyrosine or tryptophan; tyrosine substituted by tryptophan, histidine, or phenylalanine; proline substituted by threonine; alanine substituted by serine; lysine substituted by glutamic acid, glutamine, or arginine; valine substituted by methionine, isoleucine, or leucine; and tryptophan substituted by phenylalanine or tyrosine. Conservative substitutions can also mean substitutions between amino acids in the same class. Classes are as follows: Group I (hydrophobic side chains): Met, Ala, Vai, Leu, He; Group II (neutral hydrophilic side chains): Cys, Ser, Thr; Group III (acidic side chains): Asp, Glu; Group IV (basic side chains): Asn, Gin, His, Lys, Arg; Group V (residues influencing chain orientation): Gly, Pro; and Group VI (aromatic side chains): Trp, Tyr, Phe.

[0065] Two amino acid sequences have “100% amino acid sequence identity” if the amino acid residues of the two amino acid sequences are the same when aligned for maximal correspondence. Sequence comparisons can be performed using standard software programs such as those included in the LASERGENE bioinformatics computing suite, which is produced by DNASTAR (Madison, Wisconsin). Other methods for comparing two nucleotide or amino acid sequences by determining optimal alignment are well-known to those of skill in the art. (See, e.g, Peruski and Peruski, The Internet and the New Biology: Tools for Genomic and Molecular Research (ASM Press, Inc. 1997); Wu et al. (eds.), “Information Superhighway and Computer Databases of Nucleic Acids and Proteins,” in Methods in Gene Biotechnology 123-151 (CRC Press, Inc. 1997); Bishop (ed.), Guide to Human Genome Computing (2nd ed., Academic Press, Inc. 1998).) Two amino acid sequences are considered to have “substantial sequence identity” if the two sequences have at least about 80%, at least about 85%, at about least 90%, or at least about 95% sequence identity relative to each other.

[0066] Percentage sequence identities are determined with antibody sequences maximally aligned by the Kabat numbering convention. After alignment, if an individual antibody region (e.g, the entire variable domain of a heavy or light chain) is being compared with the same region of a reference antibody, the percentage sequence identity between the individual and reference antibody regions is the number of positions occupied by the same amino acid in both the individual and reference antibody region divided by the total number of aligned positions of the two regions, with gaps not counted, multiplied by 100 to convert to percentage.

[0067] Compositions or methods “comprising” one or more recited elements may include other elements not specifically recited. For example, a composition that comprises antibody may contain the antibody alone or in combination with other ingredients.

[0068] Designation of a range of values includes all integers within or defining the range.

[0069] In antibodies or other proteins described herein, reference to amino acid residues corresponding to those specified by SEQ ID NO includes post-translational modifications of such residues.

[0070] The term “antibody” denotes immunoglobulin proteins produced by the body in response to the presence of an antigen and that bind to the antigen, as well as antigen-binding fragments and engineered variants thereof. Hence, the term “antibody” includes, for example, intact monoclonal antibodies (e.g., antibodies produced using hybridoma technology) and antigen-binding antibody fragments, such as a F(ab')2, a Fv fragment, a diabody, a single-chain antibody, an scFv fragment, or an scFv-Fc. Genetically, engineered intact antibodies and fragments such as chimeric antibodies, humanized antibodies, fully human antibodies, single-chain Fv fragments, single-chain antibodies, diabodies, minibodies, linear antibodies, multivalent or multi-specific (e.g., bispecific) hybrid antibodies, and the like, are also included. Thus, the term “antibody” is used expansively to include any protein that comprises an antigen-binding site of an antibody and is capable of specifically binding to its antigen.

[0071] The term antibody or antigen-binding fragment thereof includes a “conjugated” antibody or antigen-binding fragment thereof or an “antibody-drug conjugate (ADC)” in which an antibody or antigen-binding fragment thereof is covalently or non-covalently bound to a pharmaceutical agent, e.g., to a cytostatic or cytotoxic drug.

[0072] The term “genetically engineered antibodies” refers to an antibody in which the amino acid sequence has been varied from that of the native or parental antibody. The possible variations are many, and range from the changing of just one or a few amino acids to the complete redesign of, for example, the variable or constant region. Changes in the constant region are, in general, made to improve or alter characteristics such as, e.g., complement binding and other effector functions. Typically, changes in the variable region are made to improve antigen-binding characteristics, improve variable region stability, and / or reduce the risk of immunogenicity.

[0073] The term “chimeric antibody” refers to an antibody in which a portion of the heavy and / or light chain is identical with or homologous to corresponding sequences in an antibody derived from a particular species (e.g., human) or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical with or homologous to corresponding sequences in an antibody derived from another species (e.g., mouse) or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity.

[0074] The term "human" antibody or antigen-binding fragment thereof means an antibody or antigen-binding fragment thereof having an amino acid sequence derived from a human immunoglobulin gene locus, where such antibody or antigen-binding fragment is made using techniques known in the art. This definition of a human antibody or antigenbinding fragment thereof includes intact or full-length antibodies and fragments thereof.

[0075] An “antigen-binding site of an antibody” is that portion of an antibody that is sufficient to bind to its antigen. The minimum such region is typically a variable domain or a genetically engineered variant thereof. Single domain binding sites can be generated from camelid antibodies (see Muyldermans and Lauwereys, Mol. Recog. 12: 131-140, 1999;Nguyen et al., EMBO J. 19:921-930, 2000) or from VH domains of other species to produce single-domain antibodies (“dAbs,” see Ward et al., Nature 341: 544-546, 1989; US Patent No. 6,248,516 to Winter et al). Commonly, an antigen-binding site of an antibody comprises both a heavy chain variable (VH) domain and a light chain variable (VL) domain that bind to a common epitope. Within the context of the present invention, an antibody may include one or more components in addition to an antigen-binding site, such as, for example, a second antigen-binding site of an antibody (which may bind to the same or a different epitope or to the same or a different antigen), a peptide linker, an immunoglobulin constant region, an immunoglobulin hinge, an amphipathic helix (see Pack and Pluckthun, Biochem. 31: 1579- 1584, 1992), a non-peptide linker, an oligonucleotide (see Chaudri et al., FEBS Letters 450:23-26, 1999), a cytostatic or cytotoxic drug, and the like, and may be a monomeric or multimeric protein. Examples of molecules comprising an antigen-binding site of an antibody are known in the art and include, for example, Fv, single-chain Fv (scFv), Fab, Fab', F(ab')2, F(ab)c, diabodies, minibodies, nanobodies, Fab-scFv fusions, bispecific (scFv)4-IgG, and bispecific (scFv)2-Fab. (See, e.g., Hu et al , Cancer Res. 56:3055-3061, 1996; Atwell et al., Molecular Immunology 33: 1301-1312, 1996; Carter and Merchant, Curr. Op. Biotechnol.8:449-454, 1997; Zuo et al., Protein Engineering 13:361-367, 2000; and Lu et al. , J. Immunol. Methods 267:213-226, 2002.)

[0076] The term “immunoglobulin” refers to a protein consisting of one or more polypeptides substantially encoded by immunoglobulin gene(s). One form of immunoglobulin constitutes the basic structural unit of native (i. e. , natural or parental) antibodies in vertebrates. This form is a tetramer and consists of two identical pairs of immunoglobulin chains, each pair having one light chain and one heavy chain. In each pair, the light and heavy chain variable regions (VL and VH) are together primarily responsible for binding to an antigen, and the constant regions are primarily responsible for the antibody effector functions. Five classes of immunoglobulin protein (IgG, IgA, IgM, IgD, and IgE) have been identified in higher vertebrates. IgG comprises the major class, and it normally exists as the second most abundant protein found in plasma. In humans, IgG consists of four subclasses, designated IgGl, IgG2, IgG3, and IgG4. Each immunoglobulin heavy chain possesses a constant region that consists of constant region protein domains (CHI, hinge, CH2, and CH3; IgG3 also contains a CH4 domain) that are essentially invariant for a given subclass in a species.

[0077] DNA sequences encoding human and non-human immunoglobulin chains are known in the art. (See, e.g., Ellison et al , DNA 1: 11-18, 1981; Ellison et al, Nucleic Acids Res. 10:4071-4079, 1982; Kenten et al., Proc. Natl. Acad. Set USA 79:6661-6665, 1982; Seno et al., Nucl. Acids Res. 11 :719-726, 1983; Riechmann et al., Nature 332:323-327, 1988; Amster et al., Nucl. Acids Res. 8:2055-2065, 1980; Rusconi and Kohler, Nature 314:330-334, 1985; Boss et al., Nucl. Acids Res. 12:3791-3806, 1984; Bothwell et al., Nature 298:380-382, 1982; van der Loo et al., Immunogenetics 42:333-341, 1995; Karlin et al., J. Mol. Evol. 22: 195-208, 1985; Kindsvogel et al., DNA 1 :335-343, 1982; Breiner et al., Gene 18: 165-174, 1982; Kondo et al., Eur. J. Immunol. 23:245-249, 1993; and GenBank Accession No. J00228.) For a review of immunoglobulin structure and function see Putnam, The Plasma Proteins, Vol V, Academic Press, Inc., 49-140, 1987; and Padlan, Mol. Immunol. 31: 169-217, 1994. The term “immunoglobulin” is used herein for its common meaning, denoting an intact antibody, its component chains, or fragments of chains, depending on the context.

[0078] Full-length immunoglobulin “light chains” (about 25 kDa or 214 amino acids) are encoded by a variable region gene at the amino-terminus (encoding about 110 amino acids) and a by a kappa or lambda constant region gene at the carboxyl-terminus. Full-lengthimmunoglobulin “heavy chains” (about 50 kDa or 446 amino acids) are encoded by a variable region gene (encoding about 116 amino acids) and a gamma, mu, alpha, delta, or epsilon constant region gene (encoding about 330 amino acids), the latter defining the antibody’s isotype as IgG, IgM, IgA, IgD, or IgE, respectively. Within light and heavy chains, the variable and constant regions are joined by a “J” region of about 12 or more amino acids, with the heavy chain also including a “D” region of about 10 more amino acids. (See generally Fundamental Immunology (Paul, ed., Raven Press, N.Y., 2nd ed. 1989), Ch. 7).

[0079] An immunoglobulin light or heavy chain variable region (also referred to herein as a “light chain variable domain” (“VL domain”) or “heavy chain variable domain” (“VH domain”), respectively) consists of a “framework” region interrupted by three “complementarity determining regions” or “CDRs.” The framework regions serve to align the CDRs for specific binding to an epitope of an antigen. Thus, the term “CDR” refers to the amino acid residues of an antibody that are primarily responsible for antigen binding. From amino-terminus to carboxyl-terminus, both VL and VH domains comprise the following framework (FR) and CDR regions: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.

[0080] The assignment of amino acids to each variable region domain is in accordance with the definitions of Kabat, Sequences of Proteins of Immunological Interest (National Institutes of Health, Bethesda, MD, 1987 and 1991). Kabat also provides a widely used numbering convention (Kabat numbering) in which corresponding residues between different heavy chain variable regions or between different light chain variable regions are assigned the same number. CDRs 1, 2 and 3 of a VL domain are also referred to herein, respectively, as CDR-L1, CDR-L2 and CDR-L3. CDRs 1, 2 and 3 of a VH domain are also referred to herein, respectively, as CDR-H1, CDR-H2 and CDR-H3. If so noted, the assignment of CDRs can be in accordance with IMGT® (Lefranc et al., Developmental & Comparative Immunology 27:55-77; 2003) in lieu of Kabat.

[0081] Numbering of the heavy chain constant region is via the EU index as set forth in Kabat (Kabat, Sequences of Proteins of Immunological Interest, National Institutes of Health, Bethesda, MD, 1987 and 1991).

[0082] Unless the context dictates otherwise, the term “monoclonal antibody” is not limited to antibodies produced through hybridoma technology. The term “monoclonal antibody” can include an antibody that is derived from a single clone, including anyeukaryotic, prokaryotic or phage clone. In particular embodiments, the antibodies described herein are monoclonal antibodies.

[0083] The term “humanized VH domain” or “humanized VL domain” refers to an immunoglobulin VH or VL domain comprising some or all CDRs entirely or substantially from a non-human donor immunoglobulin (e.g., a mouse or rat) and variable domain framework sequences entirely or substantially from human immunoglobulin sequences. The non-human immunoglobulin providing the CDRs is called the “donor” and the human immunoglobulin providing the framework is called the “acceptor.” In some instances, humanized antibodies will retain some non-human residues within the human variable domain framework regions to enhance proper binding characteristics (e.g., mutations in the frameworks may be required to preserve binding affinity when an antibody is humanized).

[0084] A “humanized antibody” is an antibody comprising one or both of a humanized VH domain and a humanized VL domain. Immunoglobulin constant region(s) need not be present, but if they are, they are entirely or substantially from human immunoglobulin constant regions.

[0085] A humanized antibody is a genetically engineered antibody in which the CDRs from a non-human “donor” antibody are grafted into human “acceptor” antibody sequences (see, e.g., Queen, US 5,530,101 and 5,585,089; Winter, US 5,225,539; Carter, US 6,407,213; Adair, US 5,859,205; and Foote, US 6,881,557). The acceptor antibody sequences can be, for example, a mature human antibody sequence, a composite of such sequences, a consensus sequence of human antibody sequences, or a germline region sequence.

[0086] Human acceptor sequences can be selected for a high degree of sequence identity in the variable region frameworks with donor sequences to match canonical forms between acceptor and donor CDRs among other criteria. Thus, a humanized antibody is an antibody having CDRs entirely or substantially from a donor antibody and variable region framework sequences and constant regions, if present, entirely or substantially from human antibody sequences. Similarly, a humanized heavy chain typically has all three CDRs entirely or substantially from a donor antibody heavy chain, and a heavy chain variable region framework sequence and heavy chain constant region, if present, substantially from human heavy chain variable region framework and constant region sequences. Similarly, a humanized light chain typically has all three CDRs entirely or substantially from a donor antibody light chain, and a light chain variable region framework sequence and light chainconstant region, if present, substantially from human light chain variable region framework and constant region sequences.

[0087] A CDR in a humanized antibody is substantially from a corresponding CDR in a non-human antibody when at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98% or about 99% of corresponding residues (as defined by Kabat numbering), or wherein about 100% of corresponding residues (as defined by Kabat numbering), are identical between the respective CDRs. The variable region framework sequences of an antibody chain or the constant region of an antibody chain are substantially from a human variable region framework sequence or human constant region respectively when at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98% or about 99% of corresponding residues (as defined by Kabat numbering for the variable region and EU numbering for the constant region), or about 100% of corresponding residues (as defined by Kabat numbering for the variable region and EU numbering for the constant region) are identical.

[0088] Although humanized antibodies often incorporate all six CDRs (preferably as defined by Kabat or IMGT®) from a mouse antibody, they can also be made with fewer than all six CDRs (e.g., at least 3, 4, or 5) CDRs from a mouse antibody (e.g., Pascalis et al., J. Immunol. 169:3076, 2002; Vajdos et al., Journal of Molecular Biology, 320: 415-428, 2002; Iwahashi et al., Mol. Immunol. 36: 1079-1091, 1999; Tamura et al, Journal of Immunology, 164: 1432- 1441, 2000).

[0089] A CDR in a humanized antibody is “substantially from” a corresponding CDR in a non-human antibody when at least 60%, at least 85%, at least 90%, at least 95% or 100% of corresponding residues (as defined by Kabat (or IMGT)) are identical between the respective CDRs. In particular variations of a humanized VH or VL domain in which CDRs are substantially from a non-human immunoglobulin, the CDRs of the humanized VH or VL domain have no more than six e.g., no more than five, no more than four, no more than three, no more than two, or nor more than one) amino acid substitutions (preferably conservative substitutions) across all three CDRs relative to the corresponding non-human VH or VL CDRs. The variable region framework sequences of an antibody VH or VL domain or, if present, a sequence of an immunoglobulin constant region, are “substantiallyfrom” a human VH or VL framework sequence or human constant region, respectively, when at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98% or about 99% of corresponding residues (as defined by Kabat numbering for the variable region and EU numbering for the constant region), or about 100% of corresponding residues (as defined by Kabat numbering for the variable region and EU numbering for the constant region) are identical. Hence, all parts of a humanized antibody, except the CDRs, are typically entirely or substantially from corresponding parts of natural human immunoglobulin sequences.

[0090] Antibodies are typically provided in isolated form. This means that an antibody is typically at least about 50% w / w pure of interfering proteins and other contaminants arising from its production or purification but does not exclude the possibility that the antibody is combined with an excess of pharmaceutical acceptable carrier(s) or other vehicle intended to facilitate its use. Sometimes antibodies are at least about 60%, about 70%, about 80%, about 90%, about 95% or about 99% w / w pure of interfering proteins and contaminants from production or purification. Antibodies, including isolated antibodies, can be conjugated to cytotoxic agents and provided as antibody drug conjugates.

[0091] Specific binding of an antibody to its target antigen typically refers an affinity of at least about 106, about 107, about 108, about 109, or about 1010M’1. Specific binding is detectably higher in magnitude and distinguishable from non-specific binding occurring to at least one non-specific target. Specific binding can be the result of formation of bonds between particular functional groups or particular spatial fit (e.g., lock and key type), whereas nonspecific binding is typically the result of van der Waals forces.

[0092] The term “epitope” refers to a site of an antigen to which an antibody binds. An epitope can be formed from contiguous amino acids or noncontiguous amino acids juxtaposed by tertiary folding of one or more proteins. Epitopes formed from contiguous amino acids are typically retained upon exposure to denaturing agents, e.g., solvents, whereas epitopes formed by tertiary folding are typically lost upon treatment with denaturing agents, e.g., solvents. An epitope typically includes at least about 3, and more usually, at least about 5, at least about 6, at least about 7, or about 8-10 amino acids in a unique spatial conformation. Methods of determining spatial conformation of epitopes include, for example, x-ray crystallography and two-dimensional nuclear magnetic resonance. See, e.g.,Epitope Mapping Protocols, in Methods in Molecular Biology, Vol. 66, Glenn E. Morris, Ed. (1996).

[0093] Antibodies that recognize the same or overlapping epitopes can be identified in a simple immunoassay showing the ability of one antibody to compete with the binding of another antibody to a target antigen. The epitope of an antibody can also be defined by X-ray crystallography of the antibody bound to its antigen to identify contact residues.

[0094] Alternatively, two antibodies have the same epitope if all amino acid mutations in the antigen that reduce or eliminate binding of one antibody reduce or eliminate binding of the other (provided that such mutations do not produce a global alteration in antigen structure). Two antibodies have overlapping epitopes if some amino acid mutations that reduce or eliminate binding of one antibody reduce or eliminate binding of the other antibody.

[0095] Competition between antibodies can be determined by an assay in which a test antibody inhibits specific binding of a reference antibody to a common antigen (see, e.g., Junghans et al., Cancer Res. 50: 1495, 1990). A test antibody competes with a reference antibody if an excess of a test antibody inhibits binding of the reference antibody.

[0096] Antibodies identified by competition assay (competing antibodies) include antibodies that bind to the same epitope as the reference antibody and antibodies that bind to an adjacent epitope sufficiently proximal to the epitope bound by the reference antibody for steric hindrance to occur. Antibodies identified by a competition assay also include those that indirectly compete with a reference antibody by causing a conformational change in the target protein thereby preventing binding of the reference antibody to a different epitope than that bound by the test antibody.

[0097] An antibody effector function refers to a function contributed by an Fc region of an Ig. Such functions can be, for example, antibody-dependent cellular cytotoxicity (ADCC), antibody- dependent cellular phagocytosis (ADCP), or complement-dependent cytotoxicity (CDC). Such function can be affected by, for example, binding of an Fc region to an Fc receptor on an immune cell with phagocytic or lytic activity or by binding of an Fc region to components of the complement system. Typically, the effect(s) mediated by the Fc-binding cells or complement components result in inhibition and / or depletion of the B7-H4-targeted cell. Fc regions of antibodies can recruit Fc receptor (FcR)-expressing cells and juxtapose them with antibody-coated target cells. Cells expressing surface FcR for IgGs includingFcyRIII (CD 16), FcyRII (CD32) and FcyRIII (CD64) can act as effector cells for the destruction of IgG-coated cells. Such effector cells include monocytes, macrophages, natural killer (NK) cells, neutrophils and eosinophils. Engagement of FcyR by IgG activates ADCC or ADCP. ADCC is mediated by CD 16+ effector cells through the secretion of membrane pore-forming proteins and proteases, while phagocytosis is mediated by CD32+ and CD64+ effector cells (see Fundamental Immunology, 4thed., Paul ed., Lippincott-Raven, N.Y., 1997, Chapters 3, 17 and 30; Uchida et al., J. Exp. Med. 199: 1659-69, 2004; Akewanlop et al., Cancer Res. 61:4061-65, 2001; Watanabe et al., Breast Cancer Res. Treat. 53: 199-207, 1999).

[0098] In addition to ADCC and ADCP, Fc regions of cell-bound antibodies can also activate the complement classical pathway to elicit CDC. Clq of the complement system binds to the Fc regions of antibodies when they are complexed with antigens. Binding of Clq to cell-bound antibodies can initiate a cascade of events involving the proteolytic activation of C4 and C2 to generate the C3 convertase. Cleavage of C3 to C3b by C3 convertase enables the activation of terminal complement components including C5b, C6, C7, C8 and C9. Collectively, these proteins form membrane-attack complex pores on the antibody-coated cells. These pores disrupt the cell membrane integrity, killing the target cell (see Immunobiology, 6thed., Janeway et al, Garland Science, N. Y., 2005, Chapter 2).

[0099] The term “antibody-dependent cellular cytotoxicity” or “ADCC” refers to a mechanism for inducing cell death that depends on the interaction of antibody-coated target cells with immune cells possessing lytic activity (also referred to as effector cells). Such effector cells include natural killer cells, monocytes / macrophages and neutrophils. The effector cells attach to an Fc region of Ig bound to target cells via their antigen-combining sites. Death of the antibody-coated target cell occurs as a result of effector cell activity. In certain exemplary embodiments, an anti-B7-H4 IgGl antibody of the invention mediates equal or increased ADCC relative to a parental antibody and / or relative to an anti-B7-H4 IgG3 antibody.

[0100] The term “antibody-dependent cellular phagocytosis” or “ADCP” refers to the process by which antibody-coated cells are internalized, either in whole or in part, by phagocytic immune cells (e.g., by macrophages, neutrophils and / or dendritic cells) that bind to an Fc region of Ig. In certain exemplary embodiments, an anti-B7-H4 IgGl antibody of the invention mediates equal or increased ADCP relative to a parental antibody and / or relative to an anti-B7-H4 IgG3 antibody.

[0101] The term “complement-dependent cytotoxicity” or “CDC” refers to a mechanism for inducing cell death in which an Fc region of a target-bound antibody activates a series of enzymatic reactions culminating in the formation of holes in the target cell membrane.

[0102] Typically, antigen-antibody complexes such as those on antibody-coated target cells bind and activate complement component Clq, which in turn activates the complement cascade leading to target cell death. Activation of complement may also result in deposition of complement components on the target cell surface that facilitate ADCC by binding complement receptors (e.g., CR3) on leukocytes.

[0103] A “cytotoxic effect” refers to the depletion, elimination and / or killing of a target cell. A “cytotoxic agent” refers to a compound that has a cytotoxic effect on a cell, thereby mediating depletion, elimination and / or killing of a target cell. In certain embodiments, a cytotoxic agent is conjugated to an antibody or administered in combination with an antibody. Suitable cytotoxic agents are described further herein.

[0104] A “cytostatic effect” refers to the inhibition of cell proliferation. A “cytostatic agent” refers to a compound that has a cytostatic effect on a cell, thereby mediating inhibition of growth and / or expansion of a specific cell type and / or subset of cells. Suitable cytostatic agents are described further herein.

[0105] As used herein, the terms “individual,” “patient,” and “subject” refer to organisms to be treated by the methods of the present invention. Such organisms are humans. As used herein, the terms “treat,” “treatment” and “treating” include any effect, e.g., lessening, reducing, modulating, ameliorating or eliminating, that results in the improvement of the condition, disease, disorder, and the like, or ameliorating a symptom thereof, such as for example, reduced number of cancer cells, reduced tumor size, reduced rate of cancer cell infiltration into peripheral organs, or reduced rate of tumor metastasis or tumor growth.

[0106] “Tumor” as it applies to an individual diagnosed with, or suspected of having, cancer (e.g., solid cancer or breast cancer), refers to a malignant or potentially malignant neoplasm or tissue mass of any size.

[0107] “Tumor burden” also referred to as “tumor load,” refers to the total amount of tumor material distributed throughout the body. Tumor burden refers to the total number of cancer cells or the total size of tumor(s) throughout the body, including lymph nodes and bone narrow. Tumor burden can be determined by a variety of methods known in the art, such as, e.g., by measuring the dimensions of tumor(s) upon removal from the individual,e.g., using calipers, or while in the body using imaging techniques, e.g., ultrasound, bone scan, computed tomography (CT) or magnetic resonance imaging (MRI) scans.

[0108] The term “tumor size” refers to the total size of the tumor which can be measured as the length and width of a tumor. Tumor size may be determined by a variety of methods known in the art, such as, e.g. by measuring the dimensions of tumor(s) upon removal from the individual, e.g., using calipers, or while in the body using imaging techniques, e.g., bone scan, ultrasound, CT or MRI scans.

[0109] As used herein, the term “effective amount” refers to the amount of a compound (e.g., an anti-B7-H4 antibody or antigen-binding fragment thereof or antibody-drug conjugate) sufficient to effect beneficial or desired results. An effective amount of an antibody or antigen-binding fragment thereof or antibody-drug conjugate (e.g., a B7-H4- ADC) can be administered in one or more administrations, applications or dosages and is not intended to be limited to a particular formulation or administration route.

[0110] The term “pharmaceutically acceptable” means approved or approvable by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans. The term “pharmaceutically compatible ingredient” refers to a pharmaceutically acceptable diluent, adjuvant, excipient, or vehicle with which an anti-B7-H4 antibody (e.g., a B7-H4-ADC) is formulated.

[0111] The phrase “pharmaceutically acceptable salt,” refers to pharmaceutically acceptable organic or inorganic salts. Exemplary salts include sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p toluenesulfonate, and pamoate (i.e., l,l'-methylene bis-(2 hydroxy-3-naphthoate) salts. A pharmaceutically acceptable salt may further comprise an additional molecule such as, e.g., an acetate ion, a succinate ion or other counterion. A counterion may be any organic or inorganic moiety that stabilizes the charge on the parent compound. Furthermore, a pharmaceutically acceptable salt may have more than one charged atom in its structure. Instances where multiple charged atoms are part of the pharmaceutically acceptable salt can have multiple counter ions. Hence,a pharmaceutically acceptable salt can have one or more charged atoms and / or one or more counterion.

[0112] A “platinum-based therapy” refers to treatment with a platinum-based agent. A “platinum-based agent” refers to a molecule or a composition comprising a molecule containing a coordination complex comprising the chemical element platinum and useful as a chemotherapy drug. Platinum-based agents generally act by inhibiting DNA synthesis and some have alkylating activity. Platinum-based agents encompass those that are currently being used as part of a chemotherapy regimen, those that are currently in development, and those that may be developed in the future.

[0113] Unless otherwise apparent from the context, when a value is expressed as “about” X or “approximately” X, the stated value of X will be understood to be accurate to ±10%.

[0114] Solvates in the context of the invention are those forms of the compounds of the invention that form a complex in the solid or liquid state through coordination with solvent molecules. Hydrates are one specific form of solvates, in which the coordination takes place with water. In certain exemplary embodiments, solvates in the context of the present invention are hydrates.II. Antibody-Drug Conjugates

[0115] In some aspects, provided herein is an antibody drug conjugate (ADC) comprising an antibody which specifically binds to B7-H4. In some embodiments, the ADC is a B7-H4- ADC.

[0116] In some aspects, provided herein are methods of treating an individual having cancer (e.g, breast cancer, ovarian cancer, primary peritoneal cancer, fallopian tube cancer, endometrial carcinoma, lung cancer, cholangiocarcinoma, gallbladder carcinoma, or head and neck carcinoma), comprising administering to the individual an effective amount of an antibody drug conjugate (ADC) comprising an antibody which specifically binds to B7-H4. In some embodiments, the ADC is B7-H4-ADC.

[0117] In some embodiments, the ADC comprises an antibody, wherein the antibody is an anti-B7-H4 antibody. In some embodiments, the ADC comprises an antibody, wherein the antibody is an anti-B7-H4 monoclonal antibody (mAb). In some embodiments, the ADC comprises an antibody, wherein the antibody is a fully human antibody. In some embodiments, the ADC comprises an antibody, wherein the antibody is a humanized antibody. In some embodiments, the ADC comprises an antibody, wherein the antibody isconjugated to a moiety such as a cytotoxic agent (for example, but not limited to, an antitubulin agent).

[0118] SGN-B7H4V is an antibody drug conjugate (ADC) composed of a fully human IgGl anti-B7-H4 monoclonal antibody (mAb) conjugated to the microtubule disrupting agent monomethyl auristatin E (MMAE) via a protease-cleavable peptide linker (Doronina et al., 2003. Nat Biotechnol 21, 778-784). This “vedotin” drug linker system has been clinically validated by multiple ADC programs, including brentuximab vedotin (Adcetris™), enfortumab vedotin (PADCEV™), polatuzumab vedotin (POLIVY™) , and tisotumab vedotin (Tivdak™) (Rosenberg et al., 2019, J Clin Oncol 37, 2592-2600; Senter and Sievers, 2012, Nat Biotechnol 30, 631-637; Tilly et al., 2019, Lancet Oncol 20, 998-1010; Markham, 2021, Drugs. 2021 Dec;81(18):2141-2147). The antibody component of SGN-B7H4V is a fucosylated mAb that should have a similar profile to B7H41001, an afucosylated mAh targeting B7-H4 that exhibited a favorable safety profile in a Phase 1 clinical trial (Wainberg, 2019, "Phase 1 Update in Advanced Solid Tumors: Monotherapy and in Combination with Pembrolizumab," presented at: ESMO 2019 Congress (Annals of Oncology)).

[0119] In some embodiments, the invention provides an antibody-drug conjugate for the treatment of cancer (e.g., breast cancer, ovarian cancer, primary peritoneal cancer, fallopian tube cancer, endometrial carcinoma, lung cancer, cholangiocarcinoma, gallbladder carcinoma, or head and neck carcinoma). In some embodiments, the antibody-drug conjugate comprises an antibody conjugated to an auristatin. In some embodiments, the auristatin is a monomethyl auristatin. In some embodiments, the monomethyl auristatin is monomethyl auristatin E.

[0120] Unless otherwise indicated, an anti-B7-H4-antibody drug conjugate (i.e., a B7-H4- ADC) includes an antibody specific for the human B7-H4 protein conjugated to a cytotoxic agent.

[0121] SGN-B7H4V comprises a fully human anti-B7-H4 monoclonal IgGl antibody (mAb), which is conjugated to monomethyl auristatin E (MMAE) via a protease-cleavable linker (i.e., a valine-citrulline linker). Upon binding to a B7-H4 expressing cell, SGN- B7H4V is internalized and releases MMAE, which disrupts microtubules and induces apoptosis.

[0122] B7-H4 ADCs (such as but not limited to SGN-B7H4V) comprises a fully human anti-B7-H4 antibody, where examples of such antibodies were described in US Patent PublicationUS20190085080. Methods of making certain anti-B7-H4 antibodies are also disclosed in US Patent Publication US20190085080, which is incorporated herein by reference in its entirety for all purposes.

[0123] In some embodiments, the antibodies (e.g., monoclonal antibodies, such as chimeric, humanized, or human antibodies) or antigen-binding fragments thereof which specifically bind to B7-H4 (e.g., human B7-H4). The amino acid sequences for human, cynomolgus monkey, murine, and rat B7-H4 are known in the art and also provided herein as represented by SEQ ID NOs: 1-4, respectively.Table 1A: Amino acid sequences for human, cynomolgus monkey, murine, and rat B7-H4

[0124] In certain embodiments according to any one of the methods or antibodyconjugates described herein, the ADC described herein binds to human B7-H4. In certain embodiments, the ADC binds to human and cynomolgus monkey B7-H4. In certain embodiments, the ADC binds to human, murine, and rat B7-H4. In certain embodiments, theADC specifically binds to one or more of: human, cynomolgus monkey, murine, and rat B7- H4.

[0125] B7-H4 contains an IgC ectodomain (amino acids 153-241 of SEQ ID NO: 1) and an IgV domain (amino acids 35-146 of SEQ ID NO: 1).

[0126] In certain embodiments, the ADC described herein binds to the IgV domain of human B7-H4. In some embodiments, the ADC binds to a polypeptide consisting of amino acids 35- 146 of SEQ ID NO: 1.

[0127] In certain embodiments, the ADC described herein binds to human B7-H4 and comprises the six CDRs of an antibody listed in Table IB (i.e., the three VH CDRs of the antibody listed in Table IB and the three VL CDRs of the same antibody listed in Table IB). In certain embodiments, the ADCdescribed herein binds to human B7-H4 and comprises the six CDRs comprising the SEQ ID NOs: 5, 6, 7, 8, 9, and 10 (i.e., the three VH CDRs of the antibody comprising the SEQ ID NOs: 5, 6, and 7 and the three VL CDRs comprising the SEQ ID NOs: 8, 9 and 10.

[0128] In some embodiments, the ADC described herein binds to human B7-H4, wherein the ADC comprises a VH comprising a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 5, an VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 6, and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 7; and a VL comprising a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 8, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 10.

[0129] In some embodiments, the ADC comprises a VH comprising a sequence with at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 11 and a VL comprising a sequence with at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 12. In some embodiments, the ADC comprises a VH comprising a sequence with at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 11 and a VL comprising a sequence with at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 12. In some embodiments, the ADC comprises a VH comprising a sequence with at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 11 and a VL comprising a sequence with at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 12. In some embodiments, the ADC comprises a VH comprising a sequence with at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 11 and a VLcomprising a sequence with at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 12. In some embodiments, the ADC comprises a VH comprising a sequence with at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 11 and a VL comprising a sequence with at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 12. In some embodiments, the ADC comprises a VH comprising the amino acid sequence of SEQ ID NO: 11 and a VL comprising the amino acid sequence of SEQ ID NO: 12. In certain embodiments, an ADC described herein binds to human B7-H4 and comprises the heavy chain sequence of SEQ ID NO: 13. In certain embodiments, an ADC described herein binds to human B7-H4 and comprises the light chain sequence of SEQ ID NO: 14.Table IB: CDRs, variable regions, and full-length antibody amino acid sequences for B7- H41001 mAh.

[0130] In certain embodiments, the ADC described herein binds to human B7-H4 and comprises the six CDRs of an antibody listed in Tables 2 and 3 (i.e., the three VH CDRs of the antibody listed in Table 2 and the three VL CDRs of the same antibody listed in Table 3).Table 2. VH CDR amino acid sequences (Kabat)Table 3. VL CDR amino acid sequences (Kabat)

[0131] In certain embodiments, the ADCdescribed herein binds to human B7-H4 and comprises the VH and the VL of an antibody listed in Tables 4 and 5 (i.e., the VH of the antibody listed in Table 4 and the VL of the same antibody listed in Table 5)Table 4. VH amino acid sequencesTable 5. VL amino acid sequences

[0132] In certain embodiments, an ADC described herein binds to human B7-H4 and comprises the heavy chain sequence of an antibody listed in Table 6.Table 6: Full-length heavy chain amino acid sequences

[0133] In certain embodiments, the ADC described herein binds to human B7-H4 and comprises the light chain sequence of an antibody listed in Table 7.Table 7: Full-length light chain amino acid sequences

[0134] In certain embodiments, the ADCdescribed herein binds to human B7-H4 and comprises the heavy chain sequence and the light chain sequence of an antibody listed in Tables 6 and 7 (i.e., the heavy chain sequence of the antibody listed in Table 6 and the light chain sequence of the same antibody listed in Table 7).

[0135] In certain embodiments, the ADC herein binds to human B7-H4, comprises the six CDRs of an antibody listed in Tables 2 and 3 (i.e., the three VH CDRs of the antibody listed in Table 2 and the three VL CDRs of the same antibody listed in Table 3), and comprises a VH comprising a sequence at least 80% identical to the VH sequence of the same antibody in Table 4 and a VL comprising a sequence at least 80% identical to the VL sequence of the same antibody in Table 5. In certain embodiments, an ADC described herein binds to human B7-H4, comprises the six CDRs of an antibody listed in Tables 2 and 3 (i.e., the three VH CDRs of the antibody listed in Table 2 and the three VL CDRs of the same antibody listed inTable 3), and comprises a VH comprising a sequence at least 85% identical to the VH sequence of the same antibody in Table 4 and a VL comprising a sequence at least 85% identical to the VL sequence of the same antibody in Table 5.

[0136] In certain embodiments, the ADC described herein binds to human B7-H4, comprises the six CDRs of an antibody listed in Tables 2 and 3 (i.e., the three VH CDRs of the antibody listed in Table 2 and the three VL CDRs of the same antibody listed in Table 3), and comprises a VH comprising a sequence at least 90% identical to the VH sequence of the same antibody in Table 4 and a VL comprising a sequence at least 90% identical to the VL sequence of the same antibody in Table 5. In certain embodiments, an ADC described herein binds to human B7-H4, comprises the six CDRs of an antibody listed in Tables 2 and 3 (i.e., the three VH CDRs of the antibody listed in Table IB and the three VL CDRs of the same antibody listed in Table 2), and comprises a VH comprising a sequence at least 95% identical to the VH sequence of the same antibody in Table 4 and a VL comprising a sequence at least 95% identical to the VL sequence of the same antibody in Table 5.

[0137] In certain embodiments, an ADC described herein binds to human B7-H4, comprises the six CDRs of an antibody listed in Tables 2 and 3 (i.e., the three VH CDRs of the antibody listed in Table 2 and the three VL CDRs of the same antibody listed in Table 3), and comprises a VH comprising a sequence at least 96% identical to the VH sequence of the same antibody in Table 4 and a VL comprising a sequence at least 96% identical to the VL sequence of the same antibody in Table 5. In certain embodiments, an ADC described herein binds to human B7-H4, comprises the six CDRs of an antibody listed in Tables 2 and 3 (i.e., the three VH CDRs of the antibody listed in Table 2 and the three VL CDRs of the same antibody listed in Table 3), and comprises a VH comprising a sequence at least 97% identical to the VH sequence of the same antibody in Table 4 and a VL comprising a sequence at least 97% identical to the VL sequence of the same antibody in Table 5. In certain embodiments, an ADC described herein binds to human B7-H4, comprises the six CDRs of an antibody listed in Tables 2 and 3 (i.e., the three VH CDRs of the antibody listed in Table 2 and the three VL CDRs of the same antibody listed in Table 3), and comprises a VH comprising a sequence at least 98% identical to the VH sequence of the same antibody in Table 4 and a VL comprising a sequence at least 98%) identical to the VL sequence of the same antibody in Table 5. In certain embodiments, an ADC described herein binds to human B7-H4, comprises the six CDRs of an antibody listed in Tables 2 and 3 (i.e., the three VH CDRs of the antibody listed in Table 2 and the three VL CDRs of the same antibody listed in Table 3), andcomprises a VH comprising a sequence at least 99% identical to the VH sequence of the same antibody in Table 4 and a VL comprising a sequence at least 99% identical to the VL sequence of the same antibody in Table 5. In some embodiments, the ADC to human, cynomolgus monkey, rat, and / or mouse B7- H4.

[0138] In some embodiments, the ADC increases T cell proliferation. In some embodiments, the ADC increases IFN-gamma production. In some embodiments, the ADC mediates ADCC activity against B7-H4-expressing cells. In some embodiments, the ADC mediates ADCC activity against B7-H4-expressing cells. In some embodiments, the ADC does not mediate CDC activity against B7-H4-expressing cells.

[0139] In certain aspects, an ADC described herein may be described by its VL domain alone, or its VH domain alone, or by its 3 VL CDRs alone, or its 3 VH CDRs alone. See, for example, Rader C et al., (1998) PNAS 95: 8910-8915, which is incorporated herein by reference in its entirety, describing the humanization of the mouse anti- av[33 antibody by identifying a complementing light chain or heavy chain, respectively, from a human light chain or heavy chain library, resulting in humanized antibody variants having affinities as high or higher than the affinity of the original antibody. See also Clackson T et al., (1991) Nature 352: 624-628, which is incorporated herein by reference in its entirety, describing methods of producing antibodies that bind a specific antigen by using a specific VL domain (or VH domain) and screening a library for the complementary variable domains. The screen produced 14 new partners for a specific VH domain and 13 new partners for a specific VL domain, which were strong binders, as determined by ELISA. See also Kim SJ & Hong HJ, (2007) J Microbiol 45: 572-577, which is incorporated herein by reference in its entirety, describing methods of producing antibodies that bind a specific antigen by using a specific VH domain and screening a library (e.g., human VL library) for complementary VL domains; the selected VL domains in turn could be used to guide selection of additional complementary (e.g., human) VH domains.

[0140] In certain aspects, the CDRs of an antibody on an ADC can be determined according to the Chothia numbering scheme, which refers to the location of immunoglobulin structural loops (see, e.g., Chothia C & Lesk AM, (1987), J Mol Biol 196: 901- 917; Al- Lazikani B et al., (1997) J Mol Biol 273 : 927-948; Chothia C et al., (1992) J Mol Biol 227: 799-817; Tramontane A et al., (1990) J Mol Biol 215(1): 175-82; and U.S. Patent No. 7,709,226). Typically, when using the Kabat numbering convention, the Chothia CDR-H1 loop is present at heavy chain amino acids 26 to 32, 33, or 34, the Chothia CDR-H2 loop ispresent at heavy chain amino acids 52 to 56, and the Chothia CDR-H3 loop is present at heavy chain amino acids 95 to 102, while the Chothia CDR-L1 loop is present at light chain amino acids 24 to 34, the Chothia CDR-L2 loop is present at light chain amino acids 50 to 56, and the Chothia CDR-L3 loop is present at light chain amino acids 89 to 97. The end of the Chothia CDR-H1 loop when numbered using the Kabat numbering convention varies between H32 and H34 depending on the length of the loop (this is because the Kabat numbering scheme places the insertions at H35A and H35B; if neither 35A nor 35B is present, the loop ends at 32; if only 35A is present, the loop ends at 33; if both 35A and 35B are present, the loop ends at 34).

[0141] In certain aspects, provided herein are ADCs that specifically bind to B7-H4 (e.g., human B7-H4) and comprise the Chothia VH and VL CDRs of an antibody listed in Tables 4 and 5. In certain embodiments, ADCs that specifically bind to B7-H4 (e.g., human B7-H4) comprise one or more CDRs, in which the Chothia and Kabat CDRs have the same amino acid sequence. In certain embodiments, provided herein are ADCs that specifically bind to B7-H4 (e.g., human B7-H4) and comprise combinations of Kabat CDRs and Chothia CDRs.

[0142] In certain aspects, the CDRs of an ADC can be determined according to the IMGT numbering system as described in Lefranc M-P, (1999) The Immunologist 7: 132-136 and Lefranc M-P et al., (1999) Nucleic Acids Res 27: 209-212. According to the IMGT numbering scheme, VH-CDR1 is at positions 26 to 35, VH-CDR2 is at positions 51 to 57, VH-CDR3 is at positions 93 to 102, VL-CDR1 is at positions 27 to 32, VL- CDR2 is at positions 50 to 52, and VL-CDR3 is at positions 89 to 97. In a particular embodiment, provided herein are ADCs that specifically bind to B7-H4 (e.g., human B7-H4) and comprise the IMGT VH and VL CDRs of an antibody listed in Tables 4 and 5, for example, as described in Lefranc M-P (1999) supra and Lefranc M-P et al., (1999) supra).

[0143] In certain aspects, the CDRs of an antibody on an ADC can be determined according to MacCallum RM et al., (1996) J Mol Biol 262: 732-745. See also, e.g., Martin A. "Protein Sequence and Structure Analysis of Antibody Variable Domains," in Antibody Engineering, Kontermann and Diibel, eds., Chapter 31, pp. 422-439, Springer- Verlag, Berlin (2001). In a particular embodiment, provided herein are ADCs that specifically bind to B7- H4 (e.g., human B7-H4) and comprise VH and VL CDRs of an antibody listed in Tables 4 and 5 as determined by the method in MacCallum RM et al.

[0144] In certain aspects, the CDRs of an antibody on an ADC can be determined according to the AbM numbering scheme, which refers AbM hypervariable regions which represent a compromise between the Kabat CDRs and Chothia structural loops, and are used by Oxford Molecular's AbM antibody modeling software (Oxford Molecular Group, Inc.). In a particular embodiment, provided herein are ADCs that specifically bind to B7-H4 (e.g., human B7-H4) and comprise VH and VL CDRs of an antibody listed in Tables 4 and 5 as determined by the AbM numbering scheme.

[0145] In specific aspects, provided herein are antibodies that comprise a heavy chain and a light chain. With respect to the heavy chain, in a specific embodiment, the heavy chain of an ADC described herein can be an alpha (a), delta (6), epsilon (e), gamma (y) or mu (p) heavy chain. In another specific embodiment, the heavy chain of an ADC described can comprise a human alpha (a), delta (6), epsilon (e), gamma (y) or mu (p) heavy chain. In a particular embodiment, an ADC described herein, which immunospecifically binds to B7-H4 (e.g., human B7-H4), comprises a heavy chain wherein the amino acid sequence of the VH domain comprises an amino acid sequence set forth in Table 4 and wherein the constant region of the heavy chain comprises the amino acid sequence of a human gamma (y) heavy chain constant region. In a specific embodiment, an ADC described herein, which specifically binds to B7- H4 (e.g., human B7-H4), comprises a heavy chain wherein the amino acid sequence of the VH domain comprises a sequence set forth in Table 4, and wherein the constant region of the heavy chain comprises the amino acid of a human heavy chain described herein or known in the art. Non-limiting examples of human constant region sequences have been described in the art, e.g., see U.S. Patent No. 5,693,780 and Kabat EA et al., (1991) supra.

[0146] With respect to the light chain, in a specific embodiment, the light chain of an ADC described herein is a kappa light chain. The constant region of a human kappa light chain can comprise the following amino acid sequence: RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVT EQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 89).

[0147] The constant region of a human kappa light chain can be encoded by the following nucleotide sequence: CGGACCGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAG TTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAG AGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGAC GCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATC AG GGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT (SEQ ID NO: 90).

[0148] In another specific embodiment, the light chain of an ADC described herein is a lambda light chain. In yet another specific embodiment, the light chain of an ADC described herein is a human kappa light chain or a human lambda light chain. In a particular embodiment, an ADC described herein, which immunospecifically binds to a B7-H4 polypeptide (e.g., human B7-H4) comprises a light chain wherein the amino acid sequence of the VL domain comprises a sequence set forth in Table 5, and wherein the constant region of the light chain comprises the amino acid sequence of a human kappa light chain constant region. In another particular embodiment, an ADC described herein, which immunospecifically binds to B7-H4 (e.g., human B7-H4) comprises a light chain wherein the amino acid sequence of the VL domain comprises a sequence set forth in Table 5 and wherein the constant region of the light chain comprises the amino acid sequence of a human lambda light chain constant region. In a specific embodiment, an ADC described herein, which immunospecifically binds to B7-H4 (e.g., human B7-H4) comprises a light chain wherein the amino acid sequence of the VL domain comprises a sequence set forth in Table 5 and wherein the constant region of the light chain comprises the amino acid sequence of a human kappa or lambda light chain constant region. Non-limiting examples of human constant region sequences have been described in the art, e.g., see U.S. Patent No. 5,693,780 and Kabat EA et al., (1991) supra.

[0149] In a specific embodiment, an ADC described herein, which immunospecifically binds to B7-H4 (e.g., human B7-H4) comprises a VH domain and a VL domain comprising any amino acid sequence described herein, and wherein the constant regions comprise the amino acid sequences of the constant regions of an IgG, IgE, IgM, IgD, IgA, or IgY immunoglobulin molecule, or a human IgG, IgE, IgM, IgD, IgA, or IgY immunoglobulin molecule. In another specific embodiment, an ADC described herein, which immunospecifically binds to B7-H4 (e.g., human B7-H4) comprises a VH domain and a VLdomain comprising any amino acid sequence described herein, and wherein the constant regions comprise the amino acid sequences of the constant regions of an IgG, IgE, IgM, IgD, IgA, or IgY immunoglobulin molecule, any class (e.g., IgGl, IgG2, IgG3, IgG4, IgAl, and IgA2), or any subclass (e.g., IgG2a and IgG2b) of immunoglobulin molecule. In a particular embodiment, the constant regions comprise the amino acid sequences of the constant regions of a human IgG, IgE, IgM, IgD, IgA, or IgY immunoglobulin molecule, any class (e.g., IgGl, IgG2, IgG3, IgGl, IgAl, and IgA2), or any subclass (e.g., IgG2a and IgG2b) of immunoglobulin molecule.

[0150] The constant region of a human IgGl heavy chain can comprise the following amino acid sequence: ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNS GALTSGVHTFP AVLQS SGYS S S VVTVPS S SLGTQTYICNVNHKP SNTKVDKKVEPKS CDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNW YVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPI EKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPEN NYKTTPPVLDSDGSFFLYSKLTVDK SRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO:91).

[0151] The constant region of a human IgGl heavy chain can be encoded by the following nucleotide sequence:GCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCT CTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGG TGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGG CTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTC CAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAA CACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATG CCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCC CCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTG GTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGAC GGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAG CACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGC AAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAA ACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCC CCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAA GGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCT ACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCAT GCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCT GTCTCCGGGTAAA. (SEQ ID NO: 92)

[0152] Non-limiting examples of human constant regions are described in the art, e.g., see Kabat EA et al, (1991) supra.

[0153] In certain embodiments, one, two, or more mutations (e.g., amino acid substitutions) are introduced into the Fc region of an ADCdescribed herein (e.g., CH2 domain (residues 231-340 of human IgGl) and / or CH3 domain (residues 341-447 of human IgGl) and / or the hinge region, with numbering according to the Kabat numbering system (e.g., the EU index in Kabat)) to alter one or more functional properties of the ADC, such as serum half-life, complement fixation, Fc receptor binding, and / or antigen-dependent cellular cytotoxicity.

[0154] In certain embodiments, one, two, or more mutations (e.g., amino acid substitutions) are introduced into the hinge region of the Fc region (CHI domain) such that the number of cysteine residues in the hinge region are altered (e.g., increased or decreased) as described in, e.g., U.S. Pat. No. 5,677,425. The number of cysteine residues in the hinge region of the CHI domain may be altered to, e.g., facilitate assembly of the light and heavy chains, or to alter (e.g., increase or decrease) the stability of the ADC.

[0155] In some embodiments, one, two, or more mutations (e.g., amino acid substitutions) are introduced into the Fc region of an ADCdescribed herein (e.g., CH2 domain (residues 231-340 of human IgGl) and / or CH3 domain (residues 341-447 of human IgGl) and / or the hinge region, with numbering according to the Kabat numbering system (e.g., the EU index in Kabat)) to increase or decrease the affinity of the ADC for an Fc receptor (e.g., an activated Fc receptor) on the surface of an effector cell. Mutations in the Fc region that decrease or increase affinity for an Fc receptor and techniques for introducing such mutations into the Fc receptor or fragment thereof are known to one of skill in the art. Examples of mutations in the Fc receptor that can be made to alter the affinity of the ADC for an Fc receptor are described in, e.g., Smith P et al., (2012) PNAS 109: 6181-6186, U.S. Pat. No. 6,737,056, and International Publication Nos. WO 02 / 060919; WO 98 / 23289; and WO 97 / 34631, which are incorporated herein by reference.

[0156] In a specific embodiment, one, two, or more amino acid mutations (i. e. , substitutions, insertions or deletions) are introduced into an IgG constant domain, or FcRn- binding fragment thereof (preferably an Fc or hinge-Fc domain fragment) to alter (e.g., decrease or increase) half-life of the ADC in vivo. See, e.g., International Publication Nos. WO 02 / 060919; WO 98 / 23289; and WO 97 / 34631; and U.S. Pat. Nos. 5,869,046, 6,121,022, 6,277,375 and 6,165,745 for examples of mutations that will alter (e.g., decrease or increase) the half-life of an ADC in vivo. In some embodiments, one, two or more amino acid mutations (i.e., substitutions, insertions, or deletions) are introduced into an IgG constant domain, or FcRn-binding fragment thereof (preferably an Fc or hinge-Fc domain fragment) to decrease the half-life of the ADC in vivo. In other embodiments, one, two or more amino acid mutations (i.e., substitutions, insertions or deletions) are introduced into an IgG constant domain, or FcRn-binding fragment thereof (preferably an Fc or hinge-Fc domain fragment) to increase the half-life of the ADC in vivo. In a specific embodiment, the ADCs may have one or more amino acid mutations (e.g., substitutions) in the second constant (CH2) domain (residues 231-340 of human IgGl) and / or the third constant (CH3) domain (residues 341-447 of human IgGl), with numbering according to the EU index in Kabat (Kabat E A et al., (1991) supra). In a specific embodiment, the constant region of the IgGl comprises a methionine (M) to tyrosine (Y) substitution in position 252, a serine (S) to threonine (T) substitution in position 254, and a threonine (T) to glutamic acid (E) substitution in position 256, numbered according to the EU index as in Kabat. See U.S. Pat. No. 7,658,921, which is incorporated herein by reference. This type of mutant IgG, referred to as “YTE mutant” has been shown to display fourfold increased half-life as compared to wild-type versions of the same antibody (see Dall'Acqua W F et al., (2006) J Biol Chem 281 : 23514-24). In certain embodiments, an ADC comprises an IgG constant domain comprising one, two, three or more amino acid substitutions of amino acid residues at positions 251-257, 285-290, 308- 314, 385-389, and 428-436, numbered according to the EU index as in Kabat.

[0157] In a further embodiment, one, two, or more amino acid substitutions are introduced into an IgG constant domain Fc region to alter the effector function(s) of the ADC. For example, one or more amino acids selected from amino acid residues 234, 235, 236, 237, 297, 318, 320 and 322, numbered according to the EU index as in Kabat, can be replaced with a different amino acid residue such that the ADC has an altered affinity for an effector ligand but retains the antigen-binding ability of the parent antibody. The effector ligand to which affinity is altered can be, for example, an Fc receptor or the Cl component ofcomplement. This approach is described in further detail in U.S. Pat. Nos. 5,624,821 and 5,648,260. In some embodiments, the deletion or inactivation (through point mutations or other means) of a constant region domain may reduce Fc receptor binding of the circulating ADC thereby increasing tumor localization. See, e.g., U.S. Pat. Nos. 5,585,097 and 8,591,886 for a description of mutations that delete or inactivate the constant domain and thereby increase tumor localization. In certain embodiments, one or more amino acid substitutions can be introduced into the Fc region to remove potential glycosylation sites on Fc region, which may reduce Fc receptor binding (see, e.g., Shields R L et al., (2001) J Biol Chem 276: 6591-604).

[0158] In certain embodiments, one or more amino acids selected from amino acid residues 329, 331, and 322 in the constant region, numbered according to the EU index as in Kabat, can be replaced with a different amino acid residue such that the ADC has altered Clq binding and / or reduced or abolished complement dependent cytotoxicity (CDC). This approach is described in further detail in U.S. Pat. No. 6,194,551 (Idusogie et al). In some embodiments, one or more amino acid residues within amino acid positions 231 to 238 in the N-terminal region of the CH2 domain are altered to thereby alter the ability of the antibody to fix complement. This approach is described further in International Publication No. WO 94 / 29351. In certain embodiments, the Fc region is modified to increase the ability of the ADC to mediate antibody dependent cellular cytotoxicity (ADCC) and / or to increase the affinity of the ADC for an Fey receptor by mutating one or more amino acids (e.g., introducing amino acid substitutions) at the following positions: 238, 239, 248, 249, 252, 254, 255, 256, 258, 265, 267, 268, 269, 270, 272, 276, 278, 280, 283, 285, 286, 289, 290,292, 293, 294, 295, 296, 298, 301, 303, 305, 307, 309, 312, 315, 320, 322, 324, 326, 327,328, 329, 330, 331, 333, 334, 335, 337, 338, 340, 360, 373, 376, 378, 382, 388, 389, 398,414, 416, 419, 430, 434, 435, 437, 438, or 439, numbered according to the EU index as inKabat. This approach is described further in International Publication No. WO 00 / 42072.

[0159] In certain embodiments, an ADC described herein comprises the constant domain of an IgGl with a mutation (e.g., substitution) at position 267, 328, or a combination thereof, numbered according to the EU index as in Kabat. In certain embodiments, an ADC described herein comprises the constant domain of an IgGl with a mutation (e.g., substitution) selected from the group consisting of S267E, L328F, and a combination thereof. In certain embodiments, an ADC described herein comprises the constant domain of an IgGl with a S267E / L328F mutation (e.g., substitution). In certain embodiments, an ADC described hereincomprising the constant domain of an IgGl with a S267E / L328F mutation (e.g., substitution) has an increased binding affinity for FcyRIIA, FcyRIIB, or FcyRIIA and FcyRIIB.

[0160] In specific embodiments, an ADC (i) comprises the CDR sequences of B7H41001 mAh (e.g., the amino acid sequences of SEQ ID NOs:5-10), the VH and VL sequences of 20502 (the amino acid sequences of SEQ ID NOs: 11 and 12, respectively), or the heavy and light chain sequences of 20502 (the amino acid sequences of SEQ ID NOs: 13 and 14, respectively) and (ii) is fucosylated.

[0161] The amino acid sequence of the heavy chain variable region of SGN-B7H4V is provided herein as SEQ ID NO: 11. The amino acid sequence of the light chain variable region of SGN-B7H4V is provided herein as SEQ ID NO: 12.

[0162] In certain embodiments, antibodies (e.g., anti-B7-H4 antibodies) can be conjugated to a drug to form antibody-drug conjugates (ADCs). An exemplary anti-B7-H4- ADC is SGN-B7H4V. An exemplary antibody comprised within the anti-B7-H4-ADC is B7H41001 mAh.

[0163] In certain embodiments, an antibody can be conjugated to a drug to form an antibody-drug conjugate (ADC) and may have a ratio of drug moieties per antibody of about 1 to about 8. In certain embodiments, an antibody (e.g., anti-B7-H4 antibody) can be conjugated to a drug to form an ADC and may have a ratio of drug moieties per antibody of about 2 to about 5. In some embodiments, the ratio of drug moieties per antibody is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In certain exemplary embodiments, an anti-B7-H4 antibody can be conjugated to a drug to form an ADC and have a ratio of drug moieties per antibody of about 4. In some embodiments, the average number of drug moieties per antibody in a population of antibody-drug conjugates is about 1 to about 8. In some embodiments, the average number of drug moieties per antibody in a population of antibody-drug conjugates is about 4.Methods of determining the ratio of drug moieties per antibody of an ADC are readily known to those skilled in the art.

[0164] According to certain exemplary embodiments, a B7-H4-ADC comprises monomethyl auristatin E (MMAE) (PubChem CID: 53297465):MMAE

[0165] According to certain exemplary embodiments, a B7-H4-ADC comprises vcMMAE conjugated thereto. vcMMAE is a drug-linker conjugate for ADC with potent anti-tumor activity comprising the anti-mitotic agent, MMAE, linked via the lysosomally cleavable dipeptide valine-citrulline (vc):vcMMAE.

[0166] vcMMAE may also be referred to as MC-Val-Cit-PABC-MMAE, where MC refers to a maleimidocaproyl group, Val-Cit refers to the dipeptide valine-citrulline, PABC refers to a para-aminobenzylcarbamate group, and MMAE refers to the drug monomethyl auristatin E.

[0167] The structure of a vcMMAE-antibody conjugate (e.g., a B7-H4-ADC) according to certain exemplary embodiments is set forth below. In this structure, the drug-linker portion shown within the parentheses may be referred to in some instances as vedotin. The drug-linker may be attached to the antibody via a sulfur atom of a cysteine residue of the antibody. In some embodiments, the ADC shown below is formed by reaction of the maleimide group of the vc-MMAE drug-linker precursor with a thiol of a cysteine residue of the antibody to form a succinamide bonded to the sulfur atom of the cysteine residue.

[0168] In some embodiments, the succinamide moiety of the ADC may undergo a ringopening hydrolysis to form one of the ring-opened structures shown below.

[0169] According to certain exemplary embodiments, a vcMMAE-antibody conjugate (e.g., a B7-H4-ADC) is provided as set forth above, wherein Ab may include an anti-B7-H4 antibody (e.g., B7H41001 mAb), and wherein p may be any integer from about 1 to about 8. In some embodiments, a vcMMAE-antibody conjugate (e.g., a B7-H4-ADC) is provided asset forth above, wherein Ab may include an anti-B7-H4 antibody (e.g., B7H41001 mAb), and wherein p is 1, representing a vcMMAE to antibody ratio of 1. In some embodiments, a vcMMAE-antibody conjugate (e.g., a B7-H4-ADC) is provided as set forth above, wherein Ab may include an anti-B7-H4 antibody (e.g., B7H41001 mAb), and wherein p is 2, 3, 4, 5, 6, 7, 8, 9, or 10, representing a vcMMAE to antibody ratio (also known as a “Drug-to- Antibody Ratio” or “DAR”) of 2, 3, 4, 5, 6, 7, 8, 9, or 10, respectively. Accordingly, in some embodiments, a vcMMAE-antibody conjugate (e.g., a B7-H4-ADC) is provided as set forth above, wherein a vcMMAE to antibody ratio is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In certain exemplary embodiments, a vcMMAE-antibody conjugate (e.g., a B7-H4-ADC) is provided as set forth above, wherein Ab may include an anti-B7-H4 antibody (e.g., B7H41001 mAb), and wherein p is 4, representing a vcMMAE to antibody ratio of 4. Accordingly, in certain exemplary embodiments, a vcMMAE-antibody conjugate (e.g., a B7-H4-ADC) is provided as set forth above, wherein a vcMMAE to antibody ratio is 4.

[0170] SGN-B7H4V can be administered to individuals at a level that inhibits cancer cell growth, while at the same time is tolerated by the individual.

[0171] In certain exemplary embodiments, an anti-B7-H4 antibody comprises CDRs from an HCVR set forth as SEQ ID NO: 11 and / or CDRs from an LCVR set forth as SEQ ID NO: 12. In certain exemplary embodiments, an anti-B7-H4 antibody comprises an HCVR set forth as SEQ ID NO: 11 and / or an LCVR set forth as SEQ ID NO: 12. In other embodiments, an anti-B7-H4 antibody comprises an HCVR / LCVR pair SEQ ID NO: 11 / SEQ ID NO: 12. In other embodiments, an anti-B7-H4 antibody comprises an HCVR that has at least about 80% homology or identity (e.g., 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) to SEQ ID NO: 11 and / or comprises an LCVR that has at least about 80% homology or identity (e.g., 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) to SEQ ID NO: 12.

[0172] Antibody-drug conjugates described herein (e.g., anti-B7-H4 antibodies or B7- H4-ADCs) can be expressed in a modified form. For instance, a region of additional amino acids, particularly charged amino acids, can be added to the N-terminus of an antibody-drug conjugates (e.g., a B7-H4-ADC) to improve stability and persistence in the host cell, during purification, or during subsequent handling and storage. Also, peptide moieties can be added to an antibody-drug conjugates (e.g., a B7-H4-ADC) of the present invention to facilitate purification. Such regions can be removed prior to final preparation of an antibody molecule or at least one fragment thereof. Such methods are described in many standard laboratorymanuals, such as Sambrook, supra; Ausubel, et al., ed., Current Protocols In Molecular Biology, John Wiley & Sons, Inc., NY, N.Y. (1987-2001).

[0173] The antibody-drug conjugates (e.g., anti-B7-H4 antibodies or B7-H4-ADCs) described herein typically bind the target antigen (e.g., B7-H4) with an equilibrium binding constant of about I pM, e.g., about ^100 nM, about ^10 nM, or about I nM, as measured using standard binding assays, for example, a Biacore-based binding assay.

[0174] In some embodiments, the antibody-drug conjugate (such as B7-H4-ADC) increases T cell proliferation. In some embodiments, the antibody-drug conjugate (such as B7-H4-ADC) increases IFNy production. In some embodiments, the antibody-drug conjugate (such as B7-H4-ADC) mediates ADCC activity against B7-H4-expressing cells. In some embodiments, the antibody-drug conjugate (such as B7-H4-ADC) mediates ADCC activity against B7-H4-expressing cells. In some embodiments, the antibody-drug conjugate (such as B7-H4-ADC) thereof does not mediate CDC activity against B7-H4-expressing cells

[0175] In some embodiments, the increase in T cell proliferation induced by the antibody-drug conjugate comprising an anti-B7-H4 antibody differ from that induced by the antibody B7-H4 antibody by no more than 1%, 5%, 10%, 15%, 20%, 25%, or 30%. In some embodiments, the increase in IFNy production induced by the antibody-drug conjugate comprising an anti-B7-H4 antibody differ from that induced by the antibody B7-H4 antibody by no more than any one of 1%, 5%, 10%, 15%, 20%, 25%, 30%, or 50%. In some embodiments, the increase in ADCC activity mediated by the antibody-drug conjugate comprising an anti-B7-H4 antibody differ from that mediated by the antibody B7-H4 antibody by no more than any one of 1%, 5%, 10%, 15%, 20%, 25%, 30%, or 50%. In some embodiments, the increase in ADCP activity mediated by the antibody-drug conjugate comprising an anti-B7-H4 antibody differ from that mediated by the antibody B7-H4 antibody by no more than any one of 1%, 5%, 10%, 15%, 20%, 25%, 30%, or 50%.III. Therapeutic Applications

[0176] The invention provides methods of treating disorders associated with cells that express B7-H4, e.g., cancers. In one aspect, the invention provides the use of human anti-B7- H4 antibody-drug conjugates thereof (e.g., B7-H4-antibody-drug conjugates (B7-H4-ADCs)) for the treatment of cancers (e.g., breast cancer, ovarian cancer, primary peritoneal cancer, fallopian tube cancer, endometrial carcinoma, lung cancer, cholangiocarcinoma, gallbladdercarcinoma, or head and neck carcinoma). In one aspect, the invention provides the use of human anti-B7-H4 antibody conjugates thereof (e.g., B7-H4-antibody-drug conjugates (B7- H4-ADCs)) for the treatment of cancers (e.g., breast cancer, ovarian cancer, primary peritoneal cancer, fallopian tube cancer, endometrial carcinoma, lung cancer, cholangiocarcinoma, gallbladder carcinoma, or head and neck carcinoma). In one aspect, the invention provides the use of human anti-B7-H4 antibody-drug conjugates thereof (e.g., B7- H4-ADCs) for the treatment of cancers (e.g, breast cancer, ovarian cancer, primary peritoneal cancer, fallopian tube cancer, endometrial carcinoma, lung cancer, cholangiocarcinoma, gallbladder carcinoma, or head and neck carcinoma). In some embodiments, the cancer is an adenoid cystic carcinoma. In some embodiments, the adenoid cystic carcinoma is an adenoid cystic carcinoma of the head and neck. In some embodiments, the adenoid cystic carcinoma of the head and neck is an adenoid cystic carcinoma of the salivary glands. In some embodiments, the adenoid cystic carcinoma is an adenoid cystic carcinoma of the ovary. In some embodiments, the adenoid cystic carcinoma is an adenoid cystic carcinoma of the prostate. In some embodiments, the adenoid cystic carcinoma is an adenoid cystic carcinoma of the breast. In some embodiments, the adenoid cystic carcinoma is an adenoid cystic carcinoma of the skin. In some embodiments, the adenoid cystic carcinoma is an adenoid cystic carcinoma of the cervix. In one preferred embodiment, the invention provides the use of human anti-B7-H4 antibody-drug conjugates thereof (e.g., B7- H4-ADCs) for the treatment of cancers (e.g, breast cancer, ovarian cancer, primary peritoneal cancer, fallopian tube cancer, endometrial carcinoma, lung cancer, cholangiocarcinoma, gallbladder carcinoma, or head and neck carcinoma). In some embodiments, provided is a composition comprising any one of the human anti-B7-H4 antibody-drug conjugates thereof (e.g., B7-H4-ADCs) described herein. In some embodiments, provided is a composition comprising any one of the human anti-B7-H4 antibody-drug conjugates thereof (e.g., B7-H4-ADCs) described herein for use in treatment of a cancer (e.g, breast cancer, ovarian cancer, primary peritoneal cancer, fallopian tube cancer, endometrial carcinoma, lung cancer, cholangiocarcinoma, gallbladder carcinoma, or head and neck carcinoma). In some embodiments, provided is a composition comprising the human anti-B7-H4 antibody-drug conjugates thereof (e.g., B7-H4-ADCs) described herein for use in treatment of a cancer (e.g, breast cancer, ovarian cancer, primary peritoneal cancer, fallopian tube cancer, endometrial carcinoma, lung cancer, cholangiocarcinoma, gallbladder carcinoma, or head and neck carcinoma). In some embodiments, provided are uses of a composition comprising the human anti-B7-H4 antibody-drug conjugates thereof (e.g., B7-H4-ADCs) described herein in the manufacture of a medicament for treatment of a cancer (e.g, breast cancer, ovarian cancer, primary peritoneal cancer, fallopian tube cancer, endometrial carcinoma, lung cancer, cholangiocarcinoma, gallbladder carcinoma, or head and neck carcinoma).

[0177] In certain exemplary embodiments, the present invention provides a method for treating cancer in a cell, tissue, organ, animal or individual. In certain exemplary embodiments, the present invention provides a method for treating solid tumors, such as, e.g., breast cancer, ovarian cancer, primary peritoneal cancer, fallopian tube cancer, endometrial carcinoma, lung cancer, cholangiocarcinoma, gallbladder carcinoma, or head and neck carcinoma. In a particular exemplary embodiment, the breast cancer, ovarian cancer, lung cancer, cholangiocarcinoma and endometrial cancer is locally advance or metastatic. In certain exemplary embodiments, the present invention provides a method for treating solid tumors, such as, e.g., peritoneal cancer, fallopian tube cancer, or gallbladder cancer. In some embodiments, the individual has an adenoid cystic carcinoma. In some embodiments, the individual has an adenoid cystic carcinoma of the head and neck. In some embodiments, the individual has an adenoid cystic carcinoma of the salivary glands. In some embodiments, the individual has an adenoid cystic carcinoma of the ovary. In some embodiments, the individual has an adenoid cystic carcinoma of the prostate. In some embodiments, the individual has an adenoid cystic carcinoma of the breast. In some embodiments, the individual has an adenoid cystic carcinoma of the skin. In some embodiments, the individual has an adenoid cystic carcinoma of the cervix. In certain exemplary embodiments, the present invention provides a method for treating solid tumors, such as, e.g., ovarian neoplasms, peritoneal neoplasms, fallopian tube neoplasms, HER2 negative breast neoplasms, HER2 positive breast neoplasms, triple negative breast neoplasms, endometrial neoplasms, nonsmall-cell lung carcinoma, cholangiocarcinoma or gallbladder carcinoma.

[0178] In some embodiments, the individual has been previously treated for breast cancer, or ovarian cancer. In some embodiments, the individual did not respond to the treatment (e.g, the individual experienced disease progression during treatment). In some embodiments, the individual relapsed after the treatment. In some embodiments, the individual experienced disease progression after the treatment. In some embodiments, the treatment previously administered to the individual was not an agent targeting B7-H4.

[0179] In some embodiments, the method provided herein comprises detecting levels of B7-H4 in cancers and administering the B7-H4-ADC to treat the cancer. Certain breastcancer, ovarian cancer, lung cancer, cholangiocarcinoma and endometrial cancer show detectable levels of B7-H4 measured at either the protein (e.g., by immunoassay using one of the exemplified antibodies) or the mRNA level. In certain embodiments, a breast cancer, ovarian cancer, lung cancer, cholangiocarcinoma, endometrial cancer, or head and neck carcinoma shows elevated levels of B7-H4 relative to non-cancerous tissue or cells of the same type, e.g., breast, ovarian, lung, bile duct, endometrium cells, and cells from the head and neck from the same patient. In other embodiments, a breast cancer, ovarian cancer, lung cancer, cholangiocarcinoma or endometrial cancer shows similar levels of B7-H4 relative to non-cancerous breast, ovarian, lung, bile duct and endometrium cells of the same type, e.g., from the same patient.

[0180] Certain peritoneal cancer, fallopian tube cancer, and gallbladder cancer show detectable levels of B7-H4 measured at either the protein (e.g., by immunoassay using one of the exemplified antibodies) or the mRNA level. In certain embodiments, a peritoneal cancer, fallopian tube cancer, or gallbladder cancer shows elevated levels of B7-H4 relative to non- cancerous tissue or cells of the same type, e.g., peritoneum, fallopian tube, or gall bladder cells, respectively, from the same patient. In other embodiments, a peritoneal cancer, fallopian tube cancer, or gallbladder cancer shows similar levels of B7-H4 relative to e.g., non-cancerous peritoneum, fallopian tube, or gall bladder cells of the same type, from the same patient.

[0181] In some embodiments, B7-H4 protein is highly expressed on breast cancer, ovarian cancer, lung cancer, cholangiocarcinoma and endometrial cancer that are amenable to treatment, although cancers associated with higher or lower levels of B7-H4 expression can also be treated. Optionally, B7-H4 levels (e.g., B7-H4 protein levels) in a breast cancer, ovarian cancer, lung cancer, cholangiocarcinoma, endometrial cancer, and head and neck carcinoma from an individual are measured before performing treatment. In some embodiments, at least about 0.1%, at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, or at least about 80% of the cancer cells express B7-H4. In some embodiments, expression of B7-H4 is low or absent on myeloid immune cell subsets, including monocytes, macrophages, and dendritic cells. In some embodiments, expression of B7-H4 is low or absent in CD163+ macrophages.

[0182] In some embodiments, B7-H4 protein is highly expressed on adenoid cystic carcinoma. (Panaccione et al. Clinical Breast Cancer 2017). In some embodiments, at least about 0.1%, at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, or at least about 80% of the cancer cells express B7-H4.

[0183] In some embodiments, the cancer cell expresses B7-H4. In some embodiments, the cancer cell does not express B7-H4. In some embodiments, the cancer cell expresses a higher level of B7-H4 than a non-diseased cell of the same cell type. In some embodiments, the cancer cell expresses a comparable or lower level of B7-H4 than a non-diseased cell of the same cell type.A. Lung Cancer

[0184] Lung cancer remains the leading cause of death from cancer in the United States, with over 155,000 deaths estimated in 2017. Treatments with curative intent for patients with early stage disease include surgery, chemotherapy, radiation therapy, or a combined modality approach. However, a majority of patients are diagnosed with advanced stage disease, which is usually incurable. Non-small cell lung cancer (NSCLC) represents up to 80% of all lung cancers. Within the subtypes of NSCLC, squamous cell carcinoma (SCC / NSCLC) represents approximately 30% of NSCLC. Systemic therapies used in the metastatic setting for SCC / NSCLC have shown limited benefit and are primarily aimed at prolonging survival and maintaining the quality of life for as long as possible, while minimizing side effects due to treatment. First line treatment for patients with SCC / NSCLC whose tumors do not express high levels of PD-L1 include a platinum-based chemotherapy doublet that does not contain pemetrexed, anti-VEGF antibody, or an anti-EGFR antibody necitumumab in combination with gemcitabine and cisplatin. Patients with at least 50% tumor cell staining for PD-L1 are offered first-line treatment with the anti-PD-1 inhibitor pembrolizumab. Patients who progress on an initial combination chemotherapy regimen may receive an anti-PD-1 or PD- L1 antibody, and combination chemotherapy is considered for patients whose disease has progressed after receiving PD-1 / L1 inhibitors. New classes of therapy are urgently needed that can provide meaningful benefit to SCC / NSCLC patients.

[0185] The invention provides method for treating lung cancer with an anti-B7-H4 antibody-drug conjugate (e.g., a B7-H4-ADC) described herein. In one aspect, the anti-B7- H4 antibody-drug conjugate (e.g., a B7-H4-ADC) described herein are for use in a method of treating lung cancer in an individual. The invention also provides methods for treating lung cancer with an anti-B7-H4 antibody-drug conjugate (e.g., a B7-H4-ADC) described herein in combination with an immune checkpoint inhibitor. In one aspect, the anti-B7-H4 antibodydrug conjugate (e.g., a B7-H4-ADC) described herein is for use in combination with an immune checkpoint inhibitor in a method of treating lung cancer in an individual. In some embodiments, provided are methods for treating lung cancer with an anti-B7-H4 antibodydrug conjugate (e.g., a B7-H4-ADC) described herein in combination with a PD-1 inhibitor (e.g. an anti-PD-1 antibody). In one aspect, the anti-B7-H4 antibody-drug conjugate (e.g., a B7-H4-ADC) described herein is for use in combination with a PD-1 inhibitor (e.g. an anti- PD-1 antibody) in a method of treating lung cancer in an individual. In some embodiments, the anti-PD-1 antibody is Keytruda®. In some embodiments, the lung cancer is small cell lung cancer. In some of the embodiments herein, the lung cancer is non-squamous cell carcinoma. In some of the embodiments herein, the lung cancer is squamous cell carcinoma. In some of the embodiments herein, the lung cancer is lung adenocarcinoma. In some embodiments, the lung cancer cell expresses B7-H4. In some embodiments, the lung cancer cell does not express B7-H4. In some embodiments, the lung cancer cell expresses a higher level of B7- H4 than a non-diseased cell of the same cell type. In some embodiments, the lung cancer cell expresses a comparable or lower level of B7-H4 than anon-diseased cell of the same cell type.B. Breast Cancer

[0186] Breast cancers are classified on the basis of three protein expression markers: estrogen receptor (ER), progesterone receptor (PgR), and the overexpression of the growth factor receptor HER2 / neu. Hormonal therapies, including tamoxifen and aromatase inhibitors, can be effective in treating tumors that express the hormone receptors ER and PgR. HER2-directed therapies are useful for tumors that express HER2 / neu; these tumors are the only class of breast cancer that is currently eligible for immunotherapy. For these patients, unconjugated antibodies, such as Herceptin or Peijeta, are generally used in combination with chemotherapy.

[0187] The invention provides methods of treating cancers, such as breast cancer, with antibody-drug conjugates. In some embodiments, the invention provides methods of treating cancers, such as breast cancer, with antibody-drug conjugates. In some embodiments, the antibody-drug conjugate comprises an antibody conjugated to an auristatin. In some embodiments, the auristatin is a monomethyl auristatin. In some embodiments, the monomethyl auristatin is monomethyl auristatin E. In one aspect, the invention provides methods of treating disorders associated with cells that express B7-H4, e.g., cancers (e.g., breast cancers such as locally advanced breast cancer or metastatic breast cancer). As a result, the invention provides a method of treating an individual, for example, an individual with breast cancer, using the anti-B7-H4 antibody-drug conjugates described herein. The method comprises administering an effective amount of an anti-B7-H4 antibody-drug conjugate (e.g., a B7-H4-ADC) to an individual in need thereof. In some embodiments, the cancer is an advanced stage cancer. In some embodiments, the advanced stage cancer is metastatic cancer. In some embodiments, the cancer is unresectable. In some embodiments, the cancer is locally advanced. In some embodiments, the cancer is recurrent cancer. In some embodiments, the individual received prior treatment with standard of care therapy for the cancer and failed the prior treatment. In some embodiments, the individual has been previously treated with one or more therapeutic agents and did not respond to the treatment, wherein the one or more therapeutic agents is not an antibody-drug conjugate (e.g., B7-H4- ADC). In some embodiments, the individual has been previously treated with one or more therapeutic agents and relapsed after the treatment, wherein the one or more therapeutic agents is not an antibody-drug conjugate (e.g., B7-H4-ADC). In some embodiments, the individual has been previously treated with one or more therapeutic agents and has experienced disease progression during treatment, wherein the one or more therapeutic agents is an antibody-drug conjugate (e.g., B7-H4-ADC). In some embodiments, the individual is a human.

[0188] The invention provides methods for treating breast cancer with an anti-B7-H4 antibody-drug conjugate (e.g., a B7-H4-ADC) described herein. In one aspect, the anti-B7- H4 antibody-drug conjugate (e.g., a B7-H4-ADC) described herein is for use in a method of treating breast cancer in an individual. The invention also provides methods for treating breast cancer with an anti-B7-H4 or antibody-drug conjugate (e.g., a B7-H4-ADC) described herein in combination with an immune checkpoint inhibitor. In one aspect, the anti-B7-H4 antibody-drug conjugate (e.g., a B7-H4-ADC) described herein is for use in combination withan immune checkpoint inhibitor in a method of treating breast cancer in an individual. In some embodiments, provided are methods for treating breast cancer with an anti-B7-H4 antibody-drug conjugate (e.g., a B7-H4-ADC) described herein in combination with a PD-1 inhibitor (e.g. an anti-PD-1 antibody). In one aspect, the anti-B7-H4 antibody-drug conjugate (e.g., a B7-H4-ADC) described herein is for use in combination with a PD-1 inhibitor (e.g. an anti-PD-1 antibody) in a method of treating breast cancer in an individual. In some embodiments, the anti-PD-1 antibody is Keytruda®.

[0189] Exemplary breast cancers are those that express B7-H4 in a cell expressing the cancer (i.e., B7-H4-expressing cancers). In certain exemplary embodiments, a breast cancer is selected from the group consisting of carcinomas, sarcomas, phyllodes, Paget disease, and angiosarcomas. The breast cancer may be in situ (e.g., ductal carcinoma in situ (DCIS), lobular carcinoma in situ (LCIS) and the like) or invasive / infiltrating (e.g., invasive ductal carcinoma (IDC), invasive lobular carcinoma (ILC), inflammatory breast cancer (IBC) and the like).

[0190] In some embodiments, the individual has breast cancer. In some embodiments, the individual has an estrogen receptor positive (ER+) breast cancer. In some embodiments, the individual has an estrogen receptor positive (ER-) breast cancer. In some embodiments, the individual has a progesterone receptor positive (PR+) breast cancer. In some embodiments, the individual has a progesterone receptor negative (PR-) breast cancer. In some embodiments, the individual has a hormone receptor positive (HR+) breast cancer. In some embodiments, the individual has a hormone receptor negative (HR-) breast cancer. In some embodiments, the induvial has a HER2 gene overexpressing (HER2+) breast cancer. In some embodiments, the individual has a HER2 gene wild-type breast cancer. In some embodiments, the individual has a HER2 gene under-expressing (HER2-) breast cancer. In some embodiments, the individual has a group 1 (luminal A), i.e., ER+ / PR+ / HER2-, breast cancer. In some embodiments, the individual has a group 2 (luminal B), i.e., ER+ / PR- / HER2+, breast cancer. In some embodiments, the individual has a group 3 (HER2+), i.e., ER- / PR- / HER2+, breast cancer. In some embodiments, the individual is a group 4 (basal-like or triple negative (TN)), i.e., ER- / PR- / HER2-, breast cancer.

[0191] A breast cancer can further be categorized as grade 1, 2 or 3. Grade 1 or well- differentiated (score 3, 4, or 5) breast cancer comprises cells that are slower-growing, and look more like normal breast tissue than the higher grades of breast cancer. Grade 2 or moderately differentiated (score 6, 7) breast cancer has cells that grow at a speed of and looklike cells somewhere between grades 1 and 3. Grade 3 or poorly differentiated (score 8, 9) breast cancer has cells that look very different from normal cells and typically grow and spread faster than grades 1 or 2.

[0192] In certain exemplary embodiments, a breast cancer is an incurable, unresectable, locally advanced or metastatic breast cancer (LA / MBC). In certain embodiments, a breast cancer is either a triple negative (TN) (ER- / PR- / HER2-) breast cancer, an ER- and / or PR+ / HER2- breast cancer, and an LA / MBC breast cancer. In certain exemplary embodiments, the breast cancer is HER2+ and LA / MBC. In certain exemplary embodiments, a breast cancer is TN and LA / MBC. In certain exemplary embodiments, a breast cancer is selected from the group consisting of a TN breast cancer, a metastatic breast cancer, and a metastatic, TN breast cancer. In some embodiments, the breast cancer is a TN breast cancer. In some embodiments, the breast cancer is a HER2 negative breast neoplasm. In some embodiments, the breast cancer is a HER2 positive breast neoplasm. In some embodiments, the breast cancer is a triple negative breast neoplasm.

[0193] In some embodiments, the breast cancer cell expresses B7-H4. In some embodiments, the breast cancer cell does not express B7-H4. In some embodiments, the breast cancer cell expresses a higher level of B7-H4 than a non-diseased cell of the same cell type. In some embodiments, the breast cancer cell expresses a comparable or lower level of B7-H4 than a non-diseased cell of the same cell type.C. Ovarian Cancer

[0194] The invention provides methods of treating cancers, such as ovarian cancer, with antibody-drug conjugates. In some embodiments, the invention provides methods of treating cancers, such as ovarian cancer, with antibody-drug conjugates. In some embodiments, the antibody-drug conjugate comprises an antibody conjugated to an auristatin. In some embodiments, the auristatin is a monomethyl auristatin. In some embodiments, the monomethyl auristatin is monomethyl auristatin E. In one aspect, the invention provides methods of treating disorders associated with cells that express B7-H4, e.g., cancers (e.g., ovarian cancers such as locally advanced ovarian cancer or metastatic ovarian cancer). As a result, the invention provides a method of treating an individual, for example, an individual with ovarian cancer, using the anti-B7-H4 antibody-drug conjugates described herein. The method comprises administering an effective amount of an anti-B7-H4 antibody-drug conjugate (e.g., a B7-H4-ADC) to an individual in need thereof. In some embodiments, thecancer is an advanced stage cancer. In some embodiments, the advanced stage cancer is metastatic cancer. In some embodiments, the cancer is unresectable. In some embodiments, the cancer is locally advanced. In some embodiments, the cancer is recurrent cancer. In some embodiments, the individual received prior treatment with standard of care therapy for the cancer and failed the prior treatment. In some embodiments, the individual has been previously treated with one or more therapeutic agents and did not respond to the treatment, wherein the one or more therapeutic agents is not an antibody-drug conjugate (e.g., B7-H4- ADC). In some embodiments, the individual has been previously treated with one or more therapeutic agents and relapsed after the treatment, wherein the one or more therapeutic agents is not an antibody-drug conjugate (e.g., B7-H4-ADC). In some embodiments, the individual has been previously treated with one or more therapeutic agents and has experienced disease progression during treatment, wherein the one or more therapeutic agents is an antibody-drug conjugate (e.g., B7-H4-ADC). In some embodiments, the individual is a human.

[0195] Exemplary ovarian cancers are those that express B7-H4 in a cell expressing the cancer (i.e., B7-H4-expressing cancers). In certain exemplary embodiments, an ovarian cancer is selected from the group consisting of carcinomas, sarcomas, phyllodes, Paget disease, and angiosarcomas. In some embodiments, the ovarian cancer is an ovarian neoplasm. The ovarian cancer may be in situ or invasive / infiltrating.

[0196] The invention provides methods for treating ovarian cancer with an anti-B7-H4 antibody-drug conjugate (e.g., a B7-H4-ADC) described herein. In one aspect, the anti-B7- H4 antibody-drug conjugate (e.g., a B7-H4-ADC) described herein is for use in a method of treating ovarian cancer in an individual. The invention also provides methods for treating ovarian cancer with an anti-B7-H4 antibody-drug conjugate (e.g., a B7-H4-ADC) described herein in combination with an immune checkpoint inhibitor. In one aspect, the anti-B7-H4 antibody-drug conjugate (e.g., a B7-H4-ADC) described herein is for use in combination with an immune checkpoint inhibitor in a method of treating ovarian cancer in an individual. The invention also provides methods for treating ovarian cancer with an anti-B7-H4 antibodydrug conjugate (e.g., a B7-H4-ADC) described herein in combination with a PD-1 inhibitor (e.g. an anti-PD-1 antibody). In one aspect, the anti-B7-H4 antibody-drug conjugate (e.g., a B7-H4-ADC) described herein is for use in combination with a PD-1 inhibitor (e.g. an anti- PD-1 antibody) in a method of treating ovarian cancer in an individual. In some embodiments, the anti-PD-1 antibody is Keytruda®.

[0197] An ovarian cancer can further be categorized as grade 1, 2 or 3. Grade 1 or well- differentiated (score 3, 4, or 5) ovarian cancer comprises cells that are slower-growing, and look more like normal ovarian tissue than the higher grades of ovarian cancer. Grade 2 or moderately differentiated (score 6, 7) ovarian cancer has cells that grow at a speed of and look like cells somewhere between grades 1 and 3. Grade 3 or poorly differentiated (score 8, 9) ovarian cancer has cells that look very different from normal cells and typically grow and spread faster than grades 1 or 2.

[0198] In certain exemplary embodiments, an ovarian cancer is an incurable, unresectable, locally advanced or metastatic ovarian cancer. In some embodiments, the ovarian cancer is Ovarian Serous Cystadenocarcinoma (OV). In some embodiments, the ovarian cancer is a high-grade serous epithelial ovarian cancer.

[0199] In some embodiments, the ovarian cell expresses B7-H4. In some embodiments, the ovarian cancer cell does not express B7-H4. In some embodiments, the ovarian cancer cell expresses a higher level of B7-H4 than a non-diseased cell of the same cell type. In some embodiments, the ovarian cancer cell expresses a comparable or lower level of B7-H4 than a non-diseased cell.

[0200] In some embodiments, provided is an anti-B7-H4 antibody-drug conjugate described herein (e.g., a B7-H4-ADC) for use in the treatment of a cancer (e.g, breast cancer, ovarian cancer, primary peritoneal cancer, fallopian tube cancer, endometrial carcinoma, lung cancer, cholangiocarcinoma, gallbladder carcinoma, or head and neck carcinoma). In some embodiments, provided is an anti-B7-H4 antibody-drug conjugate (e.g., a B7-H4-ADC) for use in the treatment of a cancer (e.g, breast cancer, ovarian cancer, primary peritoneal cancer, fallopian tube cancer, endometrial carcinoma, lung cancer, cholangiocarcinoma, gallbladder carcinoma, or head and neck carcinoma), wherein the anti-B7-H4 antibody-drug conjugate (e.g., a B7-H4-ADC) comprises an HCVR that has at least about 95% (such as 95%, 97%, 98%, 99%, or 100%) homology or identity to SEQ ID NO: 11 and / or comprises an LCVR that has at least about 95% (such as 95%, 97%, 98%, 99%, or 100%) homology or identity to SEQ ID NO: 12. In some embodiments, provided is B7-H4 antibody-drug conjugate (e.g., a B7-H4-ADC) for use in the treatment of a cancer (e.g, breast cancer, ovarian cancer, primary peritoneal cancer, fallopian tube cancer, endometrial carcinoma, lung cancer, cholangiocarcinoma, gallbladder carcinoma, or head and neck carcinoma), wherein the anti-B7-H4 antibody-drug conjugate (e.g., a B7-H4-ADC) comprises an HCVR that has at least about 95% (such as 95%, 97%, 98%, 99%, or 100%) homology or identity to SEQ IDNO: 11 and / or comprises an LCVR that has at least about 95% (such as 95%, 97%, 98%, 99%, or 100%) homology or identity to SEQ ID NO: 12, and wherein the antibody is conjugated to vcMMAE, wherein the vcMMAE has the structure:

[0201] In some embodiments, provided is the use of an anti-B7-H4 antibody-drug conjugate described herein (e.g., a B7-H4-ADC) for the treatment of a cancer (e.g., breast cancer, ovarian cancer, primary peritoneal cancer, fallopian tube cancer, endometrial carcinoma, lung cancer, cholangiocarcinoma, gallbladder carcinoma, or head and neck carcinoma). In some embodiments, provided is the use of an anti-B7-H4 antibody-drug conjugate (e.g., a B7-H4-ADC) for the treatment of a cancer (e.g., breast cancer, ovarian cancer, primary peritoneal cancer, fallopian tube cancer, endometrial carcinoma, lung cancer, cholangiocarcinoma, gallbladder carcinoma, or head and neck carcinoma), wherein the anti- B7-H4 antibody-drug conjugate (e.g., a B7-H4-ADC) comprises an HCVR that has at least about 95% (such as 95%, 97%, 98%, 99%, or 100%) homology or identity to SEQ ID NO: 11 and / or comprises an LCVR that has at least about 95% (such as 95%, 97%, 98%, 99%, or 100%) homology or identity to SEQ ID NO: 12. In some embodiments, provided is the use of a B7-H4 antibody-drug conjugate (e.g., a B7-H4-ADC) for the treatment of a cancer (e.g., breast cancer, ovarian cancer, primary peritoneal cancer, fallopian tube cancer, endometrial carcinoma, lung cancer, cholangiocarcinoma, gallbladder carcinoma, or head and neck carcinoma), wherein the anti-B7-H4 antibody-drug conjugate (e.g., a B7-H4-ADC) comprises an HCVR that has at least about 95% (such as 95%, 97%, 98%, 99%, or 100%) homology or identity to SEQ ID NO: 11 and / or comprises an LCVR that has at least about 95% (such as 95%, 97%, 98%, 99%, or 100%) homology or identity to SEQ ID NO: 12, and wherein the antibody is conjugated to vcMMAE, wherein the vcMMAE has the structure:

[0202] In some embodiments, provided is the use of an anti-B7-H4 antibody-drug conjugate described herein (e.g., a B7-H4-ADC) in the manufacture of a medicament for the treatment of a cancer (e.g., breast cancer, ovarian cancer, primary peritoneal cancer, fallopian tube cancer, endometrial carcinoma, lung cancer, cholangiocarcinoma, gallbladder carcinoma, or head and neck carcinoma). In some embodiments, provided is the use of an anti-B7-H4 antibody-drug conjugate (e.g., a B7-H4-ADC) in the manufacture of a medicament for the treatment of a cancer (e.g., breast cancer, ovarian cancer, primary peritoneal cancer, fallopian tube cancer, endometrial carcinoma, lung cancer, cholangiocarcinoma, gallbladder carcinoma, or head and neck carcinoma), wherein the anti- B7-H4 antibody-drug conjugate (e.g., a B7-H4-ADC) comprises an HCVR that has at least about 95% (such as 95%, 97%, 98%, 99%, or 100%) homology or identity to SEQ ID NO: 11 and / or comprises an LCVR that has at least about 95% (such as 95%, 97%, 98%, 99%, or 100%) homology or identity to SEQ ID NO: 12. In some embodiments, provided is the use of a B7-H4 antibody-drug conjugate (e.g., a B7-H4-ADC) in the manufacture of a medicament the treatment of a cancer (e.g., breast cancer, ovarian cancer, primary peritoneal cancer, fallopian tube cancer, endometrial carcinoma, lung cancer, cholangiocarcinoma, gallbladder carcinoma, or head and neck carcinoma), wherein the anti-B7-H4 antibody-drug conjugate (e.g., a B7-H4-ADC) comprises an HCVR that has at least about 95% (such as 95%, 97%, 98%, 99%, or 100%) homology or identity to SEQ ID NO: 11 and / or comprises an LCVR that has at least about 95% (such as 95%, 97%, 98%, 99%, or 100%) homology or identity to SEQ ID NO: 12, and wherein the antibody Is conjugated to vcMMAE, wherein the vcMMAE has the structure:

[0203] In some embodiments, the immune checkpoint inhibitor is targeted to PD-1 (i.e. a PD-1 inhibitor). In some embodiments, the PD-1 inhibitor is an anti-PD-1 antibody. In some embodiments, the anti-PD-1 antibody is an intact monoclonal antibody. In some embodiments, the immune checkpoint inhibitor is an anti-PD-1 antibody, such as one or more of: Nivolumab, Pembrolizumab, Cemiplimab, Dostarlimab, and Retifanlimab. In some embodiments, the anti-PD-1 antibody is Keytruda®.

[0204] In some embodiments, the cancer is breast cancer, ovarian cancer, lung cancer, cholangiocarcinoma, endometrial cancer, or head and neck carcinoma. In some embodiments, the cancer is peritoneal cancer, fallopian tube cancer, or gallbladder cancer. In one preferred embodiment, the cancer is selected from the group consisting of ovarian neoplasms, peritoneal neoplasms, fallopian tube neoplasms, HER2 negative breast neoplasms, HER2 positive breast neoplasms, triple negative breast neoplasms, endometrial neoplasms, non-small-cell lung carcinoma, cholangiocarcinoma and gallbladder carcinoma.

[0205] In some embodiments, the B7-H4-ADC is administered at a dose of about 0.75 mg / kg to about 2.4 mg / kg, according to the individual’s body weight. In some embodiments, the B7-H4-ADC is administered at a dose of 0.75 mg / kg to 2.4 mg / kg, according to the individual’s body weight. In some embodiments, the B7-H4-ADC is administered at a dose of about 0.75 mg / kg, about 1.0 mg / kg, about 1.25 mg / kg, about 1.5 mg / kg, about 1.75 mg / kg, about 2.0 mg / kg, about 2.25 mg / kg, or about 2.4 mg / kg, according to the individual’s body weight. In some embodiments, the B7-H4-ADC is administered at a dose of 0.75 mg / kg, 1.0 mg / kg, 1.25 mg / kg, 1.5 mg / kg, 1.75 mg / kg, 2.0 mg / kg, 2.25 mg / kg, or 2.4 mg / kg, according to the individual’s body weight. In some embodiments, the B7-H4-ADC is administeredonce. In some embodiments, the B7-H4-ADC is administered at multiple doses. In some embodiments, the B7-H4-ADC is administered once in athree-week period (Q3W). In some embodiments, the B7-H4-ADC is administered at a dose (e.g., single dose) of about 0.75 mg / kg to about 1.5 mg / kg, according to the Individual’s body weight. In some embodiments, the B7-H4-ADC is administered at a dose (e.g., single dose) of about 0.75 mg / kg, about 1.0 mg / kg, about 1.25 mg / kg, about 1.5 mg / kg, about 1.75 mg / kg, about 2.0 mg / kg, about 2.25 mg / kg, or about 2.4 mg / kg, according to the individual’s body weight. In some embodiments, the B7-H4-ADC is administered at a dose (e.g., single dose) of about 0.25 mg / kg / week to about 0.80 mg / kg / week, according to the individual’s body weight. In some embodiments, the B7-H4-ADC is administered at a dose (e.g., single dose) of about 0.25 mg / kg / week, about 0.33 mg / kg / week, about 0.42 mg / kg / week, about 0.50 mg / kg / week, about 0.58 mg / kg / week, about 0.67 mg / kg / week, 0.75 mg / kg / week, or about 0.80 mg / kg / week, according to the individual’s body weight. In some embodiments, the B7-H4-ADC is administered multiple times. In some embodiments, the B7-H4-ADC is administered twice in a three-week period (2Q3W). In some embodiments, the B7-H4-ADC is administered twice in a four-week period (2Q4W). In some embodiments, the B7-H4-ADC is administered three times in a four-week period (3Q4W). In some embodiments, the B7-H4-ADC is administered at multiple doses (e.g., 2Q3W, 2Q4W, or 3Q4W) of each of about any of 0.75 mg / kg, about 1.0 mg / kg, about 1.25 mg / kg, about 1.5 mg / kg, about 1.75 mg / kg, about 2.0 mg / kg, about 2.25 mg / kg, or about 2.4 mg / kg, according to the individual’s body weight. In some embodiments, the B7-H4- ADC is administered at multiple doses (e.g., 2Q3W, 2Q4W, or 3Q4W) of each of any of 0.75 mg / kg, 1.0 mg / kg, 1.25 mg / kg, 1.5 mg / kg, 1.75 mg / kg, 2.0 mg / kg, 2.25 mg / kg, or 2.4 mg / kg, according to the individual’s body weight. In some embodiments, the B7-H4-ADC is administered at a dose of about 0.38 mg / kg / week to about 1.80 mg / kg / week, according to the individual’s body weight. In some embodiments, the B7-H4-ADC is administered at a dose of about 0.50 mg / kg / week to about 1.60 mg / kg / week, according to the individual’s body weight. In some embodiments, the B7-H4-ADC is administered at a dose of about 0.50 mg / kg / week, about 0.67 mg / kg / week, about 0.83 mg / kg / week, about 1.00 mg / kg / week, about 1.17 mg / kg / week, about 1.33 mg / kg / week, about 1.50 mg / kg / week, or about 1.60 mg / kg / week, according to the individual’s body weight. In some embodiments, the B7-H4- ADC is administered at a dose of about 0.56 mg / kg / week to about 1.80 mg / kg / week, according to the individual’s body weight. In some embodiments, the B7-H4-ADC is administered at a dose of about 0.56 mg / kg / week, about 0.75 mg / kg / week, about 0.94 mg / kg / week, about 1.13 mg / kg / week, about 1.31 mg / kg / week, about 1.50 mg / kg / week, about1.69 mg / kg / week, or about 1.80 mg / kg / week, according to the individual’s body weight. In some embodiments, the B7-H4-ADC is administered at a dose of about 0.38 mg / kg / week to about 1.20 mg / kg / week, according to the individual’s body weight. In some embodiments, the B7-H4-ADC is administered at a dose of about 0.38 mg / kg / week, about 0.50 mg / kg / week, about 0.63 mg / kg / week, about 0.75 mg / kg / week, about 0.88 mg / kg / week, about 1.00 mg / kg / week, about 1.13 mg / kg / week, or about 1.20 mg / kg / week, according to the individual’s body weight. In some embodiments, the individual’s body weight is capped at 100 kg for for dose levels of 2.0 mg / kg and above (e.g., 2.0 mg / kg, 2.25 mg / kg, and 2.4 mg / kg). In some embodiments, the individual’s body weight is an actual body weight. In some embodiments, the individual’s body weight is an adjusted ideal body weight. In some embodiments, the B7-H4-ADC is administered for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or more than 10 cycles. In some embodiments, the B7-H4-ADC is administered multiple times over a period of at least 3 weeks, 4 weeks, 6 weeks, 8 weeks, 9 weeks, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, or more than 24 months. In some embodiments, the B7-H4- ADC dose is administered no fewer than 5 days apart from the last dose.

[0206] In some embodiments, the methods provided herein comprises administering to the individual a B7-H4-ADC a heavy chain comprising the amino acid sequence of SEQ ID NO: 13 and a light chain comprising the amino acid sequence of SEQ ID NO: 14. In some embodiments, the methods provided herein comprises administering to the individual a B7- H4-ADC comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 71 and a light chain comprising the amino acid sequence of SEQ ID NO: 80. In some embodiments, the methods provided herein comprises administering to the individual a B7- H4-ADC comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 72 and a light chain comprising the amino acid sequence of SEQ ID NO: 81. In some embodiments, the methods provided herein comprises administering to the individual a B7- H4-ADC comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 73 and a light chain comprising the amino acid sequence of SEQ ID NO: 82. In some embodiments, the methods provided herein comprises administering to the individual a B7- H4-ADC comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 74 and a light chain comprising the amino acid sequence of SEQ ID NO: 83. In some embodiments, the methods provided herein comprises administering to the individual a B7-H4-ADC comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 75 and a light chain comprising the amino acid sequence of SEQ ID NO: 84. In some embodiments, the methods provided herein comprises administering to the individual a B7- H4-ADC comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 76 and a light chain comprising the amino acid sequence of SEQ ID NO: 85. In some embodiments, the methods provided herein comprises administering to the individual a B7- H4-ADC comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 77 and a light chain comprising the amino acid sequence of SEQ ID NO: 86. In some embodiments, the methods provided herein comprises administering to the individual a B7- H4-ADC comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 78 and a light chain comprising the amino acid sequence of SEQ ID NO: 87. In some embodiments, the methods provided herein comprises administering to the individual a B7- H4-ADC comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 79 and a light chain comprising the amino acid sequence of SEQ ID NO: 88.

[0207] In some embodiments, there is provided a method of treating a solid tumor in an individual, comprising administering to the individual a B7-H4-ADC twice every three weeks (2Q3W) at a dose of about 0.75 mg / kg, wherein the B7-H4-ADC comprises an anti-B7-H4 antibody conjugated to a vcMMAE (valine-citruline-monomethyl auristatin E), wherein the anti-B7-H4 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region of the anti-B7-H4 antibody comprises the three complementarity determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or antigen-binding fragment thereof comprises the three CDRs of SEQ ID NO: 12. In some embodiments, the method of treating a solid tumor in an individual comprises administering to the individual a B7-H4-ADC twice every three weeks (2Q3W) at a dose of about 0.75 mg / kg on about day 1, followed by a dose of about 0.75 mg / kg on about day 8. In some embodiments, the dose is determined according to the individual’s body weight. In some embodiments, the individual’s body weight is an actual body weight. In some embodiments, the individual’s body weight is an adjusted ideal body weight. In some embodiments, the B7-H4-ADC is administered on about day 1, about day 8, about day 22, about day 29, about day 43, or about day 50. In some embodiments, the B7-H4- ADC is administered on about day 1 and about day 8 on a 21 -day cycle. In some embodiments, the B7-H4-ADC is administered between about 7 days to about 14 days of each other. In some embodiments, the B7-H4-ADC is administered about 7 days apart. Insome embodiments, the B7-H4-ADC is administered about 14 days apart. In some embodiments, the individual has an advanced solid tumor. In some embodiments, the solid tumor is selected from the group consisting of ovarian cancer, primary peritoneal cancer, fallopian tube cancer, breast cancer, endometrial carcinoma, lung cancer, cholangiocarcinoma, gallbladder carcinoma, and head and neck carcinoma.

[0208] In some embodiments, there is provided a method of treating a solid tumor in an individual, comprising administering to the individual a B7-H4-ADC twice every three weeks (2Q3W) at a dose of about 1.0 mg / kg, wherein the B7-H4-ADC comprises an anti-B7-H4 antibody conjugated to a vcMMAE (valine-citruline-monomethyl auristatin E), wherein the anti-B7-H4 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region of the anti-B7-H4 antibody comprises the three complementarity determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or antigen-binding fragment thereof comprises the three CDRs of SEQ ID NO: 12. In some embodiments, the method of treating a solid tumor in an individual comprises administering to the individual a B7-H4-ADC twice every three weeks (2Q3W) at a dose of about 1.0 mg / kg on about day 1, followed by a dose of about 1.0 mg / kg on about day 8. In some embodiments, the dose is determined according to the individual’s body weight. In some embodiments, the individual’s body weight is an actual body weight. In some embodiments, the individual’s body weight is an adjusted ideal body weight. In some embodiments, the B7-H4-ADC is administered on about day 1, about day 8, about day 22, about day 29, about day 43, or about day 50. In some embodiments, the B7-H4-ADC is administered on about day 1 and about day 8 on a 21 -day cycle. In some embodiments, the B7-H4-ADC is administered between about 7 days to about 14 days of each other. In some embodiments, the B7-H4-ADC is administered about 7 days apart. In some embodiments, the B7-H4-ADC is administered about 14 days apart. In some embodiments, the individual has an advanced solid tumor. In some embodiments, the solid tumor is selected from the group consisting of ovarian cancer, primary peritoneal cancer, fallopian tube cancer, breast cancer, endometrial carcinoma, lung cancer, cholangiocarcinoma, gallbladder carcinoma, and head and neck carcinoma.

[0209] In some embodiments, there is provided a method of treating a solid tumor in an individual, comprising administering to the individual a B7-H4-ADC twice every three weeks (2Q3W) at a dose of about 1.25 mg / kg, wherein the B7-H4-ADC comprises an anti-B7-H4 antibody conjugated to a vcMMAE (valine-citruline-monomethyl auristatin E), wherein theanti-B7-H4 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region of the anti-B7-H4 antibody comprises the three complementarity determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or antigen-binding fragment thereof comprises the three CDRs of SEQ ID NO: 12. In some embodiments, the method of treating a solid tumor in an individual comprises administering to the individual a B7-H4-ADC twice every three weeks (2Q3W) at a dose of about 1.25 mg / kg on about day 1, followed by a dose of about 1.25 mg / kg on about day 8. In some embodiments, the dose is determined according to the individual’s body weight. In some embodiments, the individual’s body weight is an actual body weight. In some embodiments, the individual’s body weight is an adjusted ideal body weight. In some embodiments, the B7-H4-ADC is administered on about day 1, about day 8, about day 22, about day 29, about day 43, or about day 50. In some embodiments, the B7-H4- ADC is administered on about day 1 and about day 8 on a 21 -day cycle. In some embodiments, the B7-H4-ADC is administered between about 7 days to about 14 days of each other. In some embodiments, the B7-H4-ADC is administered about 7 days apart. In some embodiments, the B7-H4-ADC is administered about 14 days apart. In some embodiments, the individual has an advanced solid tumor. In some embodiments, the solid tumor is selected from the group consisting of ovarian cancer, primary peritoneal cancer, fallopian tube cancer, breast cancer, endometrial carcinoma, lung cancer, cholangiocarcinoma, gallbladder carcinoma, and head and neck carcinoma.

[0210] In some embodiments, there is provided a method of treating a solid tumor in an individual, comprising administering to the individual a B7-H4-ADC twice every three weeks (2Q3W) at a dose of about 1.5 mg / kg, wherein the B7-H4-ADC comprises an anti-B7-H4 antibody conjugated to a vcMMAE (valine-citruline-monomethyl auristatin E), wherein the anti-B7-H4 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region of the anti-B7-H4 antibody comprises the three complementarity determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or antigen-binding fragment thereof comprises the three CDRs of SEQ ID NO: 12. In some embodiments, the method of treating a solid tumor in an individual comprises administering to the individual a B7-H4-ADC twice every three weeks (2Q3W) at a dose of about 1.5 mg / kg on about day 1, followed by a dose of about 1.5 mg / kg on about day 8. In some embodiments, the dose is determined according to the individual’s body weight. In some embodiments, the individual’s body weight is an actual body weight. Insome embodiments, the individual’s body weight is an adjusted ideal body weight. In some embodiments, the B7-H4-ADC is administered on about day 1, about day 8, about day 22, about day 29, about day 43, or about day 50. In some embodiments, the B7-H4-ADC is administered on about day 1 and about day 8 on a 21 -day cycle. In some embodiments, the B7-H4-ADC is administered between about 7 days to about 14 days of each other. In some embodiments, the B7-H4-ADC is administered about 7 days apart. In some embodiments, the B7-H4-ADC is administered about 14 days apart. In some embodiments, the individual has an advanced solid tumor. In some embodiments, the solid tumor is selected from the group consisting of ovarian cancer, primary peritoneal cancer, fallopian tube cancer, breast cancer, endometrial carcinoma, lung cancer, cholangiocarcinoma, gallbladder carcinoma, and head and neck carcinoma.

[0211] In some embodiments, there is provided a method of treating a solid tumor in an individual, comprising administering to the individual a B7-H4-ADC twice every three weeks (2Q3W) at a dose of about 1.75 mg / kg, wherein the B7-H4-ADC comprises an anti-B7-H4 antibody conjugated to a vcMMAE (valine-citruline-monomethyl auristatin E), wherein the anti-B7-H4 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region of the anti-B7-H4 antibody comprises the three complementarity determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or antigen-binding fragment thereof comprises the three CDRs of SEQ ID NO: 12. In some embodiments, the method of treating a solid tumor in an individual comprises administering to the individual a B7-H4-ADC twice every three weeks (2Q3W) at a dose of about 1.75 mg / kg on about day 1, followed by a dose of about 1.75 mg / kg on about day 8. In some embodiments, the dose is determined according to the individual’s body weight. In some embodiments, the individual’s body weight is an actual body weight. In some embodiments, the individual’s body weight is an adjusted ideal body weight. In some embodiments, the B7-H4-ADC is administered on about day 1, about day 8, about day 22, about day 29, about day 43, or about day 50. In some embodiments, the B7-H4- ADC is administered on about day 1 and about day 8 on a 21 -day cycle. In some embodiments, the B7-H4-ADC is administered between about 7 days to about 14 days of each other. In some embodiments, the B7-H4-ADC is administered about 7 days apart. In some embodiments, the B7-H4-ADC is administered about 14 days apart. In some embodiments, the individual has an advanced solid tumor. In some embodiments, the solid tumor is selected from the group consisting of ovarian cancer, primary peritoneal cancer,fallopian tube cancer, breast cancer, endometrial carcinoma, lung cancer, cholangiocarcinoma, gallbladder carcinoma, and head and neck carcinoma.

[0212] In some embodiments, there is provided a method of treating a solid tumor in an individual, comprising administering to the individual a B7-H4-ADC twice every three weeks (2Q3W) at a dose of about 2.0 mg / kg, wherein the B7-H4-ADC comprises an anti-B7-H4 antibody conjugated to a vcMMAE (valine-citruline-monomethyl auristatin E), wherein the anti-B7-H4 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region of the anti-B7-H4 antibody comprises the three complementarity determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or antigen-binding fragment thereof comprises the three CDRs of SEQ ID NO: 12. In some embodiments, the method of treating a solid tumor in an individual comprises administering to the individual a B7-H4-ADC twice every three weeks (2Q3W) at a dose of about 2.0 mg / kg on about day 1, followed by a dose of about 2.0 mg / kg on about day 8. In some embodiments, the dose is determined according to the individual’s body weight. In some embodiments, the individual’s body weight is an actual body weight. In some embodiments, the individual’s body weight is an adjusted ideal body weight. In some embodiments, the B7-H4-ADC is administered on about day 1, about day 8, about day 22, about day 29, about day 43, or about day 50. In some embodiments, the B7-H4-ADC is administered on about day 1 and about day 8 on a 21 -day cycle. In some embodiments, the B7-H4-ADC is administered between about 7 days to about 14 days of each other. In some embodiments, the B7-H4-ADC is administered about 7 days apart. In some embodiments, the B7-H4-ADC is administered about 14 days apart. In some embodiments, the individual has an advanced solid tumor. In some embodiments, the solid tumor is selected from the group consisting of ovarian cancer, primary peritoneal cancer, fallopian tube cancer, breast cancer, endometrial carcinoma, lung cancer, cholangiocarcinoma, gallbladder carcinoma, and head and neck carcinoma.

[0213] In some embodiments, there is provided a method of treating a solid tumor in an individual, comprising administering to the individual a B7-H4-ADC twice every three weeks (2Q3W) at a dose of about 2.25 mg / kg, wherein the B7-H4-ADC comprises an anti-B7-H4 antibody conjugated to a vcMMAE (valine-citruline-monomethyl auristatin E), wherein the anti-B7-H4 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region of the anti-B7-H4 antibody comprises the three complementarity determining regions (CDRs) of SEQ ID NO: 11, and the lightchain variable region of the antibody or antigen-binding fragment thereof comprises the three CDRs of SEQ ID NO: 12. In some embodiments, the method of treating a solid tumor in an individual comprises administering to the individual a B7-H4-ADC twice every three weeks (2Q3W) at a dose of about 2.25 mg / kg on about day 1, followed by a dose of about 2.25 mg / kg on about day 8. In some embodiments, the dose is determined according to the individual’s body weight. In some embodiments, the individual’s body weight is an actual body weight. In some embodiments, the individual’s body weight is an adjusted ideal body weight. In some embodiments, the B7-H4-ADC is administered on about day 1, about day 8, about day 22, about day 29, about day 43, or about day 50. In some embodiments, the B7-H4- ADC is administered on about day 1 and about day 8 on a 21 -day cycle. In some embodiments, the B7-H4-ADC is administered between about 7 days to about 14 days of each other. In some embodiments, the B7-H4-ADC is administered about 7 days apart. In some embodiments, the B7-H4-ADC is administered about 14 days apart. In some embodiments, the individual has an advanced solid tumor. In some embodiments, the solid tumor is selected from the group consisting of ovarian cancer, primary peritoneal cancer, fallopian tube cancer, breast cancer, endometrial carcinoma, lung cancer, cholangiocarcinoma, gallbladder carcinoma, and head and neck carcinoma.

[0214] In some embodiments, there is provided a method of treating a solid tumor in an individual, comprising administering to the individual a B7-H4-ADC twice every three weeks (2Q3W) at a dose of about 2.4 mg / kg, wherein the B7-H4-ADC comprises an anti-B7-H4 antibody conjugated to a vcMMAE (valine-citruline-monomethyl auristatin E), wherein the anti-B7-H4 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region of the anti-B7-H4 antibody comprises the three complementarity determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or antigen-binding fragment thereof comprises the three CDRs of SEQ ID NO: 12. In some embodiments, the method of treating a solid tumor in an individual comprises administering to the individual a B7-H4-ADC twice every three weeks (2Q3W) at a dose of about 2.4 mg / kg on about day 1, followed by a dose of about 2.4 mg / kg on about day 8. In some embodiments, the dose is determined according to the individual’s body weight. In some embodiments, the individual’s body weight is an actual body weight. In some embodiments, the individual’s body weight is an adjusted ideal body weight. In some embodiments, the B7-H4-ADC is administered on about day 1, about day 8, about day 22, about day 29, about day 43, or about day 50. In some embodiments, the B7-H4-ADC isadministered on about day 1 and about day 8 on a 21 -day cycle. In some embodiments, the B7-H4-ADC is administered between about 7 days to about 14 days of each other. In some embodiments, the B7-H4-ADC is administered about 7 days apart. In some embodiments, the B7-H4-ADC is administered about 14 days apart. In some embodiments, the individual has an advanced solid tumor. In some embodiments, the solid tumor is selected from the group consisting of ovarian cancer, primary peritoneal cancer, fallopian tube cancer, breast cancer, endometrial carcinoma, lung cancer, cholangiocarcinoma, gallbladder carcinoma, and head and neck carcinoma.

[0215] In some embodiments, there is provided a method of treating a solid tumor in an individual, comprising administering to the individual a B7-H4-ADC three times every four weeks (3Q4W) at a dose of about 0.75 mg / kg, wherein the B7-H4-ADC comprises an anti- B7-H4 antibody conjugated to a vcMMAE (valine-citruline-monomethyl auristatin E), wherein the anti-B7-H4 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region of the anti-B7-H4 antibody comprises the three complementarity determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or antigen-binding fragment thereof comprises the three CDRs of SEQ ID NO: 12. In some embodiments, the method of treating a solid tumor in an individual comprises administering to the individual a B7-H4-ADC three times every four weeks (3Q4W) at a dose of about 0.75 mg / kg on about day 1, followed by a dose of about 0.75 mg / kg on about day 8, followed by a dose of about 0.75 mg / kg on about day 15. In some embodiments, the dose is determined according to the individual’s body weight. In some embodiments, the individual’s body weight is an actual body weight. In some embodiments, the individual’s body weight is an adjusted ideal body weight. In some embodiments, the B7-H4-ADC is administered on about day 1, about day 8, about day 15, about day 29, about day 36, about day 43, about day 57, about day 64, or about day 71. In some embodiments, the B7-H4-ADC is administered on about day 1, about day 8, and about day 15 on a 28-day cycle. In some embodiments, the B7-H4-ADC is administered between about 7 days to about 14 days of each other. In some embodiments, the B7-H4-ADC is administered about 7 days apart. In some embodiments, the B7-H4-ADC is administered about 14 days apart. In some embodiments, the individual has an advanced solid tumor. In some embodiments, the solid tumor is selected from the group consisting of ovarian cancer, primary peritoneal cancer, fallopian tube cancer, breast cancer, endometrial carcinoma, lung cancer, cholangiocarcinoma, gallbladder carcinoma, and head and neck carcinoma.

[0216] In some embodiments, there is provided a method of treating a solid tumor in an individual, comprising administering to the individual a B7-H4-ADC three times every four weeks (3Q4W) at a dose of about 1.0 mg / kg, wherein the B7-H4-ADC comprises an anti-B7- H4 antibody conjugated to a vcMMAE (valine-citruline-monomethyl auristatin E), wherein the anti-B7-H4 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region of the anti-B7-H4 antibody comprises the three complementarity determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or antigen-binding fragment thereof comprises the three CDRs of SEQ ID NO: 12. In some embodiments, the method of treating a solid tumor in an individual comprises administering to the individual a B7-H4-ADC three times every four weeks (3Q4W) at a dose of about 1.0 mg / kg on about day 1, followed by a dose of aboutI.0 mg / kg on about day 8, followed by a dose of about 1.0 mg / kg on about day 15. In some embodiments, the dose is determined according to the individual’s body weight. In some embodiments, the individual’s body weight is an actual body weight. In some embodiments, the individual’s body weight is an adjusted ideal body weight. In some embodiments, the B7- H4-ADC is administered on about day 1, about day 8, about day 15, about day 29, about day 36, about day 43, about day 57, about day 64, or about day 71. In some embodiments, the B7- H4-ADC is administered on about day 1, about day 8, and about day 15 on a 28-day cycle. In some embodiments, the B7-H4-ADC is administered between about 7 days to about 14 days of each other. In some embodiments, the B7-H4-ADC is administered about 7 days apart. In some embodiments, the B7-H4-ADC is administered about 14 days apart. In some embodiments, the individual has an advanced solid tumor. In some embodiments, the solid tumor is selected from the group consisting of ovarian cancer, primary peritoneal cancer, fallopian tube cancer, breast cancer, endometrial carcinoma, lung cancer, cholangiocarcinoma, gallbladder carcinoma, and head and neck carcinoma.

[0217] In some embodiments, there is provided a method of treating a solid tumor in an individual, comprising administering to the individual a B7-H4-ADC three times every four weeks (3Q4W) at a dose of about 1.25 mg / kg, wherein the B7-H4-ADC comprises an anti- B7-H4 antibody conjugated to a vcMMAE (valine-citruline-monomethyl auristatin E), wherein the anti-B7-H4 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region of the anti-B7-H4 antibody comprises the three complementarity determining regions (CDRs) of SEQ ID NO:I I, and the light chain variable region of the antibody or antigen-binding fragment thereofcomprises the three CDRs of SEQ ID NO: 12. In some embodiments, the method of treating a solid tumor in an individual comprises administering to the individual a B7-H4-ADC three times every four weeks (3Q4W) at a dose of about 1.25 mg / kg on about day 1, followed by a dose of about 1.25 mg / kg on about day 8, followed by a dose of about 1.25 mg / kg on about day 15. In some embodiments, the dose is determined according to the individual’s body weight. In some embodiments, the individual’s body weight is an actual body weight. In some embodiments, the individual’s body weight is an adjusted ideal body weight. In some embodiments, the B7-H4-ADC is administered on about day 1, about day 8, about day 15, about day 29, about day 36, about day 43, about day 57, about day 64, or about day 71. In some embodiments, the B7-H4-ADC is administered on about day 1, about day 8, and about day 15 on a 28-day cycle. In some embodiments, the B7-H4-ADC is administered between about 7 days to about 14 days of each other. In some embodiments, the B7-H4-ADC is administered about 7 days apart. In some embodiments, the B7-H4-ADC is administered about 14 days apart. In some embodiments, the individual has an advanced solid tumor. In some embodiments, the solid tumor is selected from the group consisting of ovarian cancer, primary peritoneal cancer, fallopian tube cancer, breast cancer, endometrial carcinoma, lung cancer, cholangiocarcinoma, gallbladder carcinoma, and head and neck carcinoma.

[0218] In some embodiments, there is provided a method of treating a solid tumor in an individual, comprising administering to the individual a B7-H4-ADC three times every four weeks (3Q4W) at a dose of about 1.5 mg / kg, wherein the anti-B7-H4 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region of the anti-B7-H4 antibody comprises the three complementarity determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or antigen-binding fragment thereof comprises the three CDRs of SEQ ID NO: 12. In some embodiments, the method of treating a solid tumor in an individual comprises administering to the individual a B7-H4-ADC three times every four weeks (3Q4W) at a dose of about 1.5 mg / kg on about day 1, followed by a dose of about 1.5 mg / kg on about day 8, followed by a dose of about 1.5 mg / kg on about day 15. In some embodiments, the dose is determined according to the individual’s body weight. In some embodiments, the individual’s body weight is an actual body weight. In some embodiments, the individual’s body weight is an adjusted ideal body weight. In some embodiments, the B7-H4-ADC is administered on about day 1, about day 8, about day 15, about day 29, about day 36, about day 43, about day 57, about day 64, or about day 71. In some embodiments, the B7-H4-ADC is administered onabout day 1, about day 8, and about day 15 on a 28-day cycle. In some embodiments, the B7- H4-ADC is administered between about 7 days to about 14 days of each other. In some embodiments, the B7-H4-ADC is administered about 7 days apart. In some embodiments, the B7-H4-ADC is administered about 14 days apart. In some embodiments, the individual has an advanced solid tumor. In some embodiments, the solid tumor is selected from the group consisting of ovarian cancer, primary peritoneal cancer, fallopian tube cancer, breast cancer, endometrial carcinoma, lung cancer, cholangiocarcinoma, gallbladder carcinoma, and head and neck carcinoma.

[0219] In some embodiments, there is provided a method of treating a solid tumor in an individual, comprising administering to the individual a B7-H4-ADC three times every four weeks (3Q4W) at a dose of about 1.75 mg / kg, wherein the B7-H4-ADC comprises an anti- B7-H4 antibody conjugated to a vcMMAE (valine-citruline-monomethyl auristatin E), wherein the anti-B7-H4 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region of the anti-B7-H4 antibody comprises the three complementarity determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or antigen-binding fragment thereof comprises the three CDRs of SEQ ID NO: 12. In some embodiments, the method of treating a solid tumor in an individual comprises administering to the individual a B7-H4-ADC three times every four weeks (3Q4W) at a dose of about 1.75 mg / kg on about day 1, followed by a dose of about 1.75 mg / kg on about day 8, followed by a dose of about 1.75 mg / kg on about day 15. In some embodiments, the dose is determined according to the individual’s body weight. In some embodiments, the individual’s body weight is an actual body weight. In some embodiments, the individual’s body weight is an adjusted ideal body weight. In some embodiments, the B7-H4-ADC is administered on about day 1, about day 8, about day 15, about day 29, about day 36, about day 43, about day 57, about day 64, or about day 71. In some embodiments, the B7-H4-ADC is administered on about day 1, about day 8, and about day 15 on a 28-day cycle. In some embodiments, the B7-H4-ADC is administered between about 7 days to about 14 days of each other. In some embodiments, the B7-H4-ADC is administered about 7 days apart. In some embodiments, the B7-H4-ADC is administered about 14 days apart. In some embodiments, the individual has an advanced solid tumor. In some embodiments, the solid tumor is selected from the group consisting of ovarian cancer, primary peritoneal cancer, fallopian tube cancer, breast cancer, endometrial carcinoma, lung cancer, cholangiocarcinoma, gallbladder carcinoma, and head and neck carcinoma.

[0220] In some embodiments, there is provided a method of treating a solid tumor in an individual, comprising administering to the individual a B7-H4-ADC three times every four weeks (3Q4W) at a dose of about 2.0 mg / kg, wherein the B7-H4-ADC comprises an anti-B7- H4 antibody conjugated to a vcMMAE (valine-citruline-monomethyl auristatin E), wherein the anti-B7-H4 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region of the anti-B7-H4 antibody comprises the three complementarity determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or antigen-binding fragment thereof comprises the three CDRs of SEQ ID NO: 12. In some embodiments, the method of treating a solid tumor in an individual comprises administering to the individual a B7-H4-ADC three times every four weeks (3Q4W) at a dose of about 2.0 mg / kg on about day 1, followed by a dose of about 2.0 mg / kg on about day 8, followed by a dose of about 2.0 mg / kg on about day 15. In some embodiments, the dose is determined according to the individual’s body weight. In some embodiments, the individual’s body weight is an actual body weight. In some embodiments, the individual’s body weight Is an adjusted ideal body weight. In some embodiments, the B7- H4-ADC is administered on about day 1, about day 8, about day 15, about day 29, about day 36, about day 43, about day 57, about day 64, or about day 71. In some embodiments, the B7- H4-ADC is administered on about day 1, about day 8, and about day 15 on a 28-day cycle. In some embodiments, the B7-H4-ADC is administered between about 7 days to about 14 days of each other. In some embodiments, the B7-H4-ADC is administered about 7 days apart. In some embodiments, the B7-H4-ADC is administered about 14 days apart. In some embodiments, the individual has an advanced solid tumor. In some embodiments, the solid tumor is selected from the group consisting of ovarian cancer, primary peritoneal cancer, fallopian tube cancer, breast cancer, endometrial carcinoma, lung cancer, cholangiocarcinoma, gallbladder carcinoma, and head and neck carcinoma.

[0221] In some embodiments, there is provided a method of treating a solid tumor in an individual, comprising administering to the individual a B7-H4-ADC three times every four weeks (3Q4W) at a dose of about 2.25 mg / kg, wherein the B7-H4-ADC comprises an anti- B7-H4 antibody conjugated to a vcMMAE (valine-citruline-monomethyl auristatin E), wherein the anti-B7-H4 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region of the anti-B7-H4 antibody comprises the three complementarity determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or antigen-binding fragment thereofcomprises the three CDRs of SEQ ID NO: 12. In some embodiments, the method of treating a solid tumor in an individual comprises administering to the individual a B7-H4-ADC three times every four weeks (3Q4W) at a dose of about 2.25 mg / kg on about day 1, followed by a dose of about 2.25 mg / kg on about day 8, followed by a dose of about 2.25 mg / kg on about day 15. In some embodiments, the dose is determined according to the individual’s body weight. In some embodiments, the individual’s body weight is an actual body weight. In some embodiments, the individual’s body weight is an adjusted ideal body weight. In some embodiments, the B7-H4-ADC is administered on about day 1, about day 8, about day 15, about day 29, about day 36, about day 43, about day 57, about day 64, or about day 71. In some embodiments, the B7-H4-ADC is administered on about day 1, about day 8, and about day 15 on a 28-day cycle. In some embodiments, the B7-H4-ADC is administered between about 7 days to about 14 days of each other. In some embodiments, the B7-H4-ADC is administered about 7 days apart. In some embodiments, the B7-H4-ADC is administered about 14 days apart. In some embodiments, the individual has an advanced solid tumor. In some embodiments, the solid tumor is selected from the group consisting of ovarian cancer, primary peritoneal cancer, fallopian tube cancer, breast cancer, endometrial carcinoma, lung cancer, cholangiocarcinoma, gallbladder carcinoma, and head and neck carcinoma.

[0222] In some embodiments, there is provided a method of treating a solid tumor in an individual, comprising administering to the individual a B7-H4-ADC three times every four weeks (3Q4W) at a dose of about 2.4 mg / kg, wherein the B7-H4-ADC comprises an anti-B7- H4 antibody conjugated to a vcMMAE (valine-citruline-monomethyl auristatin E), wherein the anti-B7-H4 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region of the anti-B7-H4 antibody comprises the three complementarity determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or antigen-binding fragment thereof comprises the three CDRs of SEQ ID NO: 12. In some embodiments, the method of treating a solid tumor in an individual comprises administering to the individual a B7-H4-ADC three times every four weeks (3Q4W) at a dose of about 2.4 mg / kg on about day 1, followed by a dose of about 2.4 mg / kg on about day 8, followed by a dose of about 2.4 mg / kg on about day 15. In some embodiments, the dose is determined according to the individual’s body weight. In some embodiments, the individual’s body weight is an actual body weight. In some embodiments, the individual’s body weight Is an adjusted ideal body weight. In some embodiments, the B7- H4-ADC is administered on about day 1, about day 8, about day 15, about day 29, about day36, about day 43, about day 57, about day 64, or about day 71. In some embodiments, the B7- H4-ADC is administered on about day 1, about day 8, and about day 15 on a 28-day cycle. In some embodiments, the B7-H4-ADC is administered between about 7 days to about 14 days of each other. In some embodiments, the B7-H4-ADC is administered about 7 days apart. In some embodiments, the B7-H4-ADC is administered about 14 days apart. In some embodiments, the individual has an advanced solid tumor. In some embodiments, the solid tumor is selected from the group consisting of ovarian cancer, primary peritoneal cancer, fallopian tube cancer, breast cancer, endometrial carcinoma, lung cancer, cholangiocarcinoma, gallbladder carcinoma, and head and neck carcinoma.

[0223] In some embodiments, there is provided a method of treating a solid tumor in an individual, comprising administering to the individual a B7-H4-ADC twice every four weeks (2Q4W) at a dose of about 0.75 mg / kg, wherein the B7-H4-ADC comprises an anti-B7-H4 antibody conjugated to a vcMMAE (valine-citruline-monomethyl auristatin E), wherein the anti-B7-H4 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region of the anti-B7-H4 antibody comprises the three complementarity determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or antigen-binding fragment thereof comprises the three CDRs of SEQ ID NO: 12. In some embodiments, the method of treating a solid tumor in an individual comprises administering to the individual a B7-H4-ADC twice every four weeks (2Q4W) at a dose of about 0.75 mg / kg on about day 1, followed by a dose of about 0.75 mg / kg on about day 15. In some embodiments, the dose is determined according to the individual’s body weight. In some embodiments, the individual’s body weight is an actual body weight. In some embodiments, the individual’s body weight is an adjusted ideal body weight. In some embodiments, the B7-H4-ADC is administered on about day 1, about day 15, about day 29, about day 43, about day 57, or about day 71. In some embodiments, the B7-H4- ADC is administered on about day 1 and on about day 15 on a 28-day cycle. In some embodiments, the B7-H4-ADC is administered between about 14 days of each other. In some embodiments, the B7-H4-ADC is administered about 14 days apart. In some embodiments, the individual has an advanced solid tumor. In some embodiments, the solid tumor is selected from the group consisting of ovarian cancer, primary peritoneal cancer, fallopian tube cancer, breast cancer, endometrial carcinoma, lung cancer, cholangiocarcinoma, gallbladder carcinoma, and head and neck carcinoma.

[0224] In some embodiments, there is provided a method of treating a solid tumor in an individual, comprising administering to the individual a B7-H4-ADC twice every four weeks (2Q4W) at a dose of about 1.0 mg / kg, wherein the B7-H4-ADC comprises an anti-B7-H4 antibody conjugated to a vcMMAE (valine-citruline-monomethyl auristatin E), wherein the anti-B7-H4 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region of the anti-B7-H4 antibody comprises the three complementarity determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or antigen-binding fragment thereof comprises the three CDRs of SEQ ID NO: 12. In some embodiments, the method of treating a solid tumor in an individual comprises administering to the individual a B7-H4-ADC twice every four weeks (2Q4W) at a dose of about 1.0 mg / kg on about day 1, followed by a dose of about 1.0 mg / kg on about day 15. In some embodiments, the dose is determined according to the individual’s body weight. In some embodiments, the individual’s body weight is an actual body weight. In some embodiments, the individual’s body weight is an adjusted ideal body weight. In some embodiments, the B7-H4-ADC is administered on about day 1, about day 15, about day 29, about day 43, about day 57, or about day 71. In some embodiments, the B7-H4-ADC is administered on about day 1 and on about day 15 on a 28-day cycle. In some embodiments, the B7-H4-ADC is administered between about 14 days of each other. In some embodiments, the B7-H4-ADC is administered about 14 days apart. In some embodiments, the individual has an advanced solid tumor. In some embodiments, the solid tumor is selected from the group consisting of ovarian cancer, primary peritoneal cancer, fallopian tube cancer, breast cancer, endometrial carcinoma, lung cancer, cholangiocarcinoma, gallbladder carcinoma, and head and neck carcinoma.

[0225] In some embodiments, there is provided a method of treating a solid tumor in an individual, comprising administering to the individual a B7-H4-ADC twice every four weeks (2Q4W) at a dose of about 1.25 mg / kg, wherein the B7-H4-ADC comprises an anti-B7-H4 antibody conjugated to a vcMMAE (valine-citruline-monomethyl auristatin E), wherein the anti-B7-H4 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region of the anti-B7-H4 antibody comprises the three complementarity determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or antigen-binding fragment thereof comprises the three CDRs of SEQ ID NO: 12. In some embodiments, the method of treating a solid tumor in an individual comprises administering to the individual a B7-H4-ADC twice every four weeks(2Q4W) at a dose of about 1.25 mg / kg on about day 1, followed by a dose of about 1.25 mg / kg on about day 15; wherein the B7-H4-ADC comprises an anti-B7-H4 antibody conjugated to a vcMMAE (valine-citruline-monomethyl auristatin E). In some embodiments, the dose is determined according to the individual’s body weight. In some embodiments, the individual’s body weight is an actual body weight. In some embodiments, the individual’s body weight is an adjusted ideal body weight. In some embodiments, the B7-H4-ADC is administered on about day 1, about day 15, about day 29, about day 43, about day 57, or about day 71. In some embodiments, the B7-H4-ADC is administered on about day 1 and on about day 15 on a 28-day cycle. In some embodiments, the B7-H4-ADC is administered between about 14 days of each other. In some embodiments, the B7-H4-ADC is administered about 14 days apart. In some embodiments, the individual has an advanced solid tumor. In some embodiments, the solid tumor is selected from the group consisting of ovarian cancer, primary peritoneal cancer, fallopian tube cancer, breast cancer, endometrial carcinoma, lung cancer, cholangiocarcinoma, gallbladder carcinoma, and head and neck carcinoma.

[0226] In some embodiments, there is provided a method of treating a solid tumor in an individual, comprising administering to the individual a B7-H4-ADC twice every four weeks (2Q4W) at a dose of about 1.5 mg / kg, wherein the B7-H4-ADC comprises an anti-B7-H4 antibody conjugated to a vcMMAE (valine-citruline-monomethyl auristatin E), wherein the anti-B7-H4 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region of the anti-B7-H4 antibody comprises the three complementarity determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or antigen-binding fragment thereof comprises the three CDRs of SEQ ID NO: 12. In some embodiments, the method of treating a solid tumor in an individual comprising administering to the individual a B7-H4-ADC twice every four weeks (2Q4W) at a dose of about 1.5 mg / kg on about day 1, followed by a dose of about 1.5 mg / kg on about day 15. In some embodiments, the dose is determined according to the individual’s body weight. In some embodiments, the individual’s body weight is an actual body weight. In some embodiments, the individual’s body weight is an adjusted ideal body weight. In some embodiments, the B7-H4-ADC is administered on about day 1, about day 15, about day 29, about day 43, about day 57, or about day 71. In some embodiments, the B7-H4-ADC is administered on about day 1 and on about day 15 on a 28-day cycle. In some embodiments, the B7-H4-ADC is administered between about 14 days of each other. In some embodiments, the B7-H4-ADC is administered about 14 days apart. In some embodiments, the individualhas an advanced solid tumor. In some embodiments, the solid tumor is selected from the group consisting of ovarian cancer, primary peritoneal cancer, fallopian tube cancer, breast cancer, endometrial carcinoma, lung cancer, cholangiocarcinoma, gallbladder carcinoma, and head and neck carcinoma.

[0227] In some embodiments, there is provided a method of treating a solid tumor in an individual, comprising administering to the individual a B7-H4-ADC twice every four weeks (2Q4W) at a dose of about 1.75 mg / kg, wherein the B7-H4-ADC comprises an anti-B7-H4 antibody conjugated to a vcMMAE (valine-citruline-monomethyl auristatin E), wherein the anti-B7-H4 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region of the anti-B7-H4 antibody comprises the three complementarity determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or antigen-binding fragment thereof comprises the three CDRs of SEQ ID NO: 12. In some embodiments, the method of treating a solid tumor in an individual comprises administering to the individual a B7-H4-ADC twice every four weeks (2Q4W) at a dose of about 1.75 mg / kg on about day 1, followed by a dose of about 1.75 mg / kg on about day 15. In some embodiments, the dose is determined according to the individual’s body weight. In some embodiments, the individual’s body weight is an actual body weight. In some embodiments, the individual’s body weight is an adjusted ideal body weight. In some embodiments, the B7-H4-ADC is administered on about day 1, about day 15, about day 29, about day 43, about day 57, or about day 71. In some embodiments, the B7-H4- ADC is administered on about day 1 and on about day 15 on a 28-day cycle. In some embodiments, the B7-H4-ADC is administered between about 14 days of each other. In some embodiments, the B7-H4-ADC is administered about 14 days apart. In some embodiments, the individual has an advanced solid tumor. In some embodiments, the solid tumor is selected from the group consisting of ovarian cancer, primary peritoneal cancer, fallopian tube cancer, breast cancer, endometrial carcinoma, lung cancer, cholangiocarcinoma, gallbladder carcinoma, and head and neck carcinoma.

[0228] In some embodiments, there is provided a method of treating a solid tumor in an individual, comprising administering to the individual a B7-H4-ADC twice every four weeks (2Q4W) at a dose of about 2.0 mg / kg, wherein the B7-H4-ADC comprises an anti-B7-H4 antibody conjugated to a vcMMAE (valine-citruline-monomethyl auristatin E), wherein the anti-B7-H4 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region of the anti-B7-H4 antibody comprisesthe three complementarity determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or antigen-binding fragment thereof comprises the three CDRs of SEQ ID NO: 12. In some embodiments, the method of treating a solid tumor in an individual comprises administering to the individual a B7-H4-ADC twice every four weeks (2Q4W) at a dose of about 2.0 mg / kg on about day 1, followed by a dose of about 2.0 mg / kg on about day 15. In some embodiments, the dose is determined according to the individual’s body weight. In some embodiments, the individual’s body weight is an actual body weight. In some embodiments, the individual’s body weight is an adjusted ideal body weight. In some embodiments, the B7-H4-ADC is administered on about day 1, about day 15, about day 29, about day 43, about day 57, or about day 71. In some embodiments, the B7-H4-ADC is administered on about day 1 and on about day 15 on a 28-day cycle. In some embodiments, the B7-H4-ADC is administered between about 14 days of each other. In some embodiments, the B7-H4-ADC is administered about 14 days apart. In some embodiments, the individual has an advanced solid tumor. In some embodiments, the solid tumor is selected from the group consisting of ovarian cancer, primary peritoneal cancer, fallopian tube cancer, breast cancer, endometrial carcinoma, lung cancer, cholangiocarcinoma, gallbladder carcinoma, and head and neck carcinoma.

[0229] In some embodiments, there is provided a method of treating a solid tumor in an individual, comprising administering to the individual a B7-H4-ADC twice every four weeks (2Q4W) at a dose of about 2.25 mg / kg, wherein the B7-H4-ADC comprises an anti-B7-H4 antibody conjugated to a vcMMAE (valine-citruline-monomethyl auristatin E), wherein the anti-B7-H4 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region of the anti-B7-H4 antibody comprises the three complementarity determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or antigen-binding fragment thereof comprises the three CDRs of SEQ ID NO: 12. In some embodiments, the method of treating a solid tumor in an individual comprises administering to the individual a B7-H4-ADC twice every four weeks (2Q4W) at a dose of about 2.25 mg / kg on about day 1, followed by a dose of about 2.25 mg / kg on about day 15. In some embodiments, the dose is determined according to the individual’s body weight. In some embodiments, the individual’s body weight is an actual body weight. In some embodiments, the individual’s body weight is an adjusted ideal body weight. In some embodiments, the B7-H4-ADC is administered on about day 1, about day 15, about day 29, about day 43, about day 57, or about day 71. In some embodiments, the B7-H4-ADC is administered on about day 1 and on about day 15 on a 28-day cycle. In some embodiments, the B7-H4-ADC is administered between about 14 days of each other. In some embodiments, the B7-H4-ADC is administered about 14 days apart. In some embodiments, the individual has an advanced solid tumor. In some embodiments, the solid tumor is selected from the group consisting of ovarian cancer, primary peritoneal cancer, fallopian tube cancer, breast cancer, endometrial carcinoma, lung cancer, cholangiocarcinoma, gallbladder carcinoma, and head and neck carcinoma.

[0230] In some embodiments, there is provided a method of treating a solid tumor in an individual, comprising administering to the individual a B7-H4-ADC twice every four weeks (2Q4W) at a dose of about 2.4 mg / kg, wherein the B7-H4-ADC comprises an anti-B7-H4 antibody conjugated to a vcMMAE (valine-citruline-monomethyl auristatin E), wherein the anti-B7-H4 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region of the anti-B7-H4 antibody comprises the three complementarity determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or antigen-binding fragment thereof comprises the three CDRs of SEQ ID NO: 12. In some embodiments, the method of treating a solid tumor in an individual comprises administering to the individual a B7-H4-ADC twice every four weeks (2Q4W) at a dose of about 2.4 mg / kg on about day 1, followed by a dose of about 2.4 mg / kg on about day 15. In some embodiments, the dose is determined according to the individual’s body weight. In some embodiments, the individual’s body weight is an actual body weight. In some embodiments, the individual’s body weight is an adjusted ideal body weight. In some embodiments, the B7-H4-ADC is administered on about day 1, about day 15, about day 29, about day 43, about day 57, or about day 71. In some embodiments, the B7-H4-ADC is administered on about day 1 and on about day 15 on a 28-day cycle. In some embodiments, the B7-H4-ADC is administered between about 14 days of each other. In some embodiments, the B7-H4-ADC is administered about 14 days apart. In some embodiments, the individual has an advanced solid tumor. In some embodiments, the solid tumor is selected from the group consisting of ovarian cancer, primary peritoneal cancer, fallopian tube cancer, breast cancer, endometrial carcinoma, lung cancer, cholangiocarcinoma, gallbladder carcinoma, and head and neck carcinoma.

[0231] In some embodiments, there is provided a method of treating a solid tumor in an individual, comprising administering to the individual a B7-H4-ADC once every three weeks (Q3W) at a dose of about 0.75 mg / kg, wherein the B7-H4-ADC comprises an anti-B7-H4antibody conjugated to a vcMMAE (valine-citruline-monomethyl auristatin E), wherein the anti-B7-H4 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region of the anti-B7-H4 antibody comprises the three complementarity determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or antigen-binding fragment thereof comprises the three CDRs of SEQ ID NO: 12. In some embodiments, the method of treating a solid tumor in an individual comprises administering to the individual a B7-H4-ADC once every three weeks (Q3W) at a dose of about 0.75 mg / kg on about day 1. In some embodiments, the dose is determined according to the individual’s body weight. In some embodiments, the individual’s body weight is an actual body weight. In some embodiments, the individual’s body weight is an adjusted ideal body weight. In some embodiments, the B7-H4-ADC is administered on about day 1, about day 22, or about day 43. In some embodiments, the B7-H4-ADC is administered on about day 1 on a 21-day cycle. In some embodiments, the B7-H4-ADC is administered between about 21 days of each other. In some embodiments, the B7-H4-ADC is administered about 21 days apart. In some embodiments, the individual has an advanced solid tumor. In some embodiments, the solid tumor Is selected from the group consisting of ovarian cancer, primary peritoneal cancer, fallopian tube cancer, breast cancer, endometrial carcinoma, lung cancer, cholangiocarcinoma, gallbladder carcinoma, and head and neck carcinoma.

[0232] In some embodiments, there is provided a method of treating a solid tumor in an individual, comprising administering to the individual a B7-H4-ADC once every three weeks (Q3W) at a dose of about 1.0 mg / kg, wherein the B7-H4-ADC comprises an anti-B7-H4 antibody conjugated to a vcMMAE (valine-citruline-monomethyl auristatin E), wherein the anti-B7-H4 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region of the anti-B7-H4 antibody comprises the three complementarity determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or antigen-binding fragment thereof comprises the three CDRs of SEQ ID NO: 12. In some embodiments, the method of treating a solid tumor in an individual comprises administering to the individual a B7-H4-ADC once every three weeks (Q3W) at a dose of about 1.0 mg / kg on about day 1. In some embodiments, the dose is determined according to the individual’s body weight. In some embodiments, the individual’s body weight is an actual body weight. In some embodiments, the individual’s body weight is an adjusted ideal body weight. In some embodiments, the B7-H4-ADC is administered onabout day 1, about day 22, or about day 43. In some embodiments, the B7-H4-ADC is administered on about day 1 on a 21-day cycle. In some embodiments, the B7-H4-ADC is administered between about 21 days of each other. In some embodiments, the B7-H4-ADC is administered about 21 days apart. In some embodiments, the individual has an advanced solid tumor. In some embodiments, the solid tumor is selected from the group consisting of ovarian cancer, primary peritoneal cancer, fallopian tube cancer, breast cancer, endometrial carcinoma, lung cancer, cholangiocarcinoma, gallbladder carcinoma, and head and neck carcinoma.

[0233] In some embodiments, there is provided a method of treating a solid tumor in an individual, comprising administering to the individual a B7-H4-ADC once every three weeks (Q3W) at a dose of about 1.25 mg / kg, wherein the B7-H4-ADC comprises an anti-B7-H4 antibody conjugated to a vcMMAE (valine-citruline-monomethyl auristatin E), wherein the anti-B7-H4 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region of the anti-B7-H4 antibody comprises the three complementarity determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or antigen-binding fragment thereof comprises the three CDRs of SEQ ID NO: 12. In some embodiments, the method of treating a solid tumor in an individual comprises administering to the individual a B7-H4-ADC once every three weeks (Q3W) at a dose of about 1.25 mg / kg on about day 1. In some embodiments, the dose is determined according to the individual’s body weight. In some embodiments, the individual’s body weight is an actual body weight. In some embodiments, the individual’s body weight is an adjusted ideal body weight. In some embodiments, the B7-H4-ADC is administered on about day 1, about day 22, or about day 43. In some embodiments, the B7-H4-ADC is administered on about day 1 on a 21-day cycle. In some embodiments, the B7-H4-ADC is administered between about 21 days of each other. In some embodiments, the B7-H4-ADC is administered about 21 days apart. In some embodiments, the individual has an advanced solid tumor. In some embodiments, the solid tumor Is selected from the group consisting of ovarian cancer, primary peritoneal cancer, fallopian tube cancer, breast cancer, endometrial carcinoma, lung cancer, cholangiocarcinoma, gallbladder carcinoma, and head and neck carcinoma.

[0234] In some embodiments, there is provided a method of treating a solid tumor in an individual, comprising administering to the individual a B7-H4-ADC once every three weeks (Q3W) at a dose of about 1.5 mg / kg, wherein the B7-H4-ADC comprises an anti-B7-H4antibody conjugated to a vcMMAE (valine-citruline-monomethyl auristatin E), wherein the anti-B7-H4 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region of the anti-B7-H4 antibody comprises the three complementarity determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or antigen-binding fragment thereof comprises the three CDRs of SEQ ID NO: 12. In some embodiments, the method of treating a solid tumor in an individual comprises administering to the individual a B7-H4-ADC once every three weeks (Q3W) at a dose of about 1.5 mg / kg on about day 1. In some embodiments, the dose is determined according to the individual’s body weight. In some embodiments, the individual’s body weight is an actual body weight. In some embodiments, the individual’s body weight is an adjusted ideal body weight. In some embodiments, the B7-H4-ADC is administered on about day 1, about day 22, or about day 43. In some embodiments, the B7-H4-ADC is administered on about day 1 on a 21-day cycle. In some embodiments, the B7-H4-ADC is administered between about 21 days of each other. In some embodiments, the B7-H4-ADC is administered about 21 days apart. In some embodiments, the individual has an advanced solid tumor. In some embodiments, the solid tumor is selected from the group consisting of ovarian cancer, primary peritoneal cancer, fallopian tube cancer, breast cancer, endometrial carcinoma, lung cancer, cholangiocarcinoma, gallbladder carcinoma, and head and neck carcinoma.

[0235] In some embodiments, there is provided a method of treating a solid tumor in an individual, comprising administering to the individual a B7-H4-ADC once every three weeks (Q3W) at a dose of about 1.75 mg / kg, wherein the B7-H4-ADC comprises an anti-B7-H4 antibody conjugated to a vcMMAE (valine-citruline-monomethyl auristatin E), wherein the anti-B7-H4 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region of the anti-B7-H4 antibody comprises the three complementarity determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or antigen-binding fragment thereof comprises the three CDRs of SEQ ID NO: 12. In some embodiments, the method of treating a solid tumor in an individual comprises administering to the individual a B7-H4-ADC once every three weeks (Q3W) at a dose of about 1.75 mg / kg on about day 1. In some embodiments, the dose is determined according to the individual’s body weight. In some embodiments, the individual’s body weight is an actual body weight. In some embodiments, the individual’s body weight is an adjusted ideal body weight. In some embodiments, the B7-H4-ADC is administered onabout day 1, about day 22, or about day 43. In some embodiments, the B7-H4-ADC is administered on about day 1 on a 21-day cycle. In some embodiments, the B7-H4-ADC is administered between about 21 days of each other. In some embodiments, the B7-H4-ADC is administered about 21 days apart. In some embodiments, the individual has an advanced solid tumor. In some embodiments, the solid tumor Is selected from the group consisting of ovarian cancer, primary peritoneal cancer, fallopian tube cancer, breast cancer, endometrial carcinoma, lung cancer, cholangiocarcinoma, gallbladder carcinoma, and head and neck carcinoma.

[0236] In some embodiments, there is provided a method of treating a solid tumor in an individual, comprising administering to the individual a B7-H4-ADC once every three weeks (Q3W) at a dose of about 2.0 mg / kg, wherein the B7-H4-ADC comprises an anti-B7-H4 antibody conjugated to a vcMMAE (valine-citruline-monomethyl auristatin E), wherein the anti-B7-H4 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region of the anti-B7-H4 antibody comprises the three complementarity determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or antigen-binding fragment thereof comprises the three CDRs of SEQ ID NO: 12. In some embodiments, the method of treating a solid tumor in an individual comprises administering to the individual a B7-H4-ADC once every three weeks (Q3W) at a dose of about 2.0 mg / kg on about day 1. In some embodiments, the dose is determined according to the individual’s body weight. In some embodiments, the individual’s body weight is an actual body weight. In some embodiments, the individual’s body weight is an adjusted ideal body weight. In some embodiments, the B7-H4-ADC is administered on about day 1, about day 22, or about day 43. In some embodiments, the B7-H4-ADC is administered on about day 1 on a 21-day cycle. In some embodiments, the B7-H4-ADC is administered between about 21 days of each other. In some embodiments, the B7-H4-ADC is administered about 21 days apart. In some embodiments, the individual has an advanced solid tumor. In some embodiments, the solid tumor is selected from the group consisting of ovarian cancer, primary peritoneal cancer, fallopian tube cancer, breast cancer, endometrial carcinoma, lung cancer, cholangiocarcinoma, gallbladder carcinoma, and head and neck carcinoma.

[0237] In some embodiments, there is provided a method of treating a solid tumor in an individual, comprising administering to the individual a B7-H4-ADC once every three weeks (Q3W) at a dose of about 2.25 mg / kg, wherein the B7-H4-ADC comprises an anti-B7-H4antibody conjugated to a vcMMAE (valine-citruline-monomethyl auristatin E), wherein the anti-B7-H4 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region of the anti-B7-H4 antibody comprises the three complementarity determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or antigen-binding fragment thereof comprises the three CDRs of SEQ ID NO: 12. In some embodiments, the method of treating a solid tumor in an individual comprises administering to the individual a B7-H4-ADC once every three weeks (Q3W) at a dose of about 2.25 mg / kg on about day 1. In some embodiments, the dose is determined according to the individual’s body weight. In some embodiments, the individual’s body weight is an actual body weight. In some embodiments, the individual’s body weight is an adjusted ideal body weight. In some embodiments, the B7-H4-ADC is administered on about day 1, about day 22, or about day 43. In some embodiments, the B7-H4-ADC is administered on about day 1 on a 21-day cycle. In some embodiments, the B7-H4-ADC is administered between about 21 days of each other. In some embodiments, the B7-H4-ADC is administered about 21 days apart. In some embodiments, the individual has an advanced solid tumor. In some embodiments, the solid tumor is selected from the group consisting of ovarian cancer, primary peritoneal cancer, fallopian tube cancer, breast cancer, endometrial carcinoma, lung cancer, cholangiocarcinoma, gallbladder carcinoma, and head and neck carcinoma.

[0238] In some embodiments, there is provided a method of treating a solid tumor in an individual, comprising administering to the individual a B7-H4-ADC once every three weeks (Q3W) at a dose of about 2.4 mg / kg, wherein the B7-H4-ADC comprises an anti-B7-H4 antibody conjugated to a vcMMAE (valine-citruline-monomethyl auristatin E), wherein the anti-B7-H4 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region of the anti-B7-H4 antibody comprises the three complementarity determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or antigen-binding fragment thereof comprises the three CDRs of SEQ ID NO: 12. In some embodiments, the method of treating a solid tumor in an individual comprises administering to the individual a B7-H4-ADC once every three weeks (Q3W) at a dose of about 2.4 mg / kg on about day 1. In some embodiments, the dose is determined according to the individual’s body weight. In some embodiments, the individual’s body weight is an actual body weight. In some embodiments, the individual’s body weight is an adjusted ideal body weight. In some embodiments, the B7-H4-ADC is administered onabout day 1, about day 22, or about day 43. In some embodiments, the B7-H4-ADC is administered on about day 1 on a 21-day cycle. In some embodiments, the B7-H4-ADC is administered between about 21 days of each other. In some embodiments, the B7-H4-ADC is administered about 21 days apart. In some embodiments, the individual has an advanced solid tumor. In some embodiments, the solid tumor is selected from the group consisting of ovarian cancer, primary peritoneal cancer, fallopian tube cancer, breast cancer, endometrial carcinoma, lung cancer, cholangiocarcinoma, gallbladder carcinoma, and head and neck carcinoma.

[0239] In some embodiments, the methods provided herein utilize a dose determined according to an individual’s body weight. In some embodiments, the individual’s body weight is an actual body weight. In some embodiments, the individual’s body weight is an adjusted ideal body weight (AIBW). In some embodiments, the dose is adjusted for individuals who experience a >10% change in weight from baseline. In some embodiments, the dose is adjusted according to the AIBW. In some embodiments, the dose is adjusted when the individual’s actual body weight is higher than their ideal body weight. In some embodiments, the dose is adjusted when the individual’s actual body weight is lower than their ideal body weight. In some embodiments, AIBW is calculated based on the individual’s gender, height, and actual body weight. Calculation of the ideal body weight and AIBW are known in the art and described, for example, in Peterson et al., Am J Clin Nutr. 2016 May; 103(5): 1197-203; Hicks et al., Ann Hematol. 2012 Nov;91(ll):1795-801; and Yeary et al., Hosp Pharm. 2020 Dec; 55(6): 400-404, the contents of which is incorporated by reference.

[0240] In some embodiments, the B7-H4-ADC is administered in combination with a second agent. In some embodiments, the second agent is an immune checkpoint inhibitor. In some embodiments, the immune checkpoint inhibitor is targeted to, without limitation, PD-1, PD-L1, CTLA-4, LAG3, TIM-3, TIGIT, VISTA, TIM1, or BTLA. In some embodiments, the immune checkpoint inhibitor is targeted to one or more of PD-1, PD-L1, CTLA-4, LAG3, TIM-3, TIGIT, VISTA, TIM1, or BTLA. In some embodiments, the immune checkpoint inhibitor is one or more of: an antibody that binds to PD-1, an antibody that binds PD-L1, an antibody that binds CTLA-4, an antibody that binds LAG3, an antibody that binds TIM-3, an antibody that binds TIGIT, an antibody that binds VISTA, an antibody that binds TIM-1, or an antibody that binds BTLA. In some embodiments, the immune checkpoint inhibitor is targeted to one or more of PD-1, PD-L1, CTLA-4, or TIGIT. In some embodiments, theimmune checkpoint inhibitor is target to PD-1. In some embodiments, the immune checkpoint inhibitor is one or more of: an antibody that binds to PD-1, an antibody that binds PD-L1, an antibody that binds CTLA-4, or an antibody that binds TIGIT. In some embodiments, the immune checkpoint inhibitor an antibody that binds to PD-1. In some embodiments, the immune checkpoint inhibitor is an anti-PD-1 antibody, such as one or more of: Nivolumab, Pembrolizumab, Cemiplimab, Dostarlimab, and Retifanlimab. In some embodiments, the B7-H4-ADC is administered in combination with a PD-1 inhibitor (e.g. an anti-PD-1 antibody). In some embodiments, the inhibitor of PD-L1 (e.g. an anti-PD-Ll antibody) is selected from the group consisting of atezolizumab (TECENTRIQ®, MPDL3280A), avelumab (BAVENCIO®), durvalumab and BMS-936559. In some embodiments, the anti-PD-1 antibody is Keytruda®.

[0241] In some embodiments, there is provided a method of treating a solid tumor in an individual, comprising administering to the individual a B7-H4-ADC twice every four weeks (2Q4W) at a dose of about 1.5 mg / kg AiBW and adminstering pembrolizumab at a dose of about 400 mg once every 6 weeks (Q6W), wherein the B7-H4-ADC comprises an anti-B7-H4 antibody conjugated to a vcMMAE (valine-citruline-monomethyl auristatin E), wherein the anti-B7-H4 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region of the anti-B7-H4 antibody comprises the three complementarity determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or antigen-binding fragment thereof comprises the three CDRs of SEQ ID NO: 12. In some embodiments, the method of treating a solid tumor in an individual comprises administering to the individual a B7-H4-ADC twice every four weeks (2Q4W) at a dose of about 1.5 mg / kg on about day 1, followed by a dose of about 1.5 mg / kg on about day 15. In some embodiments, the B7-H4-ADC is administered on about day 1, about day 15, about day 29, about day 43, about day 57, or about day 71. In some embodiments, the B7-H4-ADC is administered on about day 1 and on about day 15 on a 28- day cycle. In some embodiments, the B7-H4-ADC is administered between about 14 days of each other. In some embodiments, the B7-H4-ADC is administered about 14 days apart. In some embodiments, the B7-H4-ADC dose is administered no fewer than 5 days apart from the last dose. In some embodiments, the pembrolizumab is administered on starting on about day 1. In some embodiments, the pembrolizuab is administered between about 42 days of each other. In some embodiments, the pembrolizumab is administered for up to about 15 months, up to about 16 months, up to about 17 months, up to about 18 months, up to about 19months, up to about 20 months, up to about 21 months, up to about 22 months, up to about 23 months, or up to about 24 months. In some embodiments, when pembrolizumab isadministered in combination with the B7-H4-ADC, pembrolizumab is administered first followed by the administration of the B7-H4-ADC. In some embodiments, pembrolizumab is administered at least 30 minutes before administration of the B7-H4-ADC. In some embodiments, the individual is administered pembrolizumab at a dose of about 200 mg every three weeks (Q3W) until the individual is able to resume treatment at the Q6W schedule. In some embodiments, the solid tumor is triple-negative breast cancer (TNBC). In some embodiments, the individual has a PD-L1 -positive (Combined Positive Score (CPS) >10) TNBC. In some embodiments, the individual has PD-L1 -negative (CPS <10) TNBC. In some embodiments, the TNBC is a first-line setting for locally advanced unresectable and / or metastatic disease.

[0242] In some embodiments, there is provided a method of treating a solid tumor in an individual, comprising administering to the individual a B7-H4-ADC twice every four weeks (2Q4W) at a dose of about 1.75 mg / kg AiBW and adminstering pembrolizumab at a dose of about 400 mg once every 6 weeks (Q6W), wherein the B7-H4-ADC comprises an anti-B7-H4 antibody conjugated to a vcMMAE (valine-citruline-monomethyl auristatin E), wherein the anti-B7-H4 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region of the anti-B7-H4 antibody comprises the three complementarity determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or antigen-binding fragment thereof comprises the three CDRs of SEQ ID NO: 12. In some embodiments, the method of treating a solid tumor in an individual comprises administering to the individual a B7-H4-ADC twice every four weeks (2Q4W) at a dose of about 1.75 mg / kg on about day 1, followed by a dose of about 1.75 mg / kg on about day 15. In some embodiments, the B7-H4-ADC is administered on about day 1, about day 15, about day 29, about day 43, about day 57, or about day 71. In some embodiments, the B7-H4-ADC is administered on about day 1 and on about day 15 on a 28- day cycle. In some embodiments, the B7-H4-ADC is administered between about 14 days of each other. In some embodiments, the B7-H4-ADC is administered about 14 days apart. In some embodiments, the B7-H4-ADC dose is administered no fewer than 5 days apart from the last dose. In some embodiments, the pembrolizumab is administered on starting on about day 1. In some embodiments, the pembrolizuab is administered between about 42 days of each other. In some embodiments, the pembrolizumab is administered for up to about 15months, up to about 16 months, up to about 17 months, up to about 18 months, up to about 19 months, up to about 20 months, up to about 21 months, up to about 22 months, up to about 23 months, or up to about 24 months. In some embodiments, when pembrolizumab isadministered in combination with the B7-H4-ADC, pembrolizumab is administered first followed by the administration of the B7-H4-ADC. In some embodiments, pembrolizumab is administered at least 30 minutes before administration of the B7-H4-ADC. In some embodiments, the individual is administered pembrolizumab at a dose of about 200 mg every three weeks (Q3W) until the individual is able to resume treatment at the Q6W schedule. In some embodiments, the solid tumor is triple-negative breast cancer (TNBC). In some embodiments, the individual has a PD-L1 -positive (Combined Positive Score (CPS) >10) TNBC. In some embodiments, the individual has PD-L1 -negative (CPS <10) TNBC. In some embodiments, the TNBC is a first-line setting for locally advanced unresectable and / or metastatic disease.

[0243] In some embodiments, there is provided a method of treating a solid tumor in an individual, comprising administering to the individual a B7-H4-ADC twice every four weeks (2Q4W) at a dose of about 1.5 mg / kg AiBW and adminstering pembrolizumab at a dose of about 400 mg once every 6 weeks (Q6W), wherein the B7-H4-ADC comprises an anti-B7-H4 antibody conjugated to a vcMMAE (valine-citruline-monomethyl auristatin E), wherein the anti-B7-H4 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region of the anti-B7-H4 antibody comprises the three complementarity determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or antigen-binding fragment thereof comprises the three CDRs of SEQ ID NO: 12. In some embodiments, the method of treating a solid tumor in an individual comprises administering to the individual a B7-H4-ADC twice every four weeks (2Q4W) at a dose of about 1.5 mg / kg on about day 1, followed by a dose of about 1.5 mg / kg on about day 15. In some embodiments, the B7-H4-ADC is administered on about day 1, about day 15, about day 29, about day 43, about day 57, or about day 71. In some embodiments, the B7-H4-ADC is administered on about day 1 and on about day 15 on a 28- day cycle. In some embodiments, the B7-H4-ADC is administered between about 14 days of each other. In some embodiments, the B7-H4-ADC is administered about 14 days apart. In some embodiments, the B7-H4-ADC dose is administered no fewer than 5 days apart from the last dose. In some embodiments, the B7-H4-ADC is administered for up to about 1 dose, up to about 2 doses, up to about 3 doses, up to about 4 doses, up to about 5 doses, up to about6 doses, up to about 7 doses, up to about 8 doses, up to about 9 doses, up to about 10 doses, up to about 11 doses, up to about 12 doses, up to about 13 doses, up to about 14 doses, up to about 15 doses, or up to about 16 doses. In some embodiments, when pembrolizumab isadministered in combination with the B7-H4-ADC, pembrolizumab is administered first followed by the administration of the B7-H4-ADC. In some embodiments, pembrolizumab is administered at least 30 minutes before administration of the B7-H4-ADC. In some embodiments, the pembrolizumab is administered on starting on about day 1. In some embodiments, the pembrolizuab is administered between about 42 days of each other. In some embodiments, the pembrolizumab is administered for up to about 1 dose, up to about 2 doses, up to about 3 doses, or up to about 4 doses. In some embodiments, the individual is administered pembrolizumab at a dose of about 200 mg every three weeks (Q3W) until the individual is able to resume treatment at the Q6W schedule. In some embodiments, the solid tumor is triple-negative breast cancer (TNBC). In some embodiments, the TNBC is residual disease post-neoadjuvant therapy and surgery.

[0244] In some embodiments, there is provided a method of treating a solid tumor in an individual, comprising administering to the individual a B7-H4-ADC twice every four weeks (2Q4W) at a dose of about 1.75 mg / kg AiBW and adminstering pembrolizumab at a dose of about 400 mg once every 6 weeks (Q6W), wherein the B7-H4-ADC comprises an anti-B7-H4 antibody conjugated to a vcMMAE (valine-citruline-monomethyl auristatin E), wherein the anti-B7-H4 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region of the anti-B7-H4 antibody comprises the three complementarity determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or antigen-binding fragment thereof comprises the three CDRs of SEQ ID NO: 12. In some embodiments, the method of treating a solid tumor in an individual comprises administering to the individual a B7-H4-ADC twice every four weeks (2Q4W) at a dose of about 1.75 mg / kg on about day 1, followed by a dose of about 1.75 mg / kg on about day 15. In some embodiments, the B7-H4-ADC is administered on about day 1, about day 15, about day 29, about day 43, about day 57, or about day 71. In some embodiments, the B7-H4-ADC is administered on about day 1 and on about day 15 on a 28- day cycle. In some embodiments, the B7-H4-ADC is administered between about 14 days of each other. In some embodiments, the B7-H4-ADC is administered about 14 days apart. In some embodiments, the B7-H4-ADC dose is administered no fewer than 5 days apart from the last dose. In some embodiments, the B7-H4-ADC is administered for up to about 1 dose,up to about 2 doses, up to about 3 doses, up to about 4 doses, up to about 5 doses, up to about 6 doses, up to about 7 doses, up to about 8 doses, up to about 9 doses, up to about 10 doses, up to about 11 doses, up to about 12 doses, up to about 13 doses, up to about 14 doses, up to about 15 doses, or up to about 16 doses. In some embodiments, when pembrolizumab isadministered in combination with the B7-H4-ADC, pembrolizumab is administered first followed by the administration of the B7-H4-ADC. In some embodiments, pembrolizumab is administered at least 30 minutes before administration of the B7-H4-ADC. In some embodiments, the pembrolizumab is administered on starting on about day 1. In some embodiments, the pembrolizuab is administered between about 42 days of each other. In some embodiments, the pembrolizumab is administered for up to about 1 dose, up to about 2 doses, up to about 3 doses, or up to about 4 doses. In some embodiments, the individual is administered pembrolizumab at a dose of about 200 mg every three weeks (Q3W) until the individual is able to resume treatment at the Q6W schedule. In some embodiments, the solid tumor is triple-negative breast cancer (TNBC). In some embodiments, the TNBC is residual disease post-neoadjuvant therapy and surgery.

[0245] In some embodiments, the method of treating a solid tumor in an individual described herein further comprises selecting an individual suitable for such treatment. In some embodiments, the individual has 1) high-grade serous epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer; 2) HER2 -negative, HR-positive breast cancer (per American Society for Clinical Oncology [ASCO] / CAP [College of American Pathologists] criteria, based on the most recent the most recently available biopsy); 3) TNBC (per ASCO / CAP criteria, based on the most recently available biopsy); 4) Endometrial carcinoma (Part C: Up to 10 subjects with endometrial carcinosarcoma may be enrolled in the monotherapy dose expansion cohort); 5) NSCLC (SqCC, AC); 6) Cholangiocarcinoma or gallbladder carcinoma; or 7) ACC. In some embodiments, the individual has a disease that is relapsed or refractory or be intolerant to SOC therapies, and, in the judgement of the investigator, should have no appropriate SOC therapeutic option. If a SOC therapy is available that has not been administered, the reason that the therapy is not appropriate must be documented. In some embodiments, the individual provides archival tumor tissue from most recent biopsy collected within 24 months. In some embodiments, if archival tissue is not available from the individual, a fresh pre-treatment biopsy must be submitted (appropriate lesions are accessible with a minimally invasive procedure that does not represent significant risk). In some embodiments, the individual provides archival tumor tissue from most recentbiopsy collected within 12 months. In some embodiments, the individual meets one or more of the criteria: 1) age 18 years or older; 2) an Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1; 3) measurable disease per RECIST version 1.1 at baseline; 4) the following baseline laboratory test results: a) absolute neutrophil count (ANC) >1500 / pL; b) hemoglobin (Hgb) >9 g / dL; c) platelet count >100,000 / pL; d) serum bilirubin <1.5 x upper limit of normal (ULN) or <3 x ULN for subjects with Gilbert’s disease; e) estimated glomerular filtration rate (eGFR) >45 mL / min / 1.73 m2 using the Modification of Diet in Renal Disease (MDRD) study equation as applicable or 24 hour creatinine clearance (CrCl) >45 mL / min / 1.73 m2; and ALT and AST <3 x ULN (<5 x ULN if there is evidence of hepatic involvement by malignant disease); 5) individuals of childbearing potential meet the following conditions: a) must have a negative serum or urine pregnancy test (minimum sensitivity 25 mIU / mL or equivalent units of beta human chorionic gonadotropin [P-hCG]) result within 7 days prior to the first dose of SGN-B7H4V. Subjects with false positive results and documented verification that the subject is not pregnant are eligible for participation; b) must agree not to try to become pregnant during the study and for at least 2 months after the final dose of SGN-B7H4V; c) must agree not to breastfeed or donate ova, starting at time of informed consent and continuing through 2 months after the final dose of SGN B7H4V; d) if sexually active in a way that could lead to pregnancy, must consistently use at least 2 acceptable methods of birth control (contraception), at least 1 of which must be highly effective from the time of informed consent and continuing through at least 2 months after the final dose of SGN B7H4V; and / or 6) individuals of who can get someone pregnant meet the following conditions: a) must agree not to donate sperm from the time of informed consent and continuing through the study period and at least 4 months after the final dose of study treatment; b) if sexually active with a person of childbearing potential in a way that could lead to pregnancy, must consistently use at least 2 acceptable methods of birth control (contraception), at least 1 of which must be highly effective from the time of informed consent and continuing through at least 4 months after the final dose of study treatment; c) if sexually active with a person who is pregnant or breastfeeding, must consistently use a condom from the time of informed consent and continuing through at least 4 months after the final dose of study treatment. In some embodiments, the individual has TNBC that is relapsed or refractory or be intolerant to SOC therapies as specified: 1) treatment with at least 1, and no more than 3, prior lines of systemic chemotherapy in the locally advanced unresectable or metastatic setting for TNBC; 2) adjuvant or neoadjuvant treatment for early-stage disease will count as 1 line of systemic chemotherapy if the subject subsequently develops locallyadvanced unresectable or metastatic disease within 12-months after the completion of adjuvant or neoadjuvant treatment; 3) received a PD-(L)1 inhibitor, if eligible by biomarker status and consistent with SOC; 4) has discussed treatment with a topoisomerase- 1 (TOPO-1) inhibitor-based ADC, if available. If a subject has received treatment with a TOPO-1 inhibitor-based ADC, it will count as 1 line of systemic chemotherapy; and / or 5) hormonal therapy will not be considered as a prior line of systemic chemotherapy.

[0246] In some embodiments, the method of treating a solid tumor in an individual described herein further comprises selecting an individual suitable for such treatment. In some embodiments, the individual has an advanced solid tumor. In some embodiments, the solid tumor is selected from the group consisting of high-grade serous epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer, TNBC, HER2-negative breast cancer, HR-positive breast cancer, endometrial carcinoma, squamous NSCLC, cholangiocarcinoma or gallbladder carcinoma, and adenoid cystic carcinoma. In some embodiments, the individual has high-grade serous epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer. In some embodiments, the individual suitable for such treatment described herein meets one or more of the following criteria: 1) has received treatment with platinum-based chemotherapy and are considered to have platinum-resistant disease defined as having radiographic progression within 6 months of completing at least 4 cycles of platinum-containing therapy; 2) the individual does not have primary platinum- refractory disease, defined as disease that did not respond to or progressed within 3 months of the last dose of first line platinum-containing chemotherapy; 3) must have received a bevacizumab-containing regimen; and 4) if the individual is eligible by biomarker status and consistent with SOC, the individual must have received a poly-ADP ribose polymerase (PARP) inhibitor. In some embodiments, the individual has TNBC. In some embodiments, the individual suitable for such treatment described herein meets one or more of the following criteria: 1) treatment with at least 1, and no more than 3, prior lines of systemic chemotherapy in the locally advanced unresectable or metastatic setting for TNBC; 2) adjuvant or neoadjuvant treatment for early-stage disease will count as 1 line of systemic chemotherapy if the subject subsequently develops locally advanced unresectable or metastatic disease within 12-months after the completion of adjuvant or neoadjuvant treatment; 3) treatment must include a PD-(L)1 inhibitor, if eligible by biomarker status and consistent with SOC; 4) has discussed treatment with a TOPO-1 inhibitor-based ADC, if available; 5) if the individual has received treatment with a TOPO-1 inhibitor-based ADC, it will count as 1 line of systemicchemotherapy; and 6) hormonal therapy will not be considered as a prior line of systemic chemotherapy. In some embodiments, the individual has HER2-negative breast cancer or HR-positive breast cancer. In some embodiments, the individual suitable for such treatment described herein meets one or more of the following criteria: 1) treatment with endocrine therapy. Subjects must have progressed on and are no longer eligible to receive endocrine therapy as per investigator assessment; 2) treatment with a cyclin D-cyclin dependent kinase (CDK) 4 / 6 inhibitor, unless treatment with a CDK 4 / 6 inhibitor was not suitable due to safety reasons as per investigator assessment; 3) treatment with at least 1, and no more than 3, prior lines of systemic chemotherapy in the locally advanced unresectable or metastatic setting for HR+ / HER2- breast; 4) adjuvant or neoadjuvant treatment for early-stage disease will count as 1 line of systemic chemotherapy if the subject subsequently develops locally advanced unresectable or metastatic disease within 12-months after the completion of adjuvant or neoadjuvant treatment; 5) has discussed treatment with a TOPO-1 inhibitor-based ADC, if available; 6) if a subject has received treatment with a TOPO-1 inhibitor-based ADC, it will count as 1 line of systemic chemotherapy; and 7) hormonal therapy will not be considered as a prior line of systemic chemotherapy. In some embodiments, the individual has endometrial carcinoma. In some embodiments, the individual suitable for such treatment described herein meets one or more of the following criteria: 1) must have received at least 1 line of systemic therapy; 2) if appropriate by biomarker status (including but not limited to microsatellite instability [MSI] and mismatch repair deficient [dMMR] status) and available per local SOC, must have received a prior PD-1 inhibitor and / or the combination of pembrolizumab and Lenvatinib; and 3) must have received at least 1 prior platinum-based regimen. In some embodiments, the individual has squamous NSCLC. In some embodiments, the individual suitable for such treatment described herein meets the following criterion: locally advanced recurrent / metastatic disease must have received prior treatment with platinum-based therapy and a PD-(L)1 inhibitor (if indicated per local SOC), separately or in combination. In some embodiments, the individual has cholangiocarcinoma or gallbladder carcinoma. In some embodiments, the individual suitable for such treatment described herein meets one or more of the following criteria: 1) must have received at least 1 line of systemic therapy; 2) if appropriate by biomarker status (including but not limited to neurotrophic tyrosine kinase receptor [NTRK], fibroblast growth factor receptor [FGFR]2 genetic alterations, MSI-high, and / or high tumor mutational burden [TMB-H] status) and available per local SOC, subjects must have received approved targeted therapy; and 3) hepatic involvement is allowed. In some embodiments, the individual has adenoid cystic carcinoma. In some embodiments, theindividual suitable for such treatment described herein meets one or more of the following criteria: 1) individuals with locally advanced recurrent / metastatic disease must have received at least 1 line of systemic therapy; and 2) individuals whose tumors harbor genomic mutations / alterations for which approved targeted therapies are available per local SOC, must have received approved and available targeted therapies. In some embodiments, the individual suitable for such treatment described herein provides a fresh pre-treatment biopsy, an on-treatment biopsy on Cycle 1 Day 15, and an end of treatment (EOT) biopsy are required.

[0247] In some embodiments, the method of treating a solid tumor in an individual described herein further comprises administering pembrolizumab. In some embodiments, the method of treating a solid tumor in an individual described herein further comprises selecting an individual suitable for such treatment. In some embodiments, the solid tumor is triplenegative breast cancer (TNBC). In some embodiments, the individual has a PD-L1 -positive (Combined Positive Score (CPS) >10) TNBC. In some embodiments, the individual suitable for such treatment described herein meets one or more of the following criteria: 1) must have histologically or cytologically confirmed locally-advanced unresectable or metastatic TNBC (per ASCO / CAP criteria, based on the most recently available biopsy). Subjects must have CPS > 10 by local testing; 2) no prior treatment for locally advanced unresectable or metastatic TNBC. Subjects who received treatment in the curative setting are eligible if it has been >6 months from the completion of curative treatment; and 3) provide archival tumor tissue from most recent biopsy collected within 12 months or a fresh pre-treatment biopsy.

[0248] In some embodiments, the method of treating a solid tumor in an individual described herein further comprises administering pembrolizumab. In some embodiments, the method of treating a solid tumor in an individual described herein further comprises selecting an individual suitable for such treatment. In some embodiments, the solid tumor is triplenegative breast cancer (TNBC). In some embodiments, the individual has PD-L1 -negative (CPS <10) TNBC. In some embodiments, the individual suitable for such treatment described herein meets one or more of the following criteria: 1) must have histologically or cytologically confirmed locally-advanced unresectable or metastatic TNBC (per ASCO / CAP criteria, based on the most recently available biopsy). Subjects must have CPS < 10 by local testing; 2) no prior treatment for locally advanced unresectable or metastatic TNBC. Subjects who received treatment in the curative setting are eligible if it has been >6 months from thecompletion of curative treatment; and 3) provide archival tumor tissue from most recent biopsy collected within 12 months or a fresh pre-treatment biopsy.

[0249] In some embodiments, the method of treating a solid tumor in an individual described herein further comprises administering pembrolizumab. In some embodiments, the method of treating a solid tumor in an individual described herein further comprises selecting an individual suitable for such treatment. In some embodiments, the solid tumor is triplenegative breast cancer (TNBC). In some embodiments, the TNBC is residual disease post- neoadjuvant therapy and surgery. In some embodiments, the individual suitable for such treatment described herein meets one or more of the following criteria: 1) must have histologically or cytologically confirmed TNBC (per ASCO / CAP criteria, based on the most recently available biopsy); 2) must have Stage I-III disease with evidence of residual disease in breast and / or axillary lymph nodes after definitive surgical resection following neoadjuvant therapy; 3) must have adequate excision and surgical removal of all clinically evident disease in the breast and / or lymph nodes; 4) completed at least 6 cycles of neoadjuvant therapy containing anthracy cline and / or ataxane, with or without an immune CPI, for locally advanced unresectable or metastatic TNBC; 5) radiotherapy (if indicated) must be administered prior to start of study treatment; 6) provide archival tumor tissue from most recent biopsy collected within 12 months or a fresh pre-treatment biopsy; and 7) left ventricular ejection fraction (LVEF) >50% by either echocardiogram (ECHO) or multigated acquisition (MUGA) scan within 28 days prior to start of study treatment.

[0250] In some embodiments, the method of treating a solid tumor in an individual described herein further comprises excluding an individual not suitable for such treatment. In some embodiments, the individual not suitable for the method of treatment described herein meets one or more of the criteria: 1) history of another malignancy within 3 years before the first dose of study drug, or any evidence of residual disease from a previously diagnosed malignancy. Exceptions are malignancies with a negligible risk of metastasis or death (eg, 5- year OS >90%), such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer; 2) known active central nervous system (CNS) metastases. Subjects with previously treated brain metastases may participate provided they are clinically stable for at least 4 weeks prior to study entry after brain metastasis treatment, they have no new or enlarging brain metastases, and are off corticosteroids prescribed for symptoms associated with brain metastases for at least 7 days prior to the first dose of study drug; 3) carcinomatousmeningitis; 4) previous receipt of an MMAE-containing agent or an agent targeting B7 H4; 5) pre-existing neuropathy > Grade 2 per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0; 6) any uncontrolled viral, bacterial, or fungal infection within 2 weeks prior to the first dose of SGN-B7H4V. Routine antimicrobial prophylaxis is permitted; 7) uncontrolled diabetes mellitus, defined as Hgb Ale >8% or Hgb Ale between 7 and <8% with associated diabetes symptoms (polyuria or polydipsia) that are not otherwise explained; 8) positive for hepatitis B by surface antigen expression and / or positive anti -Hepatitis B core (HBc) total antibody titer. Active hepatitis C infection (positive by polymerase chain reaction [PCR] or on antiviral therapy for hepatitis C within the last 6 months). Subjects who have been treated for hepatitis C infection are permitted if they have documented sustained virologic response of 12 weeks; 9) known to be positive for human immunodeficiency virus; 10) documented history of a cerebral vascular event (stroke or transient ischemic attack), unstable angina, myocardial infarction, or cardiac symptoms consistent with New York Heart Association Class III-IV within 6 months prior to their first dose of SGN B7H4V; 11) congestive heart failure, Class III or IV, by the New York Heart Association criteria; 12) active or uncontrolled pulmonary disease > Grade 2 unrelated to underlying malignancy; 13) has an active autoimmune disease that has required systemic treatment in past 2 years (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed; 14) comeal disease or injury requiring treatment or active monitoring; 15) Part A and D only: use of strong cytochrome P450 3A (CYP3A) inhibitors or inducers within 14 days prior to study treatment initiation; 16) receipt of a vaccine containing a live or attenuated virus within 30 days prior to first dose of study drug; 17) chemotherapy, immunotherapy, biologies, and / or other approved or investigational antitumor treatment that is not completed 4 weeks prior to study treatment initiation, (for all parts), or within 2 weeks prior to study treatment initiation if the underlying disease has progressed on treatment (for Parts A, B, C); 18) focal radiotherapy or major surgery that is not completed 2 weeks prior to study treatment initiation; 19) subjects who are breastfeeding, pregnant, or planning to become pregnant from time of informed consent until 2 months after final dose of SGN-B7H4V and until 4 months after final dose of pembrolizumab (for Parts D and E); 20) known hypersensitivity to any excipient contained in the drug formulation of SGN B7H4V or other treatments to be administered; 21) estimated life expectancy <12 weeks; 22) other serious underlying medical condition that, in the opinion of the investigator,would impair the subject’s ability to receive or tolerate the planned treatment and follow up; 23) any toxicity associated with prior therapy that has not returned to baseline or that is > Grade 1, with the exception of alopecia and well-controlled immune-mediated endocrine toxicity resulting from prior immune CPI use (such as Grade 2 hypothyroidism); 24) subjects dependent on the sponsor, legal representative of the sponsor, clinical research organization, or investigators in a familial or financial manner; and / or 25) Germany only, subjects committed to an institution by virtue of an order issued either by the judicial or the administrative authorities.

[0251] In some embodiments, the method of treating a solid tumor in an individual described herein further comprises administering pembrolizumab. In some embodiments, the method of treating a solid tumor in an individual described herein further comprises excluding an individual not suitable for such treatment. In some embodiments, the individual not suitable for the method of treatment described herein meets one or more of the criteria: 1) has received prior therapy with a PD 1 inhibitor, anti PD (L) 1 , or anti PD L2 agent or with an agent directed to another stimulatory or co inhibitory T cell receptor (eg, CTLA4, 0X40, CD 137) and was discontinued from that treatment due to a Grade 3 or higher IMAE; 2) has a diagnosis of immunodeficiency or is receiving chronic systemic corticosteroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study drug; 3) has had an allogeneic tissue / solid organ transplant; 4) has ahistory of (non-infectious) pneumonitis / interstitial lung disease that required steroid or has current pneumonitis / interstitial lung disease; and 4) has received radiation therapy to the lung that is >30 Gy within 6 months of the first dose of study drug.

[0252] In some embodiments, the method of treating a solid tumor in an individual described herein further comprises administering pembrolizumab. In some embodiments, the solid tumor is triple-negative breast cancer (TNBC). In some embodiments, the individual has a PD-L1 -positive (Combined Positive Score (CPS) >10) TNBC. In some embodiments, the individual has PD-L1 -negative (CPS <10) TNBC. In some embodiments, the TNBC is residual disease post-neoadjuvant therapy and surgery. In some embodiments, the individual not suitable for the method of treatment described herein meets one or more of the criteria: 1) has received prior therapy with a PD 1 inhibitor, anti PD (L)l, or anti PD L2 agent or with an agent directed to another stimulatory or co inhibitory T cell receptor (eg, CTLA4, 0X40, CD 137) and was discontinued from that treatment due to a Grade 3 or higher IMAE; 2) has adiagnosis of immunodeficiency or is receiving chronic systemic corticosteroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study drug; 3) has had an allogeneic tissue / solid organ transplant; 4) has ahistory of (non-infectious) pneumonitis / interstitial lung disease that required steroid or has current pneumonitis / interstitial lung disease; and 4) has received radiation therapy to the lung that is >30 Gy within 6 months of the first dose of study drug.

[0253] In some embodiments, the method of treating a solid tumor in an individual described herein further comprises administering pembrolizumab. In some embodiments, the TNBC is residual disease post-neoadjuvant therapy and surgery. In some embodiments, the individual not suitable for the method of treatment described herein meets one or more of the following criteria: 1) have received prior adjuvant therapy; 2) have evidence of locoregional or distant relapse; and 3) have known germline BRCA1 or BRCA2 mutations.

[0254] In some embodiments, the method of treating a solid tumor in an individual described herein further comprises treating individuals who experience infusion-related reactions. In some embodiments, the individual is administered a premedication. In some embodiments, premediation is not adminsietered prior to the first dose of the B7-H4-ADC. In some embodiments, the premedication is an antihistamine (e.g., diphenhydramine 50 mg IV or equivalent and famotidine 40 mg IV or equivalent). In some embodiments, the premedication is a corticosteroid (e.g., hydrocortisone 100 mg IV or equivalent). In some embodiments, the premedication is an antipyretic (e.g., 500 to 1000 mg oral acetaminophen).

[0255] In some embodiments, the method of treating a solid tumor in an individual described herein further comprises admistration of granulocyte colony stimulating factor (G- CSF). In some embodiments, administration of G-CSF is required if the individual meets one or more of the following criteria: 1) treatment of febrile neutropenia and 2) experience Grade 4 neutropenia or febrile neutropenia of any grade in any cycle must receive prophylactic G- CSF in all subsequent cycles. In some embodiments, the administration of G-CSF is prophylactic. In some embodiments, the administration of G-CSF starts 1 to 3 days after the administration of the B7-H4-ADC. In some embodiments, pegfilgrastim is used. In some embodiments, administration should not occur within 14 days before or on the day of the administration of the B7-H4-ADC if pegfilgrastim is used. In some embodiments, daily G- CSF is used. In some embodiments, the administration of G-CSF should not occur within24 hours prior to or on the day of the administration of the B7-H4-ADC and treatment should continue until the ANC is >1500 / pL.

[0256] In some embodiments, there is provided a method of treating a solid tumor in an individual comprising administering a B7-H4-ADC to the individual, wherein the solid tumor is selected from the group consisting of ovarian cancer, primary peritoneal cancer, fallopian tube cancer, breast cancer, endometrial carcinoma, lung cancer, cholangiocarcinoma, gallbladder carcinoma, and head and neck carcinoma. In some embodiments, the ovarian cancer is a high-grade serous ovarian cancer (HGSOC). In some embodiments, the breast cancer is a HER2-negative / HR-positive breast cancer. In some embodiments, the breast cancer is a triple negative breast cancer (TNBC). In some embodiments, the TNBC is locally advanced unresectable or metastatic TNBC. In some embodiments, the lung cancer is a nonsmall cell lung cancer (NSCLC). In some embodiments, the NSCLC is a squamous cell lung cancer or an adenocarcinoma. In some embodiments, the head and neck carcinoma is an adenoid cystic carcinoma (ACC). In some embodiments, the individual does not have a history of another malignancy within three years before the first dose of study drug, or any evidence of residual disease from a previously diagnosed malignancy. In some embodiments, the diagnosed malignancy is an exception, wherein the excepton is a negligible risk of metastasis or death (e.g., 5-year overall survival >90%). In some embodiments, the exception is selected from the group consisting of adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, and Stage I uterine cancer. In some embodiments, the individual does not have a known active central nervous system metastases. In some embodiments, the individual has treated brain metastases and are clinically stable for at least four weeks prior to study entry after brain metastasis treatment, have no new or enlarging brain metastases, and are off corticosteroids prescribed for symptoms associated with brain metastases for at least seven days prior to the first dose of study drug. In some embodiments, the individual does not have carcinomatous meningitis. In some embodiments, the individual did not previously receive an MMAE-containing agent or an agent targeting B7-H4. In some embodiments, the individual does not have pre-existing neuropathy > Grade 2 per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0.

[0257] In some embodiments, there is provided a method of treating a high-grade serous ovarian cancer (HGSOC) in an individual comprising administering a B7-H4 ADC to the individual. In some embodiments, the HGSOC is selected from the group consisting ofepithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer. In some embodiments, the individual has platinum-resistant or -refractory disease, wherein the platinum-resistant or -refractory disease has progressed. In some embodiments, the progression is evidenced by radiographic progression. In some embodiments, the progression is evidenced by a relapse during or within 6 months after previous platinum containing chemotherapy. In some embodiments, the individual has received a bevacizumab-containing regimen. In some embodiments, the individual has received a poly ADP ribose polymerase (PARP) inhibitor. In some embodiments, the individual does not have a history of another malignancy within three years before the first dose of study drug, or any evidence of residual disease from a previously diagnosed malignancy. In some embodiments, the diagnosed malignancy is an exception, wherein the excepton is a negligible risk of metastasis or death (e.g., 5-year overall survival >90%). In some embodiments, the exception is selected from the group consisting of adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, and Stage I uterine cancer. In some embodiments, the individual does not have a known active central nervous system metastases. In some embodiments, the individual has treated brain metastases and are clinically stable for at least four weeks prior to study entry after brain metastasis treatment, have no new or enlarging brain metastases, and are off corticosteroids prescribed for symptoms associated with brain metastases for at least seven days prior to the first dose of study drug. In some embodiments, the individual does not have carcinomatous meningitis. In some embodiments, the individual did not previously receive an MMAE-containing agent or an agent targeting B7-H4. In some embodiments, the individual does not have pre-existing neuropathy > Grade 2 per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0.

[0258] In some embodiments, there is provided a method of treating a HER2- negative / HR-positive breast cancer in an individual comprising administering a B7-H4-ADC to the individual. In some embodiments, there is provided a method of treating a triple negative breast cancer (TNBC) in an individual comprising administering a B7-H4-ADC to the individual. In some embodiments, the individual has received one or more prior lines of therapy for locally advanced or metastatic disease. In some embodiemtns, the prior therapy is a taxane. In some embodiments, the taxane Is administered as single agent or in combination. In some embodiments, the individual has further received cyclin D-cyclin dependent kinase (CDK)4 / 6 inhibitor therapy unless contraindicated, and at least one prior hormonal therapy.In some embodiments, the individual has received a PARP inhibitor, PD(L)1 inhibitor, and / or phosphoinositide 3 kinase (PI3K) inhibitor. In some embodiments, the individual has HER2- negative / HR-positive breast cancer and a triple negative breast cancer (TNBC). In some embodiments, the individual with HER2-negative / HR-positive breast cancer and a triple negative breast cancer (TNBC) may be provided lenvatinib govitecan. In some embodiments, the individual does not have a history of another malignancy within three years before the first dose of study drug, or any evidence of residual disease from a previously diagnosed malignancy. In some embodiments, the diagnosed malignancy is an exception, wherein the excepton is a negligible risk of metastasis or death (e.g., 5-year overall survival >90%). In some embodiments, the exception is selected from the group consisting of adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, and Stage I uterine cancer. In some embodiments, the individual does not have a known active central nervous system metastases. In some embodiments, the individual has treated brain metastases and are clinically stable for at least four weeks prior to study entry after brain metastasis treatment, have no new or enlarging brain metastases, and are off corticosteroids prescribed for symptoms associated with brain metastases for at least seven days prior to the first dose of study drug. In some embodiments, the individual does not have carcinomatous meningitis. In some embodiments, the individual did not previously receive an MMAE-containing agent or an agent targeting B7-H4. In some embodiments, the individual does not have pre-existing neuropathy > Grade 2 per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0.

[0259] In some embodiments, there is provided a method of treating an endometrial carcinoma in an individual comprising administering a B7-H4-ADC to the individual. In some embodiments, the individual has received at least 1 line of systemic therapy. In some embodiments, the individual is assessed using a biomarker status. In some embodiments, the biomarker status includes, but is not limited to, microsatellite instability (MSI) and mismatch repair deficient (dMMR) status. In some embodiments, the individual has received a prior PD-1 inhibitor or the combination of pembrolizumab and lenvatinib. In some embodiments, the individual has received a prior PD-1 inhibitor and the combination of pembrolizumab and lenvatinib. In some embodiments, the individual does not have a history of another malignancy within three years before the first dose of study drug, or any evidence of residual disease from a previously diagnosed malignancy. In some embodiments, the diagnosed malignancy is an exception, wherein the excepton is a negligible risk of metastasis or death(e.g., 5-year overall survival >90%). In some embodiments, the exception is selected from the group consisting of adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, and Stage I uterine cancer. In some embodiments, the individual does not have a known active central nervous system metastases. In some embodiments, the individual has treated brain metastases and are clinically stable for at least four weeks prior to study entry after brain metastasis treatment, have no new or enlarging brain metastases, and are off corticosteroids prescribed for symptoms associated with brain metastases for at least seven days prior to the first dose of study drug. In some embodiments, the individual does not have carcinomatous meningitis. In some embodiments, the individual did not previously receive an MMAE-containing agent or an agent targeting B7-H4. In some embodiments, the individual does not have pre-existing neuropathy > Grade 2 per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0.

[0260] In some embodiments, there is provided a method of treating a squamous NSCLC in an individual comprising administering a B7-H4-ADC to the individual. In some embodiments, the individual has locally advanced recurrent or metastatic disease. In some embodiments, the individual with locally advanced recurrent or metastatic disease has received prior treatment with platinum-based therapy or a PD(L)1 inhibitor. In some embodiments, the individual has received prior treatment with platinum-based therapy and a PD(L)1 inhibitor. In some embodiments, the individual does not have a history of another malignancy within three years before the first dose of study drug, or any evidence of residual disease from a previously diagnosed malignancy. In some embodiments, the diagnosed malignancy is an exception, wherein the excepton is a negligible risk of metastasis or death (e.g., 5-year overall survival >90%). In some embodiments, the exception is selected from the group consisting of adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, and Stage I uterine cancer. In some embodiments, the individual does not have a known active central nervous system metastases. In some embodiments, the individual has treated brain metastases and are clinically stable for at least four weeks prior to study entry after brain metastasis treatment, have no new or enlarging brain metastases, and are off corticosteroids prescribed for symptoms associated with brain metastases for at least seven days prior to the first dose of study drug. In some embodiments, the individual does not have carcinomatous meningitis. In some embodiments, the individual did not previously receive an MMAE-containing agent oran agent targeting B7-H4. In some embodiments, the individual does not have pre-existing neuropathy > Grade 2 per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0.

[0261] In some embodiments, there is provided a method of treating a cholangiocarcinoma in an individual comprising administering a B7-H4-ADC to the individual. In some embodiments, there is provided a method of treating a gallbladder carcinoma in an individual comprising administering a B7-H4-ADC to the individual. In some embodiments, the individual has received at leat one line of systemtic therapy. In some embodiments, the individual is assessed using a biomarker status. In some embodiments, the biomarker status includes, but is not limited to, neurotrophic tyrosine kinase receptor (NTRK), fibroblast growth factor receptor (FGFR)2 genetic alterations, MSI-high, and / or high tumor mutational burden (TMB-H) status. In some embodiments, the individual has received approved targeted therapy. In some embodiments, the individual has hepatic involvement. In some embodiments, the individual does not have a history of another malignancy within three years before the first dose of study drug, or any evidence of residual disease from a previously diagnosed malignancy. In some embodiments, the diagnosed malignancy is an exception, wherein the excepton is a negligible risk of metastasis or death (e.g., 5-year overall survival >90%). In some embodiments, the exception is selected from the group consisting of adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, and Stage I uterine cancer. In some embodiments, the individual does not have a known active central nervous system metastases. In some embodiments, the individual has treated brain metastases and are clinically stable for at least four weeks prior to study entry after brain metastasis treatment, have no new or enlarging brain metastases, and are off corticosteroids prescribed for symptoms associated with brain metastases for at least seven days prior to the first dose of study drug. In some embodiments, the individual does not have carcinomatous meningitis. In some embodiments, the individual did not previously receive an MMAE-containing agent or an agent targeting B7-H4. In some embodiments, the individual does not have pre-existing neuropathy > Grade 2 per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0.

[0262] In some embodiments, there is provided a method of treating an adenoid cystic carcinoma (ACC) of the head and neck in an individual comprising administering a B7-H4- ADC to the individual. In some embodiments, the individual has locally advanced recurrentor metastatic disease. In some embodiments, the individual with locally advanced recurrent or metastatic disease has received at least one line of systemic therapy. In some embodiments, the individual has tumors that harbor genomic mutations / alterations for which approved targeted therapies are available. In some embodiments, the individual has received the approved targeted therapies. In some embodiments, the individual does not have a history of another malignancy within three years before the first dose of study drug, or any evidence of residual disease from a previously diagnosed malignancy. In some embodiments, the diagnosed malignancy is an exception, wherein the excepton is a negligible risk of metastasis or death (e.g., 5-year overall survival >90%). In some embodiments, the exception is selected from the group consisting of adequately treated carcinoma in situ of the cervix, nonmelanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, and Stage I uterine cancer. In some embodiments, the individual does not have a known active central nervous system metastases. In some embodiments, the individual has treated brain metastases and are clinically stable for at least four weeks prior to study entry after brain metastasis treatment, have no new or enlarging brain metastases, and are off corticosteroids prescribed for symptoms associated with brain metastases for at least seven days prior to the first dose of study drug. In some embodiments, the individual does not have carcinomatous meningitis. In some embodiments, the individual did not previously receive an MMAE-containing agent or an agent targeting B7-H4. In some embodiments, the individual does not have pre-existing neuropathy > Grade 2 per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0.

[0263] In some embodiments, the method provided herein further comprises determining the the expression level of B7-H4 in the solid tumor. In some embodiments, the expression level is determined by immunohistochemistry (IHC). In some embodiments, greater than 25% of the solid tumor has an IHC intensity score of 1 to 3. In some embodiments, greater than 1%, greater than 5%, greater than 10%, greater than 15%, greater than 20%, greater than 25%, greater than 30%, greater than 35%, greater than 40%, greater than 45%, greater than50%, greater than 55%, greater than 60%, greater than 65%, greater than 70%, greater than75%, greater than 80%, greater than 85%, greater than 90%, greater than 91%, greater than92%, greater than 93%, greater than 94%, greater than 95%, greater than 96%, greater than97%, greater than 98%, or greater than 99% of cells of the solid tumor express B7-H4. In some embodiments, greater than 25% of cells of the solid tumor express B7-H4. In some embodiments, greater than 50% of cells of the solid tumor express B7-H4.D. Treatment Outcomes

[0264] In one embodiment of the methods or uses or product for uses provided herein, response to treatment with an antibody-drug conjugate as described herein, such as e.g, a B7- H4-ADC, is assessed by measuring the size of a tumor derived from the cancer (e.g, breast cancer, ovarian cancer, primary peritoneal cancer, fallopian tube cancer, endometrial carcinoma, lung cancer, cholangiocarcinoma, gallbladder carcinoma, or head and neck carcinoma). In one embodiment of the methods or uses or product for uses provided herein, response to treatment with B7-H4-ADC in combination with a PD-1 inhibitor (e.g. an anti- PD1 antibody) is assessed by measuring the size of a tumor derived from the cancer (e.g., breast cancer, ovarian cancer, primary peritoneal cancer, fallopian tube cancer, endometrial carcinoma, lung cancer, cholangiocarcinoma, gallbladder carcinoma, or head and neck carcinoma).

[0265] In some embodiments, the cancer is selected from peritoneal cancer, fallopian tube cancer, and gallbladder cancer. In one preferred embodiment, the cancer is selected from the group consisting of ovarian neoplasms, peritoneal neoplasms, fallopian tube neoplasms, HER2 negative breast neoplasms, HER2 positive breast neoplasms, triple negative breast neoplasms, endometrial neoplasms, non-small-cell lung carcinoma, cholangiocarcinoma and gallbladder carcinoma. In one embodiment, the size of a tumor derived from the cancer is reduced by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, or at least about 80% relative to the size of the tumor derived from the cancer before administration of the antibody-drug conjugate described herein (e.g., a B7-H4-ADC). In one embodiment, the size of a tumor derived from the cancer is reduced by at least about 10%-80%. In one embodiment, the size of a tumor derived from the cancer is reduced by at least about 20%- 80%. In one embodiment, the size of a tumor derived from the cancer is reduced by at least about 30%-80%. In one embodiment, the size of a tumor derived from the cancer is reduced by at least about 40%-80%. In one embodiment, the size of a tumor derived from the cancer is reduced by at least about 50%-80%. In one embodiment, the size of a tumor derived from the cancer is reduced by at least about 60%-80%. In one embodiment, the size of a tumor derived from the cancer is reduced by at least about 70%-80%. In one embodiment, the size of a tumor derived from the cancer is reduced by at least about 80%. In one embodiment, the size of a tumor derived from the cancer is reduced by at least about 85%. In one embodiment,the size of a tumor derived from the cancer is reduced by at least about 90%. In one embodiment, the size of a tumor derived from the cancer is reduced by at least about 95%. In one embodiment, the size of a tumor derived from the cancer is reduced by at least about 98%. In one embodiment, the size of a tumor derived from the cancer is reduced by at least about 99%. In one embodiment, the size of a tumor derived from the cancer is reduced by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 70%, or at least 80% relative to the size of the tumor derived from the cancer before administration of the antibody-drug conjugate described herein (e.g., a B7-H4-ADC). In one embodiment, the size of a tumor derived from the cancer is reduced by at least 10%-80%. In one embodiment, the size of a tumor derived from the cancer is reduced by at least 20%-80%. In one embodiment, the size of a tumor derived from the cancer is reduced by at least 30%-80%. In one embodiment, the size of a tumor derived from the cancer is reduced by at least 40%-80%. In one embodiment, the size of a tumor derived from the cancer is reduced by at least 50%-80%. In one embodiment, the size of a tumor derived from the cancer is reduced by at least 60%-80%. In one embodiment, the size of a tumor derived from the cancer is reduced by at least 70%-80%. In one embodiment, the size of a tumor derived from the cancer is reduced by at least 80%. In one embodiment, the size of a tumor derived from the cancer is reduced by at least 85%. In one embodiment, the size of a tumor derived from the cancer is reduced by at least 90%. In one embodiment, the size of a tumor derived from the cancer is reduced by at least 95%. In one embodiment, the size of a tumor derived from the cancer is reduced by at least 98%. In one embodiment, the size of a tumor derived from the cancer is reduced by at least 99%. In one embodiment, the size of a tumor derived from the cancer is reduced by 100%. In one embodiment, the size of a tumor derived from the cancer is measured by magnetic resonance imaging (MRI). In one embodiment, the size of a tumor derived from the cancer is measured by computed tomography (CT). In one embodiment, the size of a tumor derived from the cancer is measured by positron emission tomography (PET). In one embodiment, the size of a tumor derived from the cancer is measured by ultrasound. In some embodiments, the tumor cell expresses B7-H4. In some embodiments, the tumor cell does not express B7-H4. In some embodiments, the tumor cell expresses a higher level of B7-H4 than a non-diseased cell of the same cell type. In some embodiments, the tumor cell expresses a comparable or lower level of B7-H4 than a non-diseased cell of the same cell type.I l l

[0266] In one embodiment of the methods or uses or product for uses provided described herein, response to treatment with an antibody-drug conjugate described herein (e.g., a B7- H4-ADC), promotes regression of a tumor derived from the cancer (e.g., small cell lung cancer, non-small cell lung cancer, head and neck squamous cell carcinoma, esophageal squamous cell carcinoma, gastric and gastroesophageal junction adenocarcinoma, or breast cancer). In one embodiment, a tumor derived from the cancer regresses by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, or at least about 80% relative to the size of the tumor derived from the cancer before administration of the antibody-drug conjugate described herein (e.g., a B7-H4- ADC).

[0267] In one embodiment, a tumor derived from the cancer regresses by at least about 10% to about 80%. In one embodiment, a tumor derived from the cancer regresses by at least about 20% to about 80%. In one embodiment, a tumor derived from the cancer regresses by at least about 30% to about 80%. In one embodiment, a tumor derived from the cancer regresses by at least about 40% to about 80%. In one embodiment, a tumor derived from the cancer regresses by at least about 50% to about 80%. In one embodiment, a tumor derived from the cancer regresses by at least about 60% to about 80%. In one embodiment, a tumor derived from the cancer regresses by at least about 70% to about 80%. In one embodiment, a tumor derived from the cancer regresses by at least about 80%. In one embodiment, a tumor derived from the cancer regresses by at least about 85%. In one embodiment, a tumor derived from the cancer regresses by at least about 90%. In one embodiment, a tumor derived from the cancer regresses by at least about 95%. In one embodiment, a tumor derived from the cancer regresses by at least about 98%. In one embodiment, a tumor derived from the cancer regresses by at least about 99%. In one embodiment, a tumor derived from the cancer regresses by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 70%, or at least 80% relative to the size of the tumor derived from the cancer before administration of the antibody-drug conjugate described herein (e.g., a B7-H4-ADC). In one embodiment, a tumor derived from the cancer regresses by at least 10% to 80%. In one embodiment, a tumor derived from the cancer regresses by at least 20% to 80%. In one embodiment, a tumor derived from the cancer regresses by at least 30% to 80%. In one embodiment, a tumor derived from the cancer regresses by at least 40% to 80%. In one embodiment, a tumor derived from thecancer regresses by at least 50% to 80%. In one embodiment, a tumor derived from the cancer regresses by at least 60% to 80%. In one embodiment, a tumor derived from the cancer regresses by at least 70% to 80%. In one embodiment, a tumor derived from the cancer regresses by at least 80%. In one embodiment, a tumor derived from the cancer regresses by at least 85%. In one embodiment, a tumor derived from the cancer regresses by at least 90%. In one embodiment, a tumor derived from the cancer regresses by at least 95%. In one embodiment, a tumor derived from the cancer regresses by at least 98%. In one embodiment, a tumor derived from the cancer regresses by at least 99%. In one embodiment, a tumor derived from the cancer regresses by 100%. In one embodiment, regression of a tumor is determined by measuring the size of the tumor by magnetic resonance imaging (MRI). In one embodiment, regression of a tumor is determined by measuring the size of the tumor by computed tomography (CT). In one embodiment, regression of a tumor is determined by measuring the size of the tumor by positron emission tomography (PET). In one embodiment, regression of a tumor is determined by measuring the size of the tumor by ultrasound.

[0268] In some embodiments, administration of the B7-H4-ADC induces upregulation of expression of one or more cytokines and / or one or more type I interferon response genes. In some embodiments, the cytokine is CXCL10 and / or CXCL1. In some embodiments, the type I interferon response gene is IFIT2 and / or MX1. In some embodiments, administration of the B7-H4-ADC induces upregulation of expression of CXCL10 and / or CXCL1. In some embodiments, administration of the B7-H4-ADC induces upregulation of expression of 1 FIT2 and / or A£¥7. In some embodiments, administration of the B7-H4-ADC induces activation of immune cells. In some embodiments, administration of the B7-H4-ADC induces recruitment of immune cells to tumors.

[0269] In some embodiments, administration of the B7-H4-ADC induces immunogenic cell death (ICD). In some embodiments, administration of the B7-H4-ADC induces release of ATP by cancer cells. In some embodiments, administration of the B7-H4-ADC induces exposure of calreticulin on the cancer cell surface.

[0270] In some embodiments, administration of the B7-H4-ADC promotes recruitment of innate immune cells and / or adaptive immune cells to the tumor. In some embodiments, administration of the B7-H4-ADC promotes recruitment of innate immune cells and / or adaptive immune cells to the tumor, and wherein the recruited immune cells are tumor infiltrating. In some embodiments, the innate immune cells comprise antigen-presenting cellsincluding macrophages (such as CD68+ macrophages) or dendritic cells (such as CD1 lc+ dendritic cells). In some embodiments, the adaptive immune cells comprise T cells (such as CD8+ T cells, CD3+ T cells, and / or CD3+CD8+ T cells). In some embodiments, the tumor cell expresses B7-H4. In some embodiments, the tumor cell does not express B7-H4. In some embodiments, the tumor cell expresses a higher level of B7-H4 than a non-diseased cell of the same cell type. In some embodiments, the tumor cell expresses a comparable or lower level of B7-H4 than a non-diseased cell of the same cell type.

[0271] In some embodiments, administration of the B7-H4 ADC induces an anti-tumor immune response in the individual. In some embodiments, an anti-tumor immune response is determined by a change in a marker of local inflammation at the tumor site. In some embodiments, an anti-tumor response is measured by expression of a chemokine, expression of an interferon, recruitment of a pro-inflammatory immune cell, change in cell cycle marker expression level, or change in transcript level associated with inflammation.

[0272] In some embodiments, administration of the B7-H4 ADC induces upregulation of expression of one or more chemokines and / or one or more type I interferon response genes. In some embodiments, administration of the B7-H4-ADC induces upregulation of expression of CXCI O. CXCL9, CXCL1 , IFIT2, and / or MX1. In some embodiments, expression is determined by qPCR.

[0273] In some embodiments, administration of the B7-H4-ADC promotes recruitment of innate immune cells and / or adaptive immune cells to a tumor site. In some embodiments, the innate immune cells and / or adaptive immune cells are tumor infiltrating cells. Ins some embodiments, administration of the ADC causes recruitment of dendritic cells to the tumor cite. In some embodiments, dendritic cells express CD11c. In some embodiments, administration of the ADC causes recruitment of macrophages to the tumor site. In some embodiments, administration of the ADC causes recruitment of cells expressing CD86 to the tumor cite. In some embodiments, the presence or absence of cells is determined by immunohistochemistry. In some embodiments, administration of the B7-H4-ADC promotes recruitment of CDllc+ dendritic cells, CD68+ macrophages, and / or cells expressing CD86 to a tumor site.

[0274] In some embodiments, administration of the ADC causes an increase in gene expression of one or more genes associated with inflammation at the tumor site. In some embodiments, administration of the B7-H4-ADC causes an increase in expression of a geneassociated with responsiveness to anti-PD-1 agents. In some embodiments, administration of the ADC causes an increase expression of CXCL9. In some embodiments, administration of the ADC causes an increase in expression of CXCL9, CXCL10, IFIT2, 11’773. and / or MX1.

[0275] In some embodiments, administration of the ADC causes an increase in expression of a dendritic cell and macrophage marker. In some embodiments, administration of the ADC causes an increase in expression of ITGAX. BATF3, and CD68.

[0276] In some embodiments, administration of the ADC causes an increase in expression of an MHC class II molecule. In some embodiments, administration of the ADC causes an increase in expression of HLA-DP, HLA-DM, HLA-DOA, HLA-DOB, HLA-DQ, and / or HLA-DR.

[0277] In some embodiments, administration of the ADC causes an increase in expression of a costimulatory molecule. In some embodiments, administration of the ADC causes an increase in expression of ('1)80. ('7)86. and / or ICOSL.

[0278] In some embodiments, administration of the ADC causes an increase in expression of ITGAX, BATF3. ('1)68. CD80. ('1)86. and / or ICOSL.

[0279] In some embodiments, administration of the ADC causes an increase in the presence of inflammatory cells at the tumor site. In some embodiments, the presence of CD3+ cells is increased. In some embodiments, the presence of CD4+ cells is increased. In some embodiments, the presence of CD8+ cells is increased. In some embodiments, the presence of PD1+ cells is increased. In some embodiments, the presence of inflammatory cells is determined using immunhisotochemistry.

[0280] In some embodiments, administration of the ADC causes an inflammatory gene expression signature. In some embodiments, the level of expression of CD27, CXCR6, LAG3, NKG7, PDCD1IG2, ('('1.5. CD274, CMKL31, CXCL9, PSMB10, and / or STAT I is increased.

[0281] In some embodiments, administration of the B7-H4-ADC causes a change in expression of a marker of cell division and / or cell cycle progression. In some embodiment, the level of Ki67, CD163, CD206, ChiL3, and / or Granzyme B positive cells is changed at a tumor site.

[0282] In some embodiments, the vcMMAE B7-H4 ADC provided herein trigger a more potent response compared to ADC with other microtubule inhibitor drugs. In someembodiments, the vcMMAE B7-H4 ADC provided herein trigger a more potent immune response compared to an ADC comprising the same antibody conjugated to DM1 or DM4. In some embodiments, a lower amount of the vcMMAE B7-H4 ADC is needed to trigger an immune response compared to an ADC comprising the same antibody conjugated to DM1 or DM4.IV. Pharmaceutical Compositions and Formulations

[0283] For therapeutic use, an antibody-drug conjugate (e.g., a B7-H4-ADC) is combined with a pharmaceutically acceptable carrier. In some embodiments according to any of the B7- H4-ADC compositions described herein (e.g. a composition comprising a B7-H4-ADC), the composition comprises a pharmaceutically acceptable carrier. In some embodiments according to any of the B7-H4-ADC compositions described herein (e.g. a composition comprising a B7-H4-ADC and an immune checkpoint inhibitor), the composition comprises a pharmaceutically acceptable carrier. As used herein, “pharmaceutically acceptable carrier” means buffers, carriers, and excipients suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. The carrier(s) should be “acceptable” in the sense of being compatible with the other ingredients of the formulations and not deleterious to the recipient. Pharmaceutically acceptable carriers include buffers, solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is known in the art.

[0284] In some embodiments, the B7-H4-ADC compositions described herein (e.g. a composition comprising a B7-H4-ADC and a pharmaceutically acceptable carrier) is administered in combination with pembrolizumab. Pembrolizumab is an immune checkpoint inhibitor that binds to the programmed cell death protein (PD)-l receptor and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response, including the antitumor immune response. In some embodiments, the pembrolizumab is a 100 mg / 4 mL (25 mg / mL) solution in a single use vial. In some embodiments, the pembrolizumab is for intravenous (IV) injection. In some embodiments, the pembrolizumab is sterile, preservative free, clear to slightly opalescent, and colorless to slightly yellow solution. In some embodiments, the pembrolizumab requires dilution for IV infusion. In some embodiments, a vial of pembrolizumab contains 100 mg of pembrolizumab in 4 mL of solution. In some embodiments, each 1 mL of solution contains 25 mg ofpembrolizumab and is formulated in L histidine, polysorbate, sucrose, and WFI (water for injection) USP. In some embodiments, the pembrolizumab is Keytruda®.

[0285] In some embodiments, the pembrolizumab comprises the heavy chain sequence of QVQLVQSGVEVKKPGASVKVSCKASGYTFTNYYMYWVRQAPGQGLEWMGGINPS NGGTNFNEKFKNRVTLTTDSSTTTAYMELKSLQFDDTAVYYCARRDYRFDMGFDY WGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGAL TSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYG PPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDG VEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISK AKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 93).

[0286] In some embodiments, the pembrolizumab comprises the light chain sequence of EIVLTQSPATLSLSPGERATLSCRASKGVSTSGYSYLHWYQQKPGQAPRLLIYLASYL ESGVPARFSGSGSGTDFTLTISSLEPEDFAVYYCQHSRDLPLTFGGGTKVEIKRTVAAP SVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKD STYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 94).

[0287] Accordingly, antibody-drug conjugate (e.g., a B7-H4-ADC) compositions of the present invention can comprise at least one of any suitable excipients, such as, but not limited to, diluent, binder, stabilizer, buffers, salts, lipophilic solvents, preservative, adjuvant or the like. Pharmaceutically acceptable excipients are preferred. Non-limiting examples of, and methods of preparing such sterile solutions are well known in the art, such as, but not limited to, those described in Gennaro, Ed., Remington’s Pharmaceutical Sciences, 18thEdition, Mack Publishing Co. (Easton, Pa.) 1990. Pharmaceutically acceptable carriers can be routinely selected that are suitable for the mode of administration, solubility and / or stability of the antibody molecule, fragment or variant composition as well known in the art or as described herein.

[0288] Suitable pharmaceutical excipients and / or additives for use in the antibody molecule compositions according to the invention are known in the art, e.g., as listed in “Remington: The Science & Practice of Pharmacy,” 19thed., Williams & Williams, (1995), and in the “Physician’s Desk Reference,” 52nded., Medical Economics, Montvale, N.J. (1998).

[0289] Pharmaceutical compositions containing an antibody-drug conjugate (e.g., a B7- H4-ADC) as disclosed herein can be presented in a dosage unit form and can be prepared by any suitable method. A pharmaceutical composition should be formulated to be compatible with its intended route of administration. Examples of routes of administration are intravenous (IV), intradermal, inhalation, transdermal, topical, transmucosal, and rectal administration. A preferred route of administration for monoclonal antibodies is IV infusion. Useful formulations can be prepared by methods known in the pharmaceutical art. For example, see Remington’s Pharmaceutical Sciences (1990) supra. Formulation components suitable for parenteral administration include 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 EDTA; buffers such as acetates, citrates or phosphates; and agents for the adjustment of tonicity such as sodium chloride or dextrose.

[0290] For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). The carrier should be stable under the conditions of manufacture and storage, and should be preserved against microorganisms. 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 suitable mixtures thereof.

[0291] Pharmaceutical formulations are preferably sterile. Sterilization can be accomplished by any suitable method, e.g., filtration through sterile filtration membranes. Where the composition is lyophilized, filter sterilization can be conducted prior to or following lyophilization and reconstitution.

[0292] The compositions of this invention may be in a variety of forms. These include, for example, liquid, semi-solid and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, and liposomes. The particular form depends on the intended mode of administration and therapeutic application. In exemplary embodiments, compositions provided are in the form of injectable or infusible solutions. Exemplary administration is parenteral (e.g., intravenous, subcutaneous, intraocular, intraperitoneal, intramuscular). In an exemplary embodiment, the preparation is administered by intravenous infusion or injection. In another preferred embodiment, the preparation is administered by intramuscular or subcutaneous injection.

[0293] The phrases “parenteral administration” and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, subcutaneous, intraarterial, intrathecal, intracapsular, intraorbital, intravitreous, intracardiac, intradermal, intraperitoneal, transtracheal, inhaled, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrastemal injection and infusion.

[0294] In some embodiments, the therapeutically effective dose an antibody-drug conjugate (e.g. a B7-H4 ADC) is about 0.5 mg / kg to about 3.0 mg / kg of the individual’s body weight. In some embodiments according to any one of the methods described above, the antibody or antigen binding fragment or antibody-drug conjugate (e.g. a B7-H4 ADC) is administered one or more times.

[0295] The present invention provides a kit, comprising packaging material and at least one vial comprising a solution of at least an antibody-drug conjugate (e.g., a B7-H4-ADC) with the prescribed buffers and / or preservatives, optionally in an aqueous diluent. The concentration of preservative used in the formulation is a concentration sufficient to yield an anti-microbial effect. Such concentrations are dependent on the preservative selected and are readily determined by the skilled artisan.

[0296] Various delivery systems can be used to administer antibody-drug conjugate to an individual. In certain exemplary embodiments, administration of an antibody-drug conjugate (e.g., a B7-H4-ADC) is by intravenous infusion. In some embodiments, the intravenous infusion rate is fixed. In some embodiments, the fixed intravenous infusion rate is 50 mg / hour (e.g., a dose of 100 mg would be infused over 2 hours).

[0297] Any of the formulations described above can be stored in a liquid or frozen form and can be optionally individualed to a preservation process. In some embodiments, the formulations described above are lyophilized, i.e., they are individualed to lyophilization. In some embodiments, the formulations described above are subjected to a preservation process, for example, lyophilization, and are subsequently reconstituted with a suitable liquid, for example, water. By lyophilized, it is meant that the composition has been freeze-dried under a vacuum. Lyophilization typically is accomplished by freezing a particular formulation such that the solutes are separated from the solvent(s). The solvent is then removed by sublimation (i.e., primary drying) and next by desorption (i.e., secondary drying).

[0298] In some embodiments, the lyophilized formulation comprises the antibody-drug conjugate (e.g., B7-H4-ADC) described herein. In some embodiments, the lyophilized formulation comprises a buffer. In some embodiments, the buffer comprises histidine. In some embodiments, the lyophilized formulation comprises a cryoprotectant. In some embodiments, the cryoprotectant comprises trehalose dihydrate. In some embodiments, the lyophilized formulation comprises an excipient. In some embodiments, the excipient is a polysorbate. In some embodiments, the polysorbate is polysorbate 80. In some embodiments, the lyophilized formulation comprises 20 mM histidine, 6% (w / v) trehalose dihydrate, 0.02% (w / v) polysorbate 80, and pH 6.0.

[0299] The formulations of the present invention can be used with the methods described herein or with other methods for treating disease. The antibody-drug conjugate (e.g., B7-H4- ADC) formulations may be further diluted before administration to an individual. In some embodiments, the formulations will be diluted with saline and held in IV bags or syringes before administration to an individual.V. Articles of Manufacture and Kits

[0300] In another aspect, an article of manufacture or kit is provided which comprises an antibody-drug conjugate described herein (e.g., a B7-H4-ADC). The article of manufacture or kit may further comprise instructions for use of the antibody-drug conjugate described herein (e.g., a B7-H4-ADC) in the methods of the invention. Thus, in certain embodiments, the article of manufacture or kit comprises instructions for the use of an anti-B7-H4 antibodydrug conjugate described herein (e.g., a B7-H4-ADC) in methods for treating cancer (e.g., breast cancer, ovarian cancer, primary peritoneal cancer, fallopian tube cancer, endometrial carcinoma, lung cancer, cholangiocarcinoma, gallbladder carcinoma, or head and neck carcinoma) in an individual comprising administering to the individual an effective amount of an anti-B7-H4 antibody-drug conjugate described herein (e.g., a B7-H4-ADC). In one aspect, an article of manufacture or kit is provided which comprises an antibody-drug conjugate described herein (e.g., a B7-H4-ADC), and an immune checkpoint inhibitor (e.g. an anti-PDl antibody). In some embodiments, the immune checkpoint inhibitor is pembrolizumab. The article of manufacture or kit may further comprise instructions for use of the antibody-drug conjugate described herein (e.g., a B7-H4-ADC), and the immune checkpoint inhibitor (e.g. an anti-PDl antibody) in the methods of the invention. In certain embodiments, the article of manufacture or kit comprises instructions for the use of an antibody-drug conjugate described herein (e.g., a B7-H4-ADC) and an immune checkpoint inhibitor (e.g. an anti-PDl antibody)in methods for treating cancer (e.g, breast cancer, ovarian cancer, primary peritoneal cancer, fallopian tube cancer, endometrial carcinoma, lung cancer, cholangiocarcinoma, gallbladder carcinoma, or head and neck carcinoma) in an individual comprising administering to the individual an effective amount of an anti-B7-H4 antibody-drug conjugate described herein (e.g., a B7-H4-ADC), and an effective amount of the immune checkpoint inhibitor (e.g. an anti-PDl antibody). In some embodiments, the immune checkpoint inhibitor is pembrolizumab. In some embodiments the cancer is a locally advanced cancer. In some embodiments, the cancer is a metastatic cancer. In some embodiments, the cancer is breast cancer as described herein. In certain embodiments, the article of manufacture or kit comprises instructions for the use of an antibody-drug conjugate described herein (e.g., a B7- H4-ADC) in methods for treating cancer (e.g, breast cancer, ovarian cancer, primary peritoneal cancer, fallopian tube cancer, endometrial carcinoma, lung cancer, cholangiocarcinoma, gallbladder carcinoma, or head and neck carcinoma)) in an individual comprising administering to the individual an effective amount of an anti-B7-H4 antibodydrug conjugate described herein (e.g., a B7-H4-ADC). In some embodiments the cancer is a locally advanced solid tumor. In some embodiments, the cancer is a metastatic solid tumor. In some embodiments, the cancer is small cell lung cancer as described herein. In some embodiments, the cancer is non-small cell lung cancer as described herein. In some embodiments, the cancer is head and neck cancer as described herein. In some embodiments, the cancer is esophageal carcinoma as described herein. In some embodiments, the cancer is gastric cancer as described herein. In some embodiments, the cancer is gastroesophageal junction cancer as described herein. In some embodiments, the individual is a human. In some embodiments, the cancer is selected from breast cancer, ovarian cancer, lung cancer, cholangiocarcinoma and endometrial cancer. In some embodiments herein, the cancer is selected from peritoneal cancer, fallopian tube cancer, and gallbladder cancer. In one preferred embodiment, the cancer is selected from the group consisting of ovarian neoplasms, peritoneal neoplasms, fallopian tube neoplasms, HER2 negative breast neoplasms, HER2 positive breast neoplasms, triple negative breast neoplasms, endometrial neoplasms, nonsmall-cell lung carcinoma, cholangiocarcinoma and gallbladder carcinoma.

[0301] The article of manufacture or kit may further comprise a container. Suitable containers include, for example, bottles, vials (e.g, dual chamber vials), syringes (such as single or dual chamber syringes) and test tubes. In some embodiments, the container is a vial. The container may be formed from a variety of materials such as glass or plastic. The container holds the formulation.

[0302] The article of manufacture or kit may further comprise a label or a package insert, which is on or associated with the container, may indicate directions for reconstitution and / or use of the formulation. The label or package insert may further indicate that the formulation is useful or intended for subcutaneous, intravenous (e.g, intravenous infusion), or other modes of administration for treating cancer (e.g, breast cancer, ovarian cancer, primary peritoneal cancer, fallopian tube cancer, endometrial carcinoma, lung cancer, cholangiocarcinoma, gallbladder carcinoma, or head and neck carcinoma), as described herein in an individual. The label or package insert may further indicate that the formulation is useful or intended for subcutaneous, intravenous (e.g, intravenous infusion), or other modes of administration for treating lung cancer, head and neck cancer, esophageal cancer, gastric cancer, or gastroesophageal junction cancer as described herein in an individual. The label or package insert may indicate that the formulation is useful or intended for subcutaneous, intravenous (e.g, intravenous infusion), or other modes of administration for treating breast cancer, ovarian cancer, lung cancer, cholangiocarcinoma, endometrial cancer, peritoneal cancer, fallopian tube cancer, or gallbladder cancer as described herein in an indivi...

Claims

CLAIMSWhat is claimed:

1. A method of treating a solid tumor in an individual, comprising administering to the individual a B7-H4 antibody-drug conjugate (B7-H4-ADC) twice every three weeks (2Q3W), wherein the B7-H4-ADC comprises an anti-B7-H4 antibody conjugated to a vcMMAE (valine-citruline-monomethyl auristatin E), wherein the anti-B7-H4 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region of the anti-B7-H4 antibody comprises the three complementarity determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or antigen-binding fragment thereof comprises the three CDRs of SEQ ID NO: 12; wherein the vcMMAE comprises the structure:or a pharmaceutically acceptable salt thereof.

2. A method of treating a solid tumor in an individual, comprising administering to the individual a B7-H4-ADC once every three weeks (Q3W), wherein the B7-H4-ADC comprises an anti-B7-H4 antibody conjugated to a vcMMAE (valine-citruline-monomethyl auristatin E), wherein the anti-B7-H4 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region of the anti-B7-H4 antibody comprises the three complementarity determining regions (CDRs) of SEQ ID NO: 11, and the light chain variableregion of the antibody or antigen-binding fragment thereof comprises the three CDRs of SEQ ID NO: 12; wherein the vcMMAE comprises the structure:or a pharmaceutically acceptable salt thereof.

3. The method of claim 1 or 2, wherein the B7-H4-ADC is administered at a dose of about 0.75 mg / kg to about 1.5 mg / kg, according to the individual’s body weight.

4. The method of claim 3, wherein the B7-H4-ADC is administered at a dose of about 0.75 mg / kg, about 1.0 mg / kg, about 1.25 mg / kg, or about 1.5 mg / kg, according to the individual’s body weight.

5. The method of claim 1 or 2, wherein the B7-H4-ADC is administered at a dose of about 0.25 mg / kg / week to about 1.60 mg / kg / week, according to the individual’s body weight.

6. The method of claim 5, wherein the B7-H4-ADC is administered at a dose of about 0.56 mg / kg / week, 0.67 mg / kg / week, 0.83 mg / kg / week, 1.00 mg / kg / week, 1.17 mg / kg / week, 1.33 mg / kg / week, 1.50 mg / kg / week, or about 1.60 mg / kg / week, according to the individual’s body weight.

7. The method of claim 5, wherein the B7-H4-ADC is administered at a dose of about 0.25 mg / kg / week, 0.33 mg / kg / week, about 0.42 mg / kg / week, about 0.50 mg / kg / week, 0.58mg / kg / week, 0.67 mg / kg / week, about 0.75 mg / kg / week, or about 0.80 mg / kg / week, according to the individual’s body weight.

8. The method of any one of claims 1-7, wherein the individual’s body weight is an actual body weight.

9. The method of any one of claims 1-7, wherein the individual’s body weight is an adjusted ideal body weight.

10. The method of any one of claims 1 and 3-6, wherein the B7-H4-ADC is administered on day 1 and day 8 of the three-week period.

11. The method of any one of claims 2-5 and 7, wherein the B7-H4-ADC is administered on day 1 of the three-week period.

12. The method of any one of claims 1, 3-6, and 8-10, wherein the B7-H4-ADC is administered at least four times.

13. The method of any one of claims 2-5, 7-9, and 11, wherein the B7-H4-ADC is administered at least twice.

14. A method of treating a solid tumor in an individual, comprising administering to the individual a B7-H4-ADC twice every four weeks (2Q4W), wherein the B7-H4-ADC comprises an anti-B7-H4 antibody conjugated to a vcMMAE (valine-citruline-monomethyl auristatin E), wherein the anti-B7-H4 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region of the anti-B7-H4 antibody comprises the three complementarity determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or antigen-binding fragment thereof comprises the three CDRs of SEQ ID NO: 12; wherein the vcMMAE comprises the structure:or a pharmaceutically acceptable salt thereof.

15. A method of treating a solid tumor in an individual, comprising administering to the individual a B7-H4-ADC three times every four weeks (3Q4W), wherein the B7-H4-ADC comprises an anti-B7-H4 antibody conjugated to a vcMMAE (valine-citruline-monomethyl auristatin E), wherein the anti-B7-H4 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region of the anti-B7-H4 antibody comprises the three complementarity determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or antigen-binding fragment thereof comprises the three CDRs of SEQ ID NO: 12; wherein the vcMMAE comprises the structure:or a pharmaceutically acceptable salt thereof.

16. The method of claim 14 or 15, wherein the B7-H4-ADC is administered at a dose of about 1.25 mg / kg to about 2.0 mg / kg, according to the individual’s body weight.

17. The method of claim 16, wherein the B7-H4-ADC is administered at a dose of about 1.25 mg / kg, about 1.5 mg / kg, about 1.75 mg / kg, or about 2.0 mg / kg, according to the individual’s body weight.

18. The method of claim 14 or 15, wherein the B7-H4-ADC is administered at a dose of about 0.38 mg / kg / week to about 1.80 mg / kg / week, according to the individual’s body weight.

19. The method of claim 18, wherein the B7-H4-ADC is administered at a dose of about 0.38 mg / kg / week, about 0.50 mg / kg / week, about 0.63 mg / kg / week, about 0.75 mg / kg / week, about 0.88 mg / kg / week, about 1.00 mg / kg / week, 1.13 mg / kg / week, or about 1.20 mg / kg / week, according to the individual’s body weight.

20. The method of claim 18, wherein the B7-H4-ADC is administered at a dose of about 0.56 mg / kg / week, about 0.75 mg / kg / week, about 0.94 mg / kg / week, about 1.13 mg / kg / week, about 1.31 mg / kg / week, about 1.50 mg / kg / week, about 1.69 mg / kg / week, or about 1.80 mg / kg / week, according to the individual’s body weight.

21. The method of any one of claims 14-20, wherein the individual’s body weight is an actual body weight.

22. The method of any one of claims 14-20, wherein the individual’s body weight is an adjusted ideal body weight.

23. The method of any one of claims 14, 16-19, and 22, wherein the B7-H4-ADC is administered on day 1 and day 15 of the four- week period.

24. The method of any one of claims 15, 16-18, and 20-22, wherein the B7-H4-ADC is administered on day 1, day 8, and day 15 of the four- week period.

25. The method of any one of claims 14, 16-19, and 21-23, wherein the B7-H4-ADC is administered at least four times.

26. The method of any one of claims 15, 16-18, 20-22, and 24, wherein the B7-H4-ADC is administered at least six times.

27. The method of any one of claims 1-26, wherein the B7-H4-ADC is administered intravenously (IV).

28. The method of any one of claims 1-27, wherein the solid tumor is an advanced solid tumor.

29. The method of claim 28, wherein the solid tumor is selected from the group consisting of ovarian cancer, primary peritoneal cancer, fallopian tube cancer, breast cancer, endometrial carcinoma, lung cancer, cholangiocarcinoma, gallbladder carcinoma, and head and neck carcinoma.

30. The method of claim 29, wherein the ovarian cancer is a high-grade serous ovarian cancer (HGSOC).

31. The method of claim 29, wherein the breast cancer is a HER2-negative / HR-positive breast cancer.

32. The method of claim 29, wherein the breast cancer is a triple negative breast cancer (TNBC).

33. The method of claim 32, wherein the TNBC is locally advanced unresectable or metastatic TNBC.

34. The method of claim 29, wherein the lung cancer is a non-small cell lung cancer (NSCLC).

35. The method of claim 34, wherein the NSCLC is a squamous cell lung cancer or an adenocarcinoma.

36. The method of claim 29, wherein the head and neck carcinoma is an adenoid cystic carcinoma (ACC).

37. The method of any one of claims 1-36, further comprising determining the expression level of B7-H4 in the solid tumor.

38. The method of claim 37, wherein the expression level is determined by immunohistochemistry (IHC).

39. The method of claim 38, wherein greater than 25% of the solid tumor has an IHC intensity score of 1 to 3.

40. The method of claim 38, wherein greater than 25% of cells of the solid tumor express B7-H4.

41. The method of claim 38, wherein greater than 50% of cells of the solid tumor express B7-H4.

42. The method of any one of claims 1-41, wherein such treatment results in one or more therapeutic effects selected from the group consisting of size of a tumor derived from the cancer, duration of response, progression-free survival, and overall survival.

43. The method of any one of claims 1-42, wherein such treatment results in at least about 15% reduction in tumor size in the individual.

44. The method of any one of claims 1-43, wherein such treatment results in a durable response.

45. The method of claim 44, wherein the durable response lasts for at least up to 67 weeks.

46. The method of any one of claims 1-45, wherein such treatment results in one or more therapeutic effects in the individual improving after administration of the B7-H4-ADC relative to a baseline.

47. The method of any one of claims 1-46, wherein the individual exhibits progression-free survival of at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about eighteen months, at least about two years, at least about three years, at least about four years, or at least about five years after administration of the B7-H4-ADC.

48. The method of any one of claims 1-47, wherein the individual exhibits overall survival of at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about eighteen months, at least about two years, at least about three years, at least about four years, or at least about five years after administration of the B7-H4-ADC.

49. The method of any one of claims 1-48, wherein the duration of response to the B7-H4- ADC is at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about eighteen months, at least about two years, at least about three years, at least about four years, or at least about five years after administration of the B7-H4-ADC.

50. The method of any one of claims 1-49, wherein the anti-B7-H4 antibody comprises heavy chain variable region (VH)-complementarity determining region (CDR) 1, VH-CDR2, VH-CDR3 and light chain variable region (VL)-CDRl, VL-CDR2, and VL-CDR3 sequences of SEQ ID NOs: 5-10, respectively.

51. The method of any one of claims 1-50, wherein the anti-B7-H4 antibody comprises a heavy chain variable region (HCVR) having at least 95% identity to SEQ ID NO: 11, and a light chain variable region (LCVR) having at least 95% identity to SEQ ID NO: 12.

52. The method of any one of claims 1-51, wherein the B7-H4-ADC comprises an anti- B7-H4 antibody conjugated to a vcMMAE (valine-citruline-monomethyl auristatin E), wherein the anti-B7-H4 antibody comprises a heavy chain variable region (HCVR) having at least 95% identity to SEQ ID NO: 11, and a light chain variable region (LCVR) having at least 95% identity to SEQ ID NO: 12.

53. The method of any one of claims 1-52, wherein the heavy chain variable region has at least 98% identity to SEQ ID NO: 11 and the light chain variable region has at least 98% identity to SEQ ID NO: 12.

54. The method of any one of claims 1-53, wherein the heavy chain variable region has at least 99% identity to SEQ ID NO: 11 and the light chain variable region has at least 99% identity to SEQ ID NO: 12.

55. The method of any one of claims 1-54, wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 11 and the light chain variable region comprises the sequence of SEQ ID NO: 12.

56. The method of any one of claims 1-55, wherein the B7-H4-ADC comprises thewherein Ab is the anti-B7-H4 antibody, and wherein p is a vcMMAE to antibody ratio.

57. The method of any one of claims 1-55, wherein the B7-H4-ADC comprises the structure:wherein Ab is the anti-B7-H4 antibody, and wherein p is a vcMMAE to antibody ratio.

58. The method of claim 56 or 57, wherein p is about 1 to about 8.

59. The method of claim 58, wherein p is about 4.

60. The method of any one of claims 1-59, wherein the anti-B7-H4 antibody is a fully human antibody.

61. The method of any one of claims 1-60, wherein the anti-B7-H4 antibody is a IgGl monoclonal antibody.

62. The method of any one of claims 1-61, wherein the B7-H4-ADC is within a heterogeneous population of B7-H4-ADCs, wherein the anti-B7-H4 antibodies comprised within the heterogeneous population of B7-H4-ADCs exhibit variable post-translational modifications.

63. The method of claim 62, wherein within at least 50%, 60%, 70%, 80%, 90%, or 95% of the anti-B7-H4 antibodies comprised within the heterogeneous population of B7-H4- ADCs:(i) the C-terminal lysine residues are removed from both heavy chains;(ii) the N-terminal glutamine of each heavy chain cyclized to pyroglutamic acid; and / or(iii) the consensus glycosylation site at Asn300 of each heavy chain occupied predominantly with biantennary, core fucosylated glycans without terminal galactose residues.

64. The method of any one of claims 1-63, wherein the B7-H4-ADC is administered as a monotherapy.

65. The method of any one of claims 1-63, wherein the method further comprises administering to the individual about 400 mg pembrolizumab once every 6 weeks (Q6W).

66. The method of any one of claims 1-63, wherein the method further comprises administering to the individual about 200 mg pembrolizumab once every 3 weeks (Q3W).

67. The method of claim 65 or 66, wherein the pembrolizumab is administered starting day 1.

68. The method of any one of claims 65-67, wherein the pembrolizumab is administered intravenously (IV).\T1

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