TW202517301A - Methods of treating advanced solid tumors with b7-h4 antibody-drug conjugates - Google Patents

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 for treating advanced solid tumors with B7-H4 antibody-drug conjugates

The present invention relates to methods of treating solid tumors (e.g., locally advanced or metastatic solid tumors, such as ovarian cancer, primary peritoneal cancer, fallopian tube cancer, breast cancer, endometrial cancer, lung cancer, bile duct cancer, gallbladder cancer, and head and neck cancer) with B7-H4 antibody-drug conjugates (B7-H4-ADCs).

B7-H4 is a member of the B7 family of immune checkpoint ligands, and its expression is elevated in a variety of solid tumors, especially breast and ovarian tumors (Leong et al., 2015, Mol Pharm 12 , 1717-1729). Similar to B7-H1/PD-L1, B7-H4 has been shown to negatively regulate T cell function and targeted killing of tumor cells expressing B7-H4 can 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 USA 100 , 10388-10392).

B7-H4 (also known as B7X; B7H4; B7S1; B7h.5; VCTN1; PRO1291; GenBank accession number Q7Z7D3) is an immunomodulatory 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 that contains both IgV and IgC extracellular domains. Although B7-H4 expression in healthy tissues is relatively limited at the protein level, B7-H4 is expressed in several solid tumors, such as gynecological cancers of the breast, ovary, and endometrium. B7-H4 expression in tumors is often associated with poor prognosis. The receptor for B7-H4 is unknown, but it is believed to be expressed on T cells. It is believed that B7-H4 directly inhibits T cell activity.

Cancer remains one of the most deadly threats to human health. In the United States, cancer affects nearly 1.3 million new patients each year and is the second leading cause of death after heart disease, accounting for about a quarter of deaths. It is also predicted that cancer may surpass cardiovascular disease as the leading cause of death within 5 years. Solid tumors are responsible for most of these deaths. Despite significant advances in the medical treatment of certain cancers, the overall 5-year survival rate for all cancers has only increased by about 10% in the past 20 years. Cancer or malignant tumors metastasize and grow rapidly in an uncontrolled manner, making timely detection and treatment extremely difficult.

Lung cancer remains the leading cause of cancer death in the United States, with an estimated 155,000 deaths in 2017. Curative intent treatment for patients with early-stage disease includes surgery, chemotherapy, radiation therapy, or a combination modality approach. However, the majority of patients are diagnosed with advanced disease, which is generally incurable. Non-small cell lung cancer (NSCLC) accounts for up to 80% of all lung cancers. Within the subtypes of NSCLC, squamous cell carcinoma (SCC/NSCLC) accounts for approximately 30% of NSCLC. Systemic therapies used in the metastatic setting of SCC/NSCLC have shown limited benefit, with the primary goal being to prolong survival and maintain quality of life for as long as possible while minimizing side effects attributable to treatment. First-line treatment for SCC/NSCLC patients whose tumors do not express high levels of PD-L1 includes platinum-based chemotherapy doublets without pemetrexed, anti-VEGF antibodies, or the anti-EGFR antibody necituzumab in combination with gemcitabine and cisplatin. Patients with at least 50% tumor cell PD-L1 staining receive first-line treatment with the anti-PD-1 inhibitor pembrolizumab. Patients with progression on initial combination chemotherapy regimens may receive anti-PD-1 or PD-L1 antibodies, and combination chemotherapy is considered for patients with disease progression after receiving PD-1/L1 inhibitors. New treatment categories that may provide meaningful benefit to patients with SCC/NSCLC are urgently needed.

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

Ovarian cancer is classified based on the type of cell that starts out. Epithelial ovarian cancer is the most common type of ovarian cancer, accounting for approximately 90% of ovarian cancers. It includes plasmacytoid, endometrioid, and clear cell tumors. Less common epithelial ovarian tumors are mucinous and malignant Brenner tumors. Epithelial ovarian cancer develops from epithelial cells, which are a layer of cells that cover the ovaries. Poorly differentiated epithelial ovarian cancer is defined as high-grade plasmacytoid ovarian cancer (HGSOC) and it includes fallopian tube and primary peritoneal epithelial plasmacytoid tumors. HGSOC is treated with cytotoxic therapy, including platinum chemotherapy regimens and taxanes. Targeted agents such as PARP inhibitors are used in both the therapeutic and maintenance setting. Immunotherapy is a topic of current research in ovarian cancer. In some cases, the antibody bevacizumab, although still a topic of active investigation, is used in conjunction with chemotherapy to treat advanced cancers. Relapsed, platinum-resistant and refractory HGSOC is an area of high unmet medical need.

Cholangiocarcinoma (bile duct cancer) is a disease in which malignant (cancer) cells form in the bile ducts. Cholangiocarcinoma can be intrahepatic or extrahepatic. Risk factors for cholangiocarcinoma include primary sclerosing cholangitis, ulcerative colitis, cirrhosis, hepatitis C, hepatitis B, certain liver fluke infections, and some congenital liver malformations. Cholangiocarcinoma is usually incurable at the time of diagnosis.

Endometrial cancer is cancer that begins in 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, excess estrogen exposure, high blood pressure, and diabetes. It is the third most common cause of death among cancers that affect only women, after ovarian cancer and cervical cancer.

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

Peritoneal cancer is also called serous surface papillary carcinoma, primary peritoneal cancer, extraovarian serous carcinoma, primary serous papillary carcinoma, and psammomacarcinoma. It develops in the peritoneum, a thin layer of tissue that lines the abdomen and is made of epithelial cells. The cause of peritoneal cancer is unknown. Peritoneal cancer is difficult to detect in its early stages. The median survival of primary peritoneal cancer is usually 2-6 months shorter than that of serous ovarian cancer.

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. Usually, it is discovered after symptoms such as abdominal pain, jaundice, and vomiting appear, when it has already spread to other organs, such as the liver. If the cancer is discovered after symptoms begin, the outlook for recovery is poor, with a 5-year survival rate of nearly 3%.

Clearly, there is a significant need for effective treatments for solid tumors, particularly locally advanced or metastatic solid tumors, and breast cancer, particularly advanced breast cancer. The present invention meets the need for improved treatments for solid tumors, such as locally advanced or metastatic solid tumors (e.g., ovarian cancer, lung cancer, bile duct cancer, and endometrial cancer) and breast cancer by providing highly specific and effective anti-B7-H4-antibody-drug conjugates. The present invention also meets the need for improved treatments for solid tumors, such as locally advanced or metastatic solid tumors (e.g., peritoneal cancer, fallopian tube cancer, gallbladder cancer) by providing highly specific and effective anti-B7-H4-antibody-drug conjugates.

All references (including patent applications, patent publications, and scientific literature) cited herein are incorporated by reference in their entirety to the same extent as if each individual reference was specifically and individually indicated to be incorporated by reference.

In certain aspects, provided herein is a method for treating a solid tumor in an individual, the method 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 vcMMAE (valine-citrulline-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 three complementary determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or an antigen-binding fragment thereof comprises three CDRs of SEQ ID NO: 12; wherein the vcMMAE comprises the following structure: or a pharmaceutically acceptable salt thereof.

In certain aspects, provided herein is a method of treating a solid tumor in an individual, the method 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 vcMMAE (valine-citrulline-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 three complementary determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or an antigen-binding fragment thereof comprises three CDRs of SEQ ID NO: 12; wherein the vcMMAE comprises the following structure: or a pharmaceutically acceptable salt thereof.

In some embodiments, the B7-H4-ADC is administered at a dose of about 0.75 mg/kg to about 1.5 mg/kg, based on the subject's 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, based on the subject's weight.

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, depending on the subject's body weight.

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, depending on the subject's body weight.

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, depending on the subject's body weight.

In some embodiments, the individual's weight is an actual weight. In some embodiments, the individual's weight is an adjusted ideal weight.

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

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

In certain aspects, provided herein is a method for treating a solid tumor in an individual, the method 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 vcMMAE (valine-citrulline-monomethylauristatin 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 three complementary determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or an antigen-binding fragment thereof comprises three CDRs of SEQ ID NO: 12; wherein the vcMMAE comprises the following structure: or a pharmaceutically acceptable salt thereof.

In certain aspects, provided herein is a method for treating a solid tumor in a subject, the method comprising administering to the subject a B7-H4-ADC three times every four weeks (3Q4W), wherein the B7-H4-ADC comprises an anti-B7-H4 antibody conjugated to vcMMAE (valine-citrulline-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 three complementary determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or an antigen-binding fragment thereof comprises three CDRs of SEQ ID NO: 12; wherein the vcMMAE comprises the following structure: or a pharmaceutically acceptable salt thereof.

In some embodiments, the B7-H4-ADC is administered at a dose of about 1.25 mg/kg to about 2.0 mg/kg, based on the subject's 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, based on the subject's 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, depending on the subject'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, 1.13 mg/kg/week, or about 1.20 mg/kg/week, depending on the subject'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, about 1.69 mg/kg/week, or about 1.80 mg/kg/week, depending on the subject's body weight.

In some embodiments, the individual's weight is an actual weight. In some embodiments, the individual's weight is an adjusted ideal weight.

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

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

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

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 cancer, lung cancer, bile duct cancer, gallbladder cancer, and head and neck cancer. In some embodiments, ovarian cancer is high-grade serous ovarian cancer (HGSOC). In some embodiments, breast cancer is HER2-negative/HR-positive breast cancer. In some embodiments, breast cancer is triple-negative breast cancer (TNBC). In some embodiments, TNBC is locally advanced unresectable or metastatic TNBC. In some embodiments, lung cancer is non-small cell lung cancer (NSCLC). In some embodiments, NSCLC is squamous cell lung cancer or adenocarcinoma. In some embodiments, the head and neck cancer is adenoid cystic carcinoma (ACC).

In some embodiments, the methods provided herein further comprise determining the level of B7-H4 expression in the solid tumor. In some embodiments, the expression level is determined by immunohistochemistry (IHC). In some embodiments, greater than 25% of the solid tumors have an IHC intensity score of 1 to 3. In some embodiments, greater than 25% of the solid tumor cells express B7-H4. In some embodiments, greater than 50% of the solid tumor cells express B7-H4.

In some embodiments, such treatment produces one or more therapeutic effects selected from the group consisting of: size of a tumor originating from a cancer, duration of response, progression-free survival, and overall survival. In some embodiments, such treatment results in a reduction in tumor size of the subject by at least about 15%. In some embodiments, such treatment produces a durable response. In some embodiments, the durable response lasts for at least 67 weeks. In some embodiments, such treatment results in an improvement in one or more therapeutic effects in the subject relative to baseline following administration of the B7-H4-ADC.

In some embodiments, following administration of the B7-H4-ADC, the subject exhibits a 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 18 months, at least about two years, at least about three years, at least about four years, or at least about five years.

In some embodiments, following administration of the B7-H4-ADC, the subject exhibits an 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 18 months, at least about two years, at least about three years, at least about four years, or at least about five years.

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 18 months, at least about two years, at least about three years, at least about four years, or at least about five years following administration of the B7-H4-ADC.

In some embodiments, the anti-B7-H4 antibody comprises the heavy chain variable region (VH)-complementary determining region (CDR) 1, VH-CDR2, VH-CDR3 and light chain variable region (VL)-CDR1, 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 vcMMAE (valine-citrulline-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.

In some embodiments, the B7-H4-ADC comprises the following structure: wherein Ab is an anti-B7-H4 antibody, and wherein p is the vcMMAE:antibody ratio.

In some embodiments, the B7-H4-ADC comprises the following structure: or (b) wherein Ab is an anti-B7-H4 antibody, and wherein p is the vcMMAE:antibody ratio.

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

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

In some embodiments, the anti-B7-H4 antibody is an IgG1 monoclonal antibody.

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

In some embodiments, in at least 50%, 60%, 70%, 80%, 90% or 95% of the anti-B7-H4 antibodies comprised within the heterogeneous B7-H4-ADC population: (i) the C-terminal lysine residue is removed from both heavy chains; (ii) the N-terminal glutamate of each heavy chain is cyclized to pyroglutamate; and/or (iii) the consensus glycosylation site at Asn300 of each heavy chain is predominantly occupied by ditentacled, core-fucosylated glycans without a terminal galactose residue.

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

In some embodiments, the methods provided herein further comprise administering about 400 mg of pembrolizumab to the individual once every 6 weeks (Q6W). In some embodiments, the methods provided herein further comprise administering about 200 mg of pembrolizumab to the individual once every 3 weeks (Q3W). In some embodiments, pembrolizumab is administered starting on day 1. In some embodiments, pembrolizumab is administered intravenously (IV).

Cross-references to related applications

This patent application claims the benefit of priority to 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 contents of each of which are incorporated herein by reference in their entirety. Citation of Electronic Sequence Listing

The contents of the electronic sequence listing (761682010841seqlist.xml; size: 94,573 bytes; and creation date: October 1, 2024) are incorporated herein by reference in their entirety.

In order to make the present invention more easily 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 meanings commonly understood by a person of ordinary skill in the art to which the present invention belongs. I. Definitions

As used herein (including the appended claims), singular terms such as "a," "an," and "the" include their corresponding plural referents unless the context clearly indicates otherwise.

"Antibody-drug conjugate" or "ADC" refers to an antibody conjugated to a cytotoxic or cytostatic agent. Typically, the antibody-drug conjugate binds to a target antigen (e.g., B7-H4) on the surface of a cell, followed by internalization of the antibody-drug conjugate into the cell and subsequent release of the drug into the cell. In certain exemplary embodiments, the antibody-drug conjugate is B7-H4-ADC.

A "polypeptide" or "polypeptide chain" is a polymer of amino acid residues joined by peptide bonds, whether produced naturally or synthetically. Polypeptides with less than about 10 amino acid residues are usually called "peptides."

A "protein" is a macromolecule comprising one or more polypeptide chains. Proteins may also contain non-peptide components, such as carbohydrate groups. Carbohydrate and other non-peptide substituents may be added to the protein by the cell in which it is produced, and will vary with the cell type. Proteins are defined herein in terms of their amino acid backbone structure. Substituents such as carbohydrate groups are generally not specified, but may be present nonetheless.

The terms "amino terminal" and "carboxyl terminal" indicate positions within a polypeptide. Where permitted herein, these terms are used with reference to a particular sequence or portion of a polypeptide to indicate proximity or relative positions. For example, a sequence within a polypeptide that is located at the carboxyl terminus of a reference sequence is located near the carboxyl terminus of the reference sequence, but not necessarily at the carboxyl terminus of the complete polypeptide.

For the purpose of classifying amino acid substitutions as conservative or non-conservative, the following amino acid substitutions are considered conservative substitutions: serine for threonine, alanine, or asparagine; threonine for proline or serine; asparagine for aspartic acid, histidine, or serine; aspartic acid for glutamine or asparagine; glutamine for glutamine, lysine, or aspartic acid; glutamine for arginine, lysine, or glutamine; histidine for tyrosine or asparagine; arginine for lysine or glutamine methionine is substituted with isoleucine, leucine, or valine; isoleucine is substituted with leucine, valine, or methionine; leucine is substituted with valine, isoleucine, or methionine; phenylalanine is substituted with tyrosine or tryptophan; tyrosine is substituted with tryptophan, histidine, or phenylalanine; proline is substituted with threonine; alanine is substituted with serine; lysine is substituted with glutamine, glutamine, or arginine; valine is substituted with methionine, isoleucine, or leucine; and tryptophan is substituted with phenylalanine or tyrosine. Conservative substitutions may also refer to substitutions between amino acids in the same class. The categories are as follows: Group I (hydrophobic side chains): Met, Ala, Val, Leu, Ile; Group II (neutral hydrophilic side chains): Cys, Ser, Thr; Group III (acidic side chains): Asp, Glu; Group IV (basic side chains): Asn, Gln, His, Lys, Arg; Group V (residues affecting chain orientation): Gly, Pro; and Group VI (aromatic side chains): Trp, Tyr, Phe.

Two amino acid sequences have "100% amino acid sequence identity" if the amino acid residues of the two sequences are the same when aligned for maximum correspondence. Sequence comparisons can be performed using standard software programs, such as those included in the LASERGENE bioinformatics computing suite produced by DNASTAR (Madison, Wisconsin). Other methods for comparing two nucleotide or amino acid sequences by determining the best alignment are well known to those skilled 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," 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 they have at least about 80%, at least about 85%, at least about 90%, or at least about 95% sequence identity relative to each other.

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

A composition or method "comprising" one or more recited elements may include other elements not specifically recited. For example, a composition comprising an antibody may contain the antibody alone or in combination with other ingredients.

The name of a value range includes all integers within or that define the range.

In the antibodies or other proteins described herein, references to amino acid residues corresponding to those designated by a SEQ ID NO include post-translational modifications of such residues.

The term "antibody" refers to an immunoglobulin produced by the body in response to the presence of an antigen and that binds to the antigen, as well as antigen-binding fragments and engineered variants thereof. Thus, the term "antibody" includes, for example, intact monoclonal antibodies (e.g., antibodies produced using fusion tumor technology) and antigen-binding antibody fragments, such as F(ab') ₂ , Fv fragments, bifunctional antibodies, single-chain antibodies, scFv fragments, or scFv-Fc. Also included are genetically engineered intact antibodies and fragments, such as chimeric antibodies, humanized antibodies, fully human antibodies, single-chain Fv fragments, single-chain antibodies, bifunctional antibodies, minibodies, linear antibodies, multivalent or multispecific (e.g., bispecific) hybrid antibodies, and the like. Thus, the term "antibody" is used broadly to include any protein that contains an antibody antigen binding site and is capable of specifically binding to its antigen.

The term antibody or antigen-binding fragment thereof includes "conjugated" antibodies or antigen-binding fragments thereof or "antibody-drug conjugates (ADCs)" wherein the antibody or antigen-binding fragment thereof is covalently or non-covalently bound to a pharmaceutical agent, such as a cytostatic or cytotoxic drug.

The term "genetically engineered antibody" refers to an antibody in which the amino acid sequence differs from that of the native or parent antibody. The possible variations are numerous and range from changes of only one or a few amino acids to complete redesign of, for example, the variable or constant regions. Typically, changes in the constant regions are to improve or alter characteristics, such as complement binding and other effector functions. Typically, changes in the variable regions are to improve antigen binding characteristics, improve variable region stability and/or reduce the risk of immunogenicity.

The term "chimeric antibody" refers to an antibody in which a portion of the heavy chain and/or light chain is identical or homologous to the corresponding sequence in an antibody derived from a particular species (e.g., human) or belonging to a particular antibody class or subclass, and the remainder of the chain(s) is identical or homologous to the corresponding sequence 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 as long as they exhibit the desired biological activity.

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

The "antigen binding site of an antibody" is that portion of an antibody that is sufficient to bind to its antigen. The smallest such region is usually a variable domain or a genetically engineered variant thereof. Single domain binding sites can be generated from VH domains of camel antibodies (see Muyldermans and Lauwereys, Mol. Recog. 12: 131-140, 1999; Nguyen et al., EMBO J. 19:921-930, 2000) or other species to produce single domain antibodies ("dAbs", see Ward et al., Nature 341: 544-546, 1989; U.S. Patent No. 6,248,516, Winter et al.). Typically, the antigen binding site of an antibody comprises a heavy chain variable (VH) domain and a light chain variable (VL) domain that bind to a common antigenic determinant. In the context of the present invention, in addition to the antigen binding site, an antibody may also include one or more components, such as a second antigen binding site of the antibody (which may bind to the same or different antigenic determinant or the same or 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 the 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, bifunctional antibodies, minibodies, nanobodies, Fab-scFv fusions, bispecificity (scFv)4-IgG and bispecificity (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.)

The term "immunoglobulin" refers to a protein consisting of one or more polypeptides substantially encoded by immunoglobulin genes. One form of immunoglobulin constitutes the basic structural unit of native (i.e., natural or parent) 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) together are primarily responsible for binding to antigen, while the constant regions are primarily responsible for antibody effector functions. Five classes of immunoglobulins (IgG, IgA, IgM, IgD, and IgE) have been identified in higher vertebrates. IgG constitutes the major class, and it is usually present as the second most abundant protein found in plasma. In humans, IgG consists of four subclasses, which are called IgG1, IgG2, IgG3 and IgG4. Each immunoglobulin heavy chain has a constant region composed of constant region protein domains (CH1, hinge, CH2 and CH3; IgG3 also contains the CH4 domain) that are essentially invariant for a given subclass within a species.

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 number 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 in its ordinary sense to refer to intact antibodies, component chains thereof, or fragments of chains, as the context requires.

The full-length immunoglobulin "light chain" (about 25 kDa or 214 amino acids) is encoded by a variable region gene (encoding about 110 amino acids) at the amino terminus and a kappa or lambda constant region gene at the carboxyl terminus. The full-length immunoglobulin "heavy chain" (about 50 kDa or 446 amino acids) is 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 isotype as IgG, IgM, IgA, IgD, or IgE, respectively. Within the 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), Chapter 7).

An immunoglobulin light chain or heavy chain variable region (also referred to herein as a "light chain variable domain" ("VL domain") or a "heavy chain variable domain" ("VH domain"), respectively) consists of a "framework" region interrupted by three "complementary determining regions" or "CDRs". The framework regions are used to align the CDRs for specific binding to antigenic determinants of an antigen. Thus, the term "CDR" refers to the amino acid residues in an antibody that are primarily responsible for antigen binding. From the amino terminus to the carboxyl terminus, both the VL and VH domains contain the following framework (FR) and CDR regions: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.

The amino acid assignments for each variable region domain are based on the definition 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 the VL domain are also referred to herein as CDR-L1, CDR-L2, and CDR-L3, respectively. CDRs 1, 2, and 3 of the VH domain are also referred to herein as CDR-H1, CDR-H2, and CDR-H3, respectively. If so indicated, CDR assignments may be according to IMGT® (Lefranc et al., Developmental & Comparative Immunology 27:55-77; 2003) instead of Kabat.

The numbering of recombinant protein constant regions is according to the EU index as described in Kabat (Kabat, Sequences of Proteins of Immunological Interest, National Institutes of Health, Bethesda, MD, 1987 and 1991).

Unless otherwise specified herein, the term "monoclonal antibody" is not limited to antibodies produced by fusion tumor technology. The term "monoclonal antibody" can include antibodies derived from a single clone, including any eukaryotic, prokaryotic or phage clone. In specific embodiments, the antibodies described herein are monoclonal antibodies.

The term "humanized VH domain" or "humanized VL domain" refers to an immunoglobulin VH or VL domain that comprises some or all CDRs that are completely or substantially derived from a non-human donor immunoglobulin (e.g., mouse or rat) and variable domain framework sequences that are completely or substantially derived from human immunoglobulin sequences. The non-human immunoglobulin that provides the CDRs is called the "donor" and the human immunoglobulin that provides the framework is called the "acceptor." In some cases, a humanized antibody will retain some non-human residues within the human variable domain framework regions to enhance appropriate binding characteristics (e.g., mutations in the framework may be required to maintain binding affinity when an antibody is humanized).

A "humanized antibody" is an antibody comprising one or both of a humanized VH domain and a humanized VL domain. The presence of immunoglobulin constant regions is not required, but if such constant regions are present, they are derived entirely or substantially from human immunoglobulin constant regions.

Humanized antibodies are genetically engineered antibodies 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 sequence can be, for example, a mature human antibody sequence, a complex of such sequences, a consensus sequence of human antibody sequences, or a germline region sequence.

The human acceptor sequence can be selected to have a high degree of sequence identity with the donor sequence in the variable region framework, thereby matching the canonical format between the acceptor and donor CDRs and other criteria. Thus, a humanized antibody is an antibody having CDRs that are completely or substantially derived from a donor antibody and variable region framework sequences and constant regions (if present) that are completely or substantially derived from human antibody sequences. Likewise, a humanized heavy chain typically has all three CDRs that are completely or substantially derived from a donor antibody heavy chain, and heavy chain variable region framework sequences and heavy chain constant regions (if present) that are substantially derived from human heavy chain variable region framework and constant region sequences. Likewise, a humanized light chain typically has all three CDRs derived completely or substantially from the donor antibody light chain, as well as light chain variable region framework sequences and light chain constant region sequences (if present) derived substantially from human light chain variable region framework and constant region sequences.

A CDR in a humanized antibody is substantially derived from the 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 the corresponding residues (as defined by Kabat numbering) or wherein about 100% of the corresponding residues (as defined by Kabat numbering) are identical between each CDR. The variable region framework sequence of the antibody chain or the constant region of the antibody chain is substantially derived from human variable region framework sequences or human constant regions, 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 the corresponding residues (as defined by Kabat numbering for variable regions and by EU numbering for constant regions) or about 100% of the corresponding residues (as defined by Kabat numbering for variable regions and by EU numbering for constant regions) are identical.

Although humanized antibodies generally incorporate all six CDRs from a mouse antibody (preferably as defined by Kabat or IMGT®), 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).

A CDR in a humanized antibody is "substantially derived 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 the corresponding residues (as defined by Kabat (or IMGT)) are identical between each CDR. In specific variations of humanized VH or VL domains in which the CDRs are substantially derived from non-human immunoglobulins, the CDRs of the humanized VH or VL domains have no more than six ( e.g. , no more than five, no more than four, no more than three, no more than two, or no more than one) amino acid substitutions (preferably conservative substitutions) in all three CDRs relative to the corresponding non-human VH or VL CDRs. The variable region framework sequence of an antibody VH or VL domain or, if present, the immunoglobulin constant region sequence is "substantially" derived from a human VH or VL framework sequence or a 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 the corresponding residues (as defined by Kabat numbering for variable regions and by EU numbering for constant regions) or about 100% of the corresponding residues (as defined by Kabat numbering for variable regions and by EU numbering for constant regions) are identical. Thus, all parts of humanized antibodies (except CDRs) are typically derived entirely or substantially from corresponding parts of natural human immunoglobulin sequences.

Antibodies are typically provided in an isolated form. This means that the antibody is typically at least about 50% w/w free of interfering proteins and other contaminants from its production or purification, but does not exclude the possibility of combining the antibody with an excess of a pharmaceutically acceptable carrier or other medium intended to facilitate its use. Sometimes, the antibody is at least about 60%, about 70%, about 80%, about 90%, about 95% or about 99% w/w free of interfering proteins and contaminants from its production or purification. Antibodies, including isolated antibodies, can be conjugated to a cytotoxic agent and provided as an antibody-drug conjugate.

Specific binding of an antibody to its target antigen generally refers to an affinity of at least about 10 ⁶ , about 10 ⁷ , about 10 ⁸ , about 10 ⁹ , or about 10 ¹⁰ M ^-1 . Specific binding is detectably higher in magnitude and can be distinguished from nonspecific binding occurring on at least one nonspecific target. Specific binding can be the result of bond formation between specific functional groups or specific steric coordination (e.g., lock and key type), while nonspecific binding is generally the result of van der Waals forces.

The term "antigenic determinant" refers to an antigenic site to which an antibody binds. An antigenic determinant may be formed from consecutive amino acids or non-consecutive amino acids juxtaposed by triple folding of one or more proteins. An antigenic determinant formed from consecutive amino acids is typically retained after exposure to a denaturing agent (e.g., a solvent), whereas an antigenic determinant formed from a triple fold is typically lost after treatment with a denaturing agent (e.g., a solvent). An antigenic determinant typically includes at least about 3, and more typically at least about 5, at least about 6, at least about 7, or about 8-10 amino acids in a unique spatial configuration. Methods for determining the spatial configuration of an antigenic determinant include, for example, x-ray crystallography and two-dimensional nuclear magnetic resonance. See, e.g., Epitope Mapping Protocols, Methods in Molecular Biology, Vol. 66, ed. Glenn E. Morris (1996).

Antibodies that recognize identical or overlapping antigenic determinants can be identified in simple immunoassays that show the ability of one antibody to compete with another for binding to a target antigen. Antibody antigenic determinants can also be defined by X-ray crystallography of antibodies bound to their antigens to identify contact residues.

Alternatively, if all amino acid mutations in the antigen that reduce or eliminate binding of one antibody reduce or eliminate binding of the other antibody (provided that such mutations do not produce an overall change in the structure of the antigen), then the two antibodies have identical antigenic determinants. If some amino acid mutations that reduce or eliminate binding of one antibody reduce or eliminate binding of the other antibody, then the two antibodies have overlapping antigenic determinants.

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). If an excess of the test antibody inhibits binding of the reference antibody, the test antibody competes with the reference antibody.

Antibodies identified by competition analysis (competing antibodies) include antibodies that bind to the same epitope as the reference antibody, and antibodies that bind to adjacent epitopes that are sufficiently close to the epitope bound by the reference antibody to cause steric hindrance. Antibodies identified by competition analysis also include those antibodies that indirectly compete with the reference antibody by causing conformational changes in the target protein, thereby preventing the reference antibody from binding to an epitope different from the epitope bound by the test antibody.

Antibody effector functions refer to functions contributed by the Fc region of an Ig. Such functions can be, for example, antibody-dependent cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), or complement-dependent cytotoxicity (CDC). Such functions can be affected, for example, by binding of the Fc region to Fc receptors on immune cells with phagocytic or lytic activity or by binding of the Fc region to components of the complement system. Typically, effects mediated by Fc-bound cells or complement components result in inhibition and/or depletion of B7-H4 targeted cells. The Fc region of an antibody can recruit Fc receptor (FcR) expressing cells and associate them with antibody-coated target cells. Cells that express surface FcRs for IgG, including FcγRIII (CD16), FcγRII (CD32), and FcγRIII (CD64), can act as effector cells to destroy IgG-coated cells. Such effector cells include monocytes, macrophages, natural killer (NK) cells, neutrophils, and eosinophils. Binding of IgG to FcγR activates ADCC or ADCP. ADCC is mediated by CD16+ 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, 4th edition, 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).

In addition to ADCC and ADCP, the Fc region of cell-bound antibodies can also activate the complement classical pathway to induce CDC. When the antibody is complexed with the antigen, the C1q of the complement system binds to the Fc region of the antibody. The binding of C1q to the cell-bound antibody can initiate a cascade of events involving the proteolytic activation of C4 and C2 to generate the C3 convertase. The C3 convertase cleaves C3 into C3b, enabling the activation of the terminal complement components, including C5b, C6, C7, C8, and C9. In summary, these proteins form membrane attack complex holes on antibody-coated cells. These holes destroy the integrity of the cell membrane, thereby killing the target cell (see Immunobiology, 6th edition, Janeway et al., Garland Science, N.Y., 2005, Chapter 2).

The term "antibody-dependent cytotoxicity" or "ADCC" refers to a mechanism of inducing cell death that is dependent on the interaction of antibody-coated target cells with immune cells with lytic activity (also called effector cells). Such effector cells include natural killer cells, monocytes/macrophages, and neutrophils. Effector cells attach to the Fc region of Ig that binds to the target cell via its antigen-binding site. Death of the antibody-coated target cell is a result of effector cell activity. In certain exemplary embodiments, the anti-B7-H4 IgG1 antibodies of the present invention mediate ADCC that is equal to or increased relative to the parent antibody and/or relative to the anti-B7-H4 IgG3 antibody.

The term "antibody-dependent cellular phagocytosis" or "ADCP" refers to the process by which antibody-coated cells are fully or partially internalized by phagocytic immune cells (e.g., macrophages, neutrophils and/or dendritic cells) that bind to the Fc region of the Ig. In certain exemplary embodiments, the anti-B7-H4 IgG1 antibodies of the present invention mediate ADCP that is equal to or increased relative to the parental antibody and/or relative to the anti-B7-H4 IgG3 antibody.

The term "complement-dependent cytotoxicity" or "CDC" refers to a mechanism of cell death induction in which the Fc region of a target-bound antibody activates a series of enzymatic reactions that ultimately form pores in the target cell membrane.

Typically, antigen-antibody complexes (such as those on antibody-coated target cells) bind and activate complement component C1q, which in turn activates the complement cascade, leading to target cell death. Complement activation can also result in the deposition of complement components on the surface of target cells, where they promote ADCC by binding to complement receptors (e.g., CR3) on leukocytes.

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 cells, thereby mediating the depletion, elimination and/or killing of a target cell. In certain embodiments, a cytotoxic agent is conjugated to an antibody, or is administered in combination with an antibody. Suitable cytotoxic agents are further described herein.

A "cytostatic effect" refers to the inhibition of cell proliferation. A "cytostatic agent" refers to a compound that has a cytostatic effect on cells, thereby mediating the inhibition of the growth and/or proliferation of specific cell types and/or cell subsets. Suitable cytostatic agents are further described herein.

As used herein, the terms "individual", "patient" and "subject" refer to an organism to be treated by the methods of the present invention. Such an organism is a human. As used herein, the terms "treat", "treatment" and "treating" include any effect that results in improvement of a disorder, disease, condition and the like or amelioration of its symptoms, such as reduction, diminution, regulation, improvement or elimination, such as a reduction in the number of cancer cells, a reduction in tumor size, a reduction in the rate of cancer cell infiltration into peripheral organs, or a reduction in the rate of tumor metastasis or tumor growth.

The term "tumor" applies to individuals diagnosed with or suspected of having cancer (e.g., solid cancer or breast cancer) and refers to any malignant or potentially malignant tumor or mass of tissue of any size.

"Tumor burden," also called "tumor burden," 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 the tumor throughout the body, including lymph nodes and bone marrow. Tumor burden can be determined by a variety of methods known in the art, such as by measuring the size of the tumor when removed from the individual, such as with a caliper, or in vivo using imaging techniques such as ultrasound, bone scan, computed tomography (CT), or magnetic resonance imaging (MRI) scans.

The term "tumor size" refers to the overall size of the tumor, which can be measured as the length and width of the tumor. Tumor size can be determined by a variety of methods known in the art, such as by measuring the dimensions of the tumor when removed from the individual, such as using a caliper, or in vivo using imaging techniques such as bone scans, ultrasound, CT or MRI scans.

As used herein, the term "effective amount" refers to an amount of a compound (e.g., an anti-B7-H4 antibody or antigen-binding fragment thereof or antibody-drug conjugate) sufficient to produce a beneficial or desired result. An effective amount of an antibody or antigen-binding fragment thereof or antibody-drug conjugate (e.g., 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 route of administration.

The term "pharmaceutically acceptable" means approved or approvable by a federal or state regulatory agency 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 the anti-B7-H4 antibody (e.g., B7-H4-ADC) is formulated.

The phrase "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable organic or inorganic salt. Exemplary salts include sulfates, citrates, acetates, oxalates, chlorides, bromides, iodides, nitrates, bisulfates, phosphates, acid phosphates, isonicotinates, lactates, salicylates, acid citrates, tartaric acid, oleic acid, tannates, pantothenates, tartaric acid, and the like. Hydrogenated salts, ascorbic acid salts, succinate salts, maleates, gentians, fumarates, gluconates, glucuronates, sucrose salts, formate salts, benzoates, glutamine salts, methane sulfonates, ethane sulfonates, benzene sulfonates, p-toluene sulfonates, and bis(hydroxy)naphthoates (i.e., 1, 1'-methylenebis-(2-hydroxy-3-naphthoate). Pharmaceutically acceptable salts may further comprise additional molecules, such as acetate ions, succinate ions, or other counter ions. Counter ions may be any organic or inorganic moiety that stabilizes the charge on the parent compound. In addition, pharmaceutically acceptable salts may have more than one charged atom in their structure. Cases where multiple charged atoms are part of a pharmaceutically acceptable salt may have multiple counter ions. Thus, a pharmaceutically acceptable salt may have one or more charged atoms and/or one or more counter ions.

"Platum-based therapy" means treatment with a platinum-based agent. "Platum-based agent" means a molecule or composition comprising a molecule containing a coordination complex comprising the chemical element platinum and which agent is useful as a chemotherapy drug. Platinum-based agents generally act by inhibiting DNA synthesis and some have alkylating activity. Platinum-based agents encompass those agents currently used as part of a chemotherapy regimen, those agents currently under development, and those agents that may be developed in the future.

Unless the context is clear otherwise, when a value is expressed as "about" X or "approximately" X, the specified value of X is understood to be accurate to ±10%.

Solvosomes in the context of the present invention are those forms of the compounds of the present invention that form solid or liquid complexes by coordination with solvent molecules. Hydrates are a specific form of solvate in which coordination occurs with water. In certain exemplary embodiments, solvates in the context of the present invention are hydrates. II. Antibody-Drug Conjugates

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

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 cancer, lung cancer, bile duct cancer, gallbladder cancer, or head and neck cancer), the methods comprising administering to the individual an effective amount of an antibody-drug conjugate (ADC) comprising an antibody that specifically binds to B7-H4. In some embodiments, the ADC is B7-H4-ADC.

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 is conjugated to a moiety such as a cytotoxic agent, such as, but not limited to, an anti-tubulin agent.

SGN-B7H4V is an antibody-drug conjugate (ADC) composed of a fully human IgG1 anti-B7-H4 monoclonal antibody (mAb) conjugated to the microtubule disruptor 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 vedotin (Adcetris ^™ ), vedotin (PADCEV ^™ ), vedotin (POLIVY™), and 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, which should have a similar profile to B7H41001, a non-fucosylated mAb targeting B7-H4 that showed 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)).

In some embodiments, the present invention provides an antibody-drug conjugate for treating cancer ( e.g. , breast cancer, ovarian cancer, primary peritoneal cancer, fallopian tube cancer, endometrial cancer, lung cancer, bile duct cancer, gallbladder cancer, or head and neck cancer). In some embodiments, the antibody-drug conjugate comprises an antibody conjugated to an auristatin. In some embodiments, the auristatin is monomethyl auristatin. In some embodiments, the monomethyl auristatin is monomethyl auristatin E.

Unless otherwise indicated, an anti-B7-H4-antibody drug conjugate (ie, B7-H4-ADC) includes an antibody specific for human B7-H4 protein conjugated to a cytotoxic agent.

SGN-B7H4V comprises a fully human anti-B7-H4 monoclonal IgG1 antibody (mAb) conjugated to monomethyl auristatin E (MMAE) via a protease-cleavable linker (i.e., a valine-citrulline linker). Upon binding to B7-H4-expressing cells, SGN-B7H4V is internalized and releases MMAE, thereby disrupting microtubules and inducing apoptosis.

B7-H4 ADCs (such as but not limited to SGN-B7H4V) include fully human anti-B7-H4 antibodies, examples of which are described in U.S. Patent Publication No. US20190085080. Methods of preparing certain anti-B7-H4 antibodies are also disclosed in U.S. Patent Publication No. US20190085080, which is incorporated herein by reference in its entirety for all purposes.

In some embodiments, the antibodies (e.g., monoclonal antibodies, such as chimeric, humanized or human antibodies) or antigen-binding fragments thereof specifically bind to B7-H4 (e.g., human B7-H4). The amino acid sequences of human, cynomolgus macaque, murine, and rat B7-H4 are known in the art and are also provided herein as SEQ ID NOs: 1-4, respectively. Table 1A: Amino acid sequences of human, cynomolgus macaque, murine, and rat B7-H4 Protein Amino acid sequence Human B7-H4 MASLGQILFWSIISIIIILAGAIALIIGFGISGRHSITVTTVASAGNIGEDGILSCTFEP DIKLSDIVIQWLKEGVLGLVHEFKEGKDELSEQDEMFRGRTAVFADQVIV GNASLRLKNVQLTDAGTYKCYIITSKGKGNANLEYKTGAFSMPEVNVDYN ASSETLRCEA PRWFPQPTVV WASQVDQGAN FSEVSNTSFELNSENVTMKV VSVLYNVTINNTYSCMIENDIAKATGDIKVTESEIKRRSHLQLLNSKASL CVSSFFAISWALLPLSPYLMLK (SEQ ID NO: 1) Crab-eating macaque B7-H4 MASLGQILFW SIISIIFILA GAIALIIGFG ISGRHSITVT TVASAGNIGE DGILSCTFEP DIKLSDIVIQ WLKEGVIGLV HEFKEGKDEL SEQDEMFRGR TAVFADQVIV GNASLRLKNV QLTDAGTYKC YIITSKGKGN ANLEYKTGAF SMPEVNVDYN ASSETLRCEA PRWFPQPTVV WASQVDQGAN FSEVSNTSFE LNSENVTMKV VSVLYNVTIN NTYSCMIEND IAKATGDIKV TESEIKRRSH LQLLNSKASL CVSSFLAISW ALLPLAPYLM LK (SEQ ID NO: 2) Murine B7-H4 MASLGQIIFW SIINIIIILA GAIALIIGFG ISGKHFITVT TFTSAGNIGE DGTLSCTFEP DIKLNGIVIQ WLKEGIKGLV HEFKEGKDDL SQQHEMFRGR TAVFADQVVV GNASLRLKNV QLTDAGTYTC YIRTSKGKGN ANLEYKTGAF SMPEINVDYN ASSESLRCEA PRWFPQPTVA WASQVDQGAN FSEVSNTSFE LNSENVTMKV VSVLYNVTIN NTYSCMIEND IAKATGDIKV TDSEVKRRSQ LQLLNSGPSP CVFSSAFVAG WALLSLSCCL MLR (SEQ ID NO: 3) Rat B7-H4 MASLGQIIFW SIINVIIILA GAIVLIIGFG ISGKHFITVT TFTSAGNIGE DGTLSCTFEP DIKLNGIVIQ WLKEGIKGLV HEFKEGKDDL SQQHEMFRGR TAVFADQVVV GNASLRLKNV QLTDAGTYTC YIHTSKGKGN ANLEYKTGAF SMPEINVDYN ASSESLRCEA PRWFPQPTVA WASQVDQGAN FSEVSNTSFE LNSENVTMKV VSVLYNVTIN NTYSCMIEND IAKATGDIKV TDSEVKRRSQ LELLNSGPSP CVSSVSAAGW ALLSLSCCLM LR (SEQ ID NO: 4)

In certain embodiments according to any of the methods or antibody-conjugates described herein, the ADC described herein binds to human B7-H4. In certain embodiments, the ADC binds to human and cynomolgus macaque B7-H4. In certain embodiments, the ADC binds to human, murine, and rat B7-H4. In certain embodiments, the ADC specifically binds to one or more of: human, cynomolgus macaque, murine, and rat B7-H4.

B7-H4 contains the IgC extracellular domain (amino acids 153-241 of SEQ ID NO: 1) and the IgV domain (amino acids 35-146 of SEQ ID NO: 1).

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.

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

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, a 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.

In some embodiments, the ADC comprises a VH comprising a sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 11; and a VL comprising a sequence having 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 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 11; and a VL comprising a sequence having 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 having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 11; and a VL comprising a sequence having 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 having at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 11; and a VL comprising a sequence having 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 having at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 11; and a VL comprising a sequence having 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, the ADC described herein binds to human B7-H4 and comprises the heavy chain sequence of SEQ ID NO: 13. In certain embodiments, the ADC described herein binds to human B7-H4 and comprises the light chain sequence of SEQ ID NO: 14. Table 1B: CDR, variable region, and full-length antibody amino acid sequences of B7-H41001 mAb. sequence SEQ ID NO: sequence VH CDR1 5 GSIKSGSYYWG VH CDR2 6 NIYYSGSTYYNPSLRS VH CDR3 7 AREGSYPNQFDP VL CDR1 8 RASQSVSSNLA VL CDR2 9 GASTRAT VL CDR3 10 QQYHSFPFT VH 11 QLQLQESGPGLVKPSETLSLTCTVSGGSIKSGSYYWGWIRQPPGKGLEWIGNIYYSGSTYYNPSLRSRVTISVDTSKNQFSLKLSSVTAADTAVYYCAREGSYPNQFDPWGQGTLVTVSS V L 12 EIVMTQSPATLSVSPGERATLSCRASQSVSSNLAWYQQKPGQAPRLLIYGASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYHSFPFTFGGGTKVEIK Full length chain 13 QLQLQESGPGLVKPSETLSLTCTVSGGSIKSGSYYWGWIRQPPGKGLEWIGNIYYSGSTYYNPSLRSRVTISSVDTSKNQFSLKLSSVTAADTAVYYCAREGSYPNQFDPWGQ GTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDK THTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK Full length chain 14 EIVMTQSPATLSVSPGERATLSCRASQSVSSNLAWYQQKPGQAPRLLIYGASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYHSFPFTFGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

In certain embodiments, the ADCs described herein bind to human B7-H4 and comprise six CDRs of the antibodies listed in Tables 2 and 3 (i.e., three VH CDRs of the antibodies listed in Table 2 and three VL CDRs of the same antibodies listed in Table 3). Table 2. VH CDR amino acid sequences (Kabat) antibody VH CDR1 VH CDR2 VH CDR3 15495 GTFSSYAIS (SEQ ID NO: 15) GIIPIFGTA S YAQKFQG (SEQ ID NO: 22) ARQQYDGRRYFGL (SEQ ID NO: 29) 15503 FTFSSYAMS (SEQ ID NO: 16) AISGSGGSTYYADSVKG (SEQ ID NO: 23) ARVGFRALNY (SEQ ID NO: 30) 15465 GSISSGGYYWS (SEQ ID NO: 17) NIYYSGSTYYNPSLKS (SEQ ID NO: 24) ARESSTISADFDL (SEQ ID NO: 31) 20506 GSISHGGYYWS (SEQ ID NO: 18) NIYYSGSTYYNPSLKS (SEQ ID NO: 24) ARESSTISADFDL (SEQ ID NO: 31) 20513 GSISDGSYYWS (SEQ ID NO: 19) NIYYSGSTYYNPSLRS (SEQ ID NO: 6) ARGLSTIDEAFDP (SEQ ID NO: 32) 20516 GSIISYYWG (SEQ ID NO: 20) YIYSSGSTSYNPSLKS (SEQ ID NO: 25) ARGSGLYAAPDYGLDV (SEQ ID NO: 33) 15472 FTFSSYAMS (SEQ ID NO: 16) TISGSGGSTYYADSVKG (SEQ ID NO: 26) ARGAGHYDLVGRY (SEQ ID NO: 34) 15478 GTFSSYAIS (SEQ ID NO: 15) GIIPIFGTANYAQKFQG (SEQ ID NO: 27) ARGGPWFDP (SEQ ID NO: 35) 20496 GSISSSVYYWS (SEQ ID NO: 21) SILVSGSTYYNPSLKS (SEQ ID NO: 28) ARAVSFLDV (SEQ ID NO: 36) Table 3. VL CDR amino acid sequences (Kabat) antibody VL CDR1 VL CDR2 VL CDR3 15495 RASQSVSSNLA (SEQ ID NO: 8) SASTRAT (SEQ ID NO: 41) QQVNVWPPT (SEQ ID NO: 45) 15503 RASQDISSWLA (SEQ ID NO: 37) AASSLQS (SEQ ID NO: 42) QQATSYPPWT (SEQ ID NO: 46) 15465 RASQGISRWLA (SEQ ID NO: 38) AASSLQS (SEQ ID NO: 42) QQAHTFPYT (SEQ ID NO: 47) 20506 RASQGISRWLA (SEQ ID NO: 38) AASSLQS (SEQ ID NO: 42) QQAHTFPYT (SEQ ID NO: 47) 20513 RASQSISSWLA (SEQ ID NO: 39) KASSLES (SEQ ID NO: 43) QQDNSYPYT (SEQ ID NO: 48) 20516 RASQSISSWLA (SEQ ID NO: 39) KASSLES (SEQ ID NO: 43) QQDNSFPFT (SEQ ID NO: 49) 15472 RASQSISSYLN (SEQ ID NO: 40) AASSLQS (SEQ ID NO: 42) QQLYSLPPT (SEQ ID NO: 50) 15478 RASQSISSWLA (SEQ ID NO: 39) KASSLES (SEQ ID NO: 43) QQYNSYPPFT (SEQ ID NO: 51) 20496 RASQSISSYLN (SEQ ID NO: 40) GASSLQS (SEQ ID NO: 44) QQSYDPPWT (SEQ ID NO: 52)

In certain embodiments, the ADCs described herein bind to human B7-H4 and comprise the VH and VL of the antibodies 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 sequences antibody VH amino acid sequence 15495 QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPIFGTASYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARQQYDGRRYFGLWGRGTLVTVSS (SEQ ID NO: 53) 15503 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARVGFRALNYWGQGTTVTVSS (SEQ ID NO: 54) 15465 QVQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQHPGKGLEWIGNIYYSGSTYYNPSLKSRVTISSVDTSKNQFSLKLSSVTAADTAVYYCARESSTISADFDLWGRGTLVTVSS (SEQ ID NO: 55) 20506 QLQLQESGPGLVKPSETLSLTCTASGGSISHGGYYWSWIRQHPGKGLEWIGNIYYSGSTYYNPSLKSRVTMSVDTSKNQFSLKLSSVTAADTAVYYCARESSTISADFDLWGRGTLVTVSS (SEQ ID NO: 56) 20513 QLQLQESGPGLVKPSETLSLTCTVSGGSISDGSYYWSWIRQHPGKGLEWIGNIYYSGSTYYNPSLRSRVTMSSVDTSKNQFSLKLSSVTAADTAVYYCARGLSTIDEAFDPWGQGTLVTVSS (SEQ ID NO: 57) 20516 QVQLQESGPGLVKPSETLSLTTCTVSGGSIISYYWGWIRQPPGKGLEWIGYIYSSGSTSYNPSLKSRVTISSVDTSKNQFSLKLSSVTAADTAVYYCARGSGLYAAPDYGLDVWGQGTTVTVSS (SEQ ID NO: 58) 15472 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSTISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGAGHYDLVGRYWGQGTLVTVSS (SEQ ID NO: 59) 15478 QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARGGPWFDPWGQGTLVTVSS (SEQ ID NO: 60) 20496 QLQLQESGPGLVKPSETLSLTCTVSGGSISSSVYYWSWIRQPPGKGLEWIGSILVSGSTYYNPSLKSRVTISSVDTSKNQFSLKLSSVTAADTAVYYCARAVSFLDVWGQGTMVIVSS (SEQ ID NO: 61) Table 5. VL amino acid sequence antibody VL amino acid sequence 15495 EIVMTQSPATLSVSPGERATLSCRASQSVSSNLAWYQQKPGQAPRLLIYSASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQVNVWPPTTFGGGTKVEIK (SEQ ID NO: 62) 15503 DIQLTQSPSSVSASVGDRVTITCRASQDISSWLAWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQATSYPPWTFGGGTKVEIK (SEQ ID NO: 63) 15465 DIQMTQSPSSVSASVGDRVTITCRASQGISRWLAWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQAHTFPYTFGGGTKVEIK (SEQ ID NO: 64) 20506 DIQMTQSPSSVSASVGDRVTITCRASQGISRWLAWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQAHTFPYTFGGGTKVEIK (SEQ ID NO: 65) 20513 DIQMTQSPSTLSASSVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLIYKASSLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQDNSYPYTFGGGTKVEIK (SEQ ID NO: 66) 20516 DIQMTQSPSTLSASSVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLIYKASSLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQDNSFPFTFGGGTKVEIK (SEQ ID NO: 67) 15472 DIQMTQSPSSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQLYSLPPTFGGGTKVEIK (SEQ ID NO: 68) 15478 DIQMTQSPSTLSASSVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLIYKASSLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQYNSYPPFTFGGGTKVEIK (SEQ ID NO: 69) 20496 DIQMTQSPSSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYGASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYDPPWTFGGGTKVEIK (SEQ ID NO: 70)

In certain embodiments, the ADC described herein binds to human B7-H4 and comprises the heavy chain sequence of the antibodies listed in Table 6. Table 6: Full-length heavy chain amino acid sequences antibody Full-length heavy chain amino acid sequence 15495 QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPIFGTASYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARQQYDGRRYFGLWGR GTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDK THTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 71) 15503 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARVGFRALNYWGQGT TVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKT HTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT ISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 72) 15465 QVQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQHPGKGLEWIGNIYYSGSTYYNPSLKSRVTISSVDTSKNQFSLKLSSVTAADTAVYYCARESSTISADFDLWG RGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCD KTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 73) 20506 QLQLQESGPGLVKPSETLSLTCTASGGSISHGGYYWSWIRQHPGKGLEWIGNIYYSGSTYYNPSLKSRVTMSVDTSKNQFSLKLSSVTAADTAVYYCARESSTISADFDLWG RGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCD KTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 74) 20513 QLQLQESGPGLVKPSETLSLTCTVSGGSISDGSYYWSWIRQHPGKGLEWIGNIYYSGSTYYNPSLRSRVTMSVDTSKNQFSLKLSSVTAADTAVYYCARGLSTIDEAFDPWG QGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCD KTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 75) 20516 QVQLQESGPGLVKPSETLSLTCTVSGGSIISYYWGWIRQPPGKGLEWIGYIYSSGSTSYNPSLKSRVTISSVDTSKNQFSLKLSSVTAADTAVYYCARGSGLYAAPDYGLDVWG QGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCD KTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 76) 15472 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSTISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGAGHYDLVGRYWGQ GTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDK THTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 77) 15478 QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARGGPWFDPWGQGTL VTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH TCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT ISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 78) 20496 QLQLQESGPGLVKPSETLSLTCTVSGGSISSSVYYWSWIRQPPGKGLEWIGSILVSGSTYYNPSLKSRVTISSVDTSKNQFSLKLSSVTAADTAVYYCARAVSFLDVWGQGT MVIVSSASTKGPSVFPLAPSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKT HTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT ISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 79)

In certain embodiments, the ADCs described herein bind to human B7-H4 and comprise the light chain sequences of the antibodies listed in Table 7. Table 7: Full length light chain amino acid sequences antibody Full-length light chain amino acid sequence 15495 EIVMTQSPATLSVSPGERATLSCRASQSVSSNLAWYQQKPGQAPRLLIYSASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQVNVWPPTFGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 80) 15503 DIQLTQSPSSVSASVGDRVTITCRASQDISSWLAWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQATSYPPWTFGGGTKVEI KRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 81) 15465 DIQMTQSPSSVSASVGDRVTITCRASQGISRWLAWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQAHTFPYTFGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 82) 20506 DIQMTQSPSSVSASVGDRVTITCRASQGISRWLAWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQAHTFPYTFGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 83) 20513 DIQMTQSPSTLSASSVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLIYKASSLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQDNSYPYTFGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 84) 20516 DIQMTQSPSTLSASSVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLIYKASSLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQDNSFPFTFGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 85) 15472 DIQMTQSPSSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQLYSLPPTFGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 86) 15478 DIQMTQSPSTLSASSVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLIYKASSLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQYNSYPPFTFGGGTKVEI KRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 87) 20496 DIQMTQSPSSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYGASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYDPPWTFGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 88)

In certain embodiments, the ADC described herein binds to human B7-H4 and comprises the heavy chain sequence and light chain sequence of the antibodies 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).

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

In certain embodiments, the ADC described herein binds to human B7-H4, comprises six CDRs of an antibody listed in Tables 2 and 3 (i.e., three VH CDRs of the antibody listed in Table 2 and three VL CDRs of the same antibody listed in Table 3), and comprises a VH comprising a sequence at least 90% identical to a VH sequence of the same antibody in Table 4; and a VL comprising a sequence at least 90% identical to a VL sequence of the same antibody in Table 5. In certain embodiments, the ADC described herein binds to human B7-H4, comprises six CDRs of an antibody listed in Tables 2 and 3 (i.e., three VH CDRs of an antibody listed in Table 1B and three VL CDRs of the same antibody listed in Table 2), and comprises a VH comprising a sequence at least 95% identical to a VH sequence of the same antibody in Table 4; and a VL comprising a sequence at least 95% identical to a VL sequence of the same antibody in Table 5.

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

In some embodiments, the ADC increases T cell proliferation. In some embodiments, the ADC increases IFN-γ 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.

In certain aspects, the ADC described herein can be described by its VL domain alone, or by its VH domain alone, or by its three VL CDRs alone, or by its three VH CDRs alone. See, e.g., Rader C et al., (1998) PNAS 95: 8910-8915, which is incorporated herein by reference in its entirety, describing the humanization of mouse anti-αvβ3 antibodies by identifying complementary light chains or heavy chains from human light chain or heavy chain libraries, respectively, thereby generating humanized antibody variants having an affinity as high as or higher than that 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 a method for generating antibodies that bind to a specific antigen by using a specific VL domain (or VH domain) and screening a library of complementary variable domains. The screening generated 14 new partners for the specific VH domain and 13 new partners for the specific VL domain that were strong binders as determined by ELISA. See also Kim SJ and Hong HJ, (2007) J Microbiol 45: 572-577, which is incorporated herein by reference in its entirety, describing methods for generating antibodies that bind to a specific antigen by using a particular VH domain and screening a library (e.g., a human VL library) against complementary VL domains; the selected VL domains can in turn be used to guide the selection of additional complementary (e.g., human) VH domains.

In certain aspects, the CDRs of an antibody on an ADC can be identified according to the Chothia numbering scheme, which refers to the location of immunoglobulin structural loops (see, e.g., Chothia C and 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; Tramontano A et al., (1990) J Mol Biol 215(1): 175-82; and U.S. Patent No. 7,709,226). Typically, when the Kabat numbering convention is used, the Chothia CDR-H1 loop is present at heavy chain amino acids 26 to 32, 33, or 34, the Chothia CDR-H2 loop is present 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. When numbering using the Kabat numbering convention, the end of the Chothia CDR-H1 loop varies between H32 and H34, depending on the loop length (this is because the Kabat numbering scheme places the insertion at H35A and H35B; if both 35A and 35B are absent, 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).

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 the antibodies listed in Tables 4 and 5. In certain embodiments, the ADCs that specifically bind to B7-H4 (e.g., human B7-H4) comprise one or more CDRs wherein 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 a combination of Kabat CDRs and Chothia CDRs.

In certain aspects, the CDRs of an ADC can be identified 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 the antibodies listed in Tables 4 and 5, e.g., as described in Lefranc M-P (1999) supra and Lefranc M-P et al., (1999) supra).

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", Antibody Engineering, Kontermann and Diibel, eds., Chapter 31, pp. 422-439, Springer-Verlag, Berlin (2001). In a particular embodiment, provided herein is an ADC that specifically binds to B7-H4 (e.g., human B7-H4) and comprises the VH and VL CDRs of the antibodies listed in Tables 4 and 5, as determined by the method of MacCallum RM et al.

In certain aspects, the CDRs of an antibody on an ADC can be identified according to the AbM numbering scheme, which refers to the AbM hypervariable regions, which represent a compromise between the Kabat CDRs and the 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 the VH and VL CDRs of the antibodies listed in Tables 4 and 5, as identified by the AbM numbering scheme.

In a specific embodiment, antibodies comprising a heavy chain and a light chain are provided herein. With respect to the heavy chain, in a specific embodiment, the heavy chain of the ADC described herein may be an alpha, delta, epsilon, gamma, or mu heavy chain. In another specific embodiment, the heavy chain of the ADC may comprise a human alpha, delta, epsilon, gamma, or mu heavy chain. In a specific embodiment, the ADC described herein immunospecifically binds to B7-H4 (e.g., human B7-H4), comprises a heavy chain, wherein the amino acid sequence of the VH domain comprises the 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 heavy chain constant region. In a particular embodiment, the ADC described herein 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 acids 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.

With respect to the light chain, in a specific embodiment, the light chain of the ADC described herein is a kappa light chain. The constant region of the human kappa light chain may comprise the following amino acid sequence: RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 89).

The constant region of the human kappa light chain can be encoded by the following nucleotide sequence: CGGACCGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT (SEQ ID NO: 90).

In another specific embodiment, the light chain of the ADC described herein is a lambda light chain. In yet another specific embodiment, the light chain of the ADC described herein is a human kappa light chain or a human lambda light chain. In a specific embodiment, the ADC described herein 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 lambda light chain constant region. In another specific embodiment, the ADC described herein 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 λ light chain constant region. In a specific embodiment, the ADC described herein 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 κ or λ 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.

In a specific embodiment, the ADC described herein immunospecifically binds to B7-H4 (e.g., human B7-H4), comprises a VH domain and a VL domain comprising any of the amino acid sequences described herein, and wherein the constant region comprises an amino acid sequence of a constant region 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, the ADC described herein immunospecifically binds to B7-H4 (e.g., human B7-H4), comprises a VH domain and a VL domain comprising any of the amino acid sequences described herein, and wherein the constant region comprises an amino acid sequence of a constant region of an IgG, IgE, IgM, IgD, IgA, or IgY immunoglobulin molecule, any class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2) or any subclass (e.g., IgG2a and IgG2b) of immunoglobulin molecules. In a specific embodiment, the constant region comprises the amino acid sequence of a human IgG, IgE, IgM, IgD, IgA or IgY immunoglobulin molecule, any class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2) or any subclass (e.g., IgG2a and IgG2b) of immunoglobulin molecules.

The constant region of the human IgG1 heavy chain may include the following amino acid sequence: ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGYSSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISR TPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDK SRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO:91).

The constant region of the human IgG1 heavy chain can be encoded by the following nucleotide sequence: GCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGG GCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTAC GTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGT CAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTC CTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA. (SEQ ID NO: 92)

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

In certain embodiments, one, two or more mutations (e.g., amino acid substitutions) are introduced into the Fc region (e.g., CH2 domain (residues 231-340 of human IgG1) and/or CH3 domain (residues 341-447 of human IgG1) and/or hinge region, wherein the numbering is according to the Kabat numbering system (e.g., EU index in Kabat)) of the ADC described herein 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.

In certain embodiments, one, two or more mutations (e.g., amino acid substitutions) are introduced into the hinge region of the Fc region (CH1 domain) to alter (e.g., increase or decrease) the number of cysteine residues in the hinge region, as described, for example, in U.S. Patent No. 5,677,425. The number of cysteine residues in the hinge region of the CH1 domain can be altered, for example, to facilitate the assembly of the light and heavy chains or to alter (e.g., increase or decrease) the stability of the ADC.

In some embodiments, one, two or more mutations (e.g., amino acid substitutions) are introduced into the Fc region (e.g., CH2 domain (residues 231-340 of human IgG1) and/or CH3 domain (residues 341-447 of human IgG1) and/or hinge region, wherein the numbering is according to the Kabat numbering system (e.g., EU index in Kabat)) of the ADC described herein 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. Fc region mutations that decrease or increase affinity for an Fc receptor and techniques for introducing such mutations into an Fc receptor or fragment thereof are known to those skilled in the art. Examples of Fc receptor mutations that can be used to alter the affinity of the ADC for the Fc receptor are described, for example, in Smith P et al., (2012) PNAS 109: 6181-6186, U.S. Patent No. 6,737,056, and International Publication Nos. WO 02/060919; WO 98/23289; and WO 97/34631, which are incorporated herein by reference.

In a specific embodiment, one, two or more amino acid mutations (i.e., substitutions, insertions or deletions) are introduced into an IgG coherent domain or an FcRn binding fragment thereof (preferably, an Fc or hinge-Fc domain fragment) to alter (e.g., reduce or increase) the in vivo half-life of the ADC. For examples of mutations that will alter (e.g., reduce or increase) the in vivo half-life of an ADC, see, e.g., International Publication Nos. WO 02/060919; WO 98/23289; and WO 97/34631; and U.S. Patent Nos. 5,869,046, 6,121,022, 6,277,375, and 6,165,745. In some embodiments, one, two or more amino acid mutations (i.e., substitutions, insertions or deletions) are introduced into an IgG constant domain or an FcRn binding fragment thereof (preferably, an Fc or hinge-Fc domain fragment) to reduce the in vivo half-life of the ADC. In other embodiments, one, two or more amino acid mutations (i.e., substitutions, insertions or deletions) are introduced into an IgG constant domain or an FcRn binding fragment thereof (preferably, an Fc or hinge-Fc domain fragment) to increase the in vivo half-life of the ADC. 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 IgG1) and/or the third constant (CH3) domain (residues 341-447 of human IgG1), wherein the EU index numbering is according to Kabat (Kabat EA et al., (1991) supra). In a specific embodiment, the constant region of IgG1 comprises a methionine (M) to tyrosine (Y) substitution at position 252, a serine (S) to threonine (T) substitution at position 254, and a threonine (T) to glutamine (E) substitution at position 256, wherein the EU index numbering is according to Kabat. See U.S. Patent No. 7,658,921, which is incorporated herein by reference. This type of mutant IgG is called a "YTE mutant" and has been shown to exhibit a four-fold increased half-life compared to the wild-type of the same antibody (see Dall'Acqua W F et al., (2006) J Biol Chem 281: 23514-24). In certain embodiments, the 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, according to the EU index numbering in Kabat.

In another embodiment, one, two or more amino acid substitutions are introduced into the Fc region of the IgG constant domain to change the effector function of the ADC. For example, one or more amino acids selected from amino acid residues 234, 235, 236, 237, 297, 318, 320 and 322 according to the EU index number in Kabat can be replaced by different amino acid residues so that the ADC has a changed affinity for the effector ligand, but retains the antigen binding ability of the parent antibody. The effector ligand with changed affinity can be, for example, the C1 component of an Fc receptor or complement. This method is described in more detail in U.S. Patent Nos. 5,624,821 and 5,648,260. In some embodiments, deletion or inactivation of the homeostasis region domain (via point mutation or otherwise) can reduce Fc receptor binding of circulating ADCs, thereby increasing tumor localization. For descriptions of mutations that delete or inactivate homeostasis domains and thereby increase tumor localization, see, e.g., U.S. Patent Nos. 5,585,097 and 8,591,886. In certain embodiments, one or more amino acid substitutions can be introduced into the Fc region to remove potential glycosylation sites on the Fc region, which can reduce Fc receptor binding (see, e.g., Shields RL et al., (2001) J Biol Chem 276: 6591-604).

In certain embodiments, one or more amino acids selected from amino acid residues 329, 331 and 322 in the constant region according to the EU index numbering in Kabat can be replaced by different amino acid residues so that the ADC changes C1q binding and/or reduces or eliminates complement-dependent cytotoxicity (CDC). This method is described in more detail in U.S. Patent 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 changed to change the ability of the antibody to fix complement. This method is further described in International Publication No. WO 94/29351. In certain embodiments, the Fc region is modified by mutating (e.g., introducing amino acid substitutions) one or more amino acids at the following positions to increase the ability of the ADC to mediate antibody-dependent cellular cytotoxicity (ADCC) and/or increase the affinity of the ADC for the Fey receptor: 238, 239, 248, 249, 252, 254, 255, 256, 258, 265, 267, 268, 269, 270, 272, 276, 278, 280, 283, 285, 286, 289, 290, 292, 294, 295 3, 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 according to the EU index numbering in Kabat. This method is further described in International Publication No. WO 00/42072.

In certain embodiments, the ADC described herein comprises a constant domain of IgG1 having a mutation (e.g., substitution) at position 267, 328, or a combination thereof, numbered according to the EU index in Kabat. In certain embodiments, the ADC described herein comprises a constant domain of IgG1 having a mutation (e.g., substitution) selected from the group consisting of S267E, L328F, and a combination thereof. In certain embodiments, the ADC described herein comprises a constant domain of IgG1 having a S267E/L328F mutation (e.g., substitution). In certain embodiments, the ADC described herein comprises a constant domain of IgG1 having a S267E/L328F mutation (e.g., substitution) with increased binding affinity to FcγRIIA, FcγRIIB, or FcγRIIA and FcγRIIB.

In certain embodiments, the ADC (i) comprises the CDR sequences of B7H41001 mAb (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 chain and light chain sequences of 20502 (the amino acid sequences of SEQ ID NOs: 13 and 14, respectively), and (ii) is fucosylated.

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.

In certain embodiments, an antibody (e.g., an anti-B7-H4 antibody) can be conjugated to a drug to form an antibody-drug conjugate (ADC). An exemplary anti-B7-H4-ADC is SGN-B7H4V. An exemplary antibody contained in the anti-B7-H4-ADC is B7H41001 mAb.

In certain embodiments, an antibody may be conjugated to a drug to form an antibody-drug conjugate (ADC) and may have a ratio of about 1 to about 8 drug moieties per antibody. In certain embodiments, an antibody (e.g., an anti-B7-H4 antibody) may be conjugated to a drug to form an ADC and may have a ratio of about 2 to about 5 drug moieties per antibody. 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 may be conjugated to a drug to form an ADC and may have a ratio of about 4 drug moieties per antibody. 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 for determining the ratio of the drug moiety of each antibody of an ADC are readily known to those skilled in the art.

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

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

vcMMAE can also be referred to as MC-Val-Cit-PABC-MMAE, where MC refers to maleimidohexanoyl group, Val-Cit refers to dipeptide valine-citrulline, PABC refers to p-aminobenzylcarbamate group, and MMAE refers to the drug monomethyl auristatin E.

The structure of a vcMMAE-antibody conjugate (e.g., B7-H4-ADC) according to certain exemplary embodiments is set forth below. In this structure, the drug-linker moiety shown in brackets may be referred to as Vitin in some cases. The drug-linker may be attached to the antibody via the sulfur atom of a cysteine residue of the antibody. In some embodiments, the ADC shown below is formed by reacting the maleimide group of the vc-MMAE drug-linker prodrome with the thiol of a cysteine residue of the antibody to form a succinamide bonded to the sulfur atom of the cysteine residue.

In some embodiments, the succinylamide moiety of the ADC can undergo ring-opening hydrolysis to form one of the ring-opened structures shown below.

According to certain exemplary embodiments, a vcMMAE-antibody conjugate (e.g., B7-H4-ADC) as described above is provided, 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., B7-H4-ADC) as described above is provided, wherein Ab may include an anti-B7-H4 antibody (e.g., B7H41001 mAb), and wherein p is 1, indicating a vcMMAE:antibody ratio of 1. In some embodiments, a vcMMAE-antibody conjugate (e.g., B7-H4-ADC) as described above is provided, wherein the 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, indicating that the vcMMAE:antibody ratio (also referred to as "drug:antibody ratio" or "DAR") is 2, 3, 4, 5, 6, 7, 8, 9, or 10, respectively. Thus, in some embodiments, a vcMMAE-antibody conjugate (e.g., B7-H4-ADC) as described above is provided, wherein the vcMMAE:antibody ratio is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In certain exemplary embodiments, a vcMMAE-antibody conjugate (e.g., B7-H4-ADC) as described above is provided, wherein the Ab may include an anti-B7-H4 antibody (e.g., B7H41001 mAb), and wherein p is 4, indicating that the vcMMAE:antibody ratio is 4. Therefore, in certain exemplary embodiments, a vcMMAE-antibody conjugate (e.g., B7-H4-ADC) as described above is provided, wherein the vcMMAE:antibody ratio is 4.

SGN-B7H4V can inhibit cancer cell growth while being administered to an individual at a level that is tolerated by the individual.

In certain exemplary embodiments, the anti-B7-H4 antibody comprises CDRs from the HCVR set forth in SEQ ID NO: 11 and/or CDRs from the LCVR set forth in SEQ ID NO: 12. In certain exemplary embodiments, the anti-B7-H4 antibody comprises the HCVR set forth in SEQ ID NO: 11 and/or the LCVR set forth in SEQ ID NO: 12. In other embodiments, the anti-B7-H4 antibody comprises the HCVR/LCVR pair SEQ ID NO: 11/SEQ ID NO: 12. In other embodiments, the anti-B7-H4 antibody comprises a HCVR having 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 a LCVR having 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.

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

The antibody-drug conjugates described herein (e.g., anti-B7-H4 antibodies or B7-H4-ADCs) typically bind to a target antigen (e.g., B7-H4) with an equilibrium binding constant of about ≦1 μM (e.g., about ≦100 nM, about ≦10 nM, or about ≦1 nM) as measured using a standard binding assay (e.g., a Biacore-based binding assay).

In some embodiments, the antibody-drug conjugate (e.g., B7-H4-ADC) increases T cell proliferation. In some embodiments, the antibody-drug conjugate (e.g., B7-H4-ADC) increases IFNy production. In some embodiments, the antibody-drug conjugate (e.g., B7-H4-ADC) mediates ADCC activity against B7-H4 expressing cells. In some embodiments, the antibody-drug conjugate (e.g., B7-H4-ADC) mediates ADCC activity against B7-H4 expressing cells. In some embodiments, the antibody-drug conjugate (e.g., B7-H4-ADC) does not mediate CDC activity against B7-H4 expressing cells.

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

The present invention provides methods for treating disorders associated with cells expressing B7-H4, such as cancer. In one aspect, the present invention provides the use of a human anti-B7-H4 antibody-drug conjugate (e.g., a B7-H4-antibody-drug conjugate (B7-H4-ADC)) thereof for treating cancer ( e.g. , breast cancer, ovarian cancer, primary peritoneal cancer, fallopian tube cancer, endometrial cancer, lung cancer, bile duct cancer, gallbladder cancer, or head and neck cancer). In one aspect, the present invention provides a use of a human anti-B7-H4 antibody conjugate (e.g., B7-H4-antibody-drug conjugate (B7-H4-ADC)) thereof for treating cancer ( e.g. , breast cancer, ovarian cancer, primary peritoneal cancer, fallopian tube cancer, endometrial cancer, lung cancer, bile duct cancer, gall bladder cancer, or head and neck cancer). In one aspect, the present invention provides a use of a human anti-B7-H4 antibody-drug conjugate (e.g., B7-H4-ADC) thereof for treating cancer ( e.g. , breast cancer, ovarian cancer, primary peritoneal cancer, fallopian tube cancer, endometrial cancer, lung cancer, bile duct cancer, gall bladder cancer, or head and neck cancer). In some embodiments, the cancer is adenoid cystic carcinoma. In some embodiments, adenoid cystic carcinoma is adenoid cystic carcinoma of the head and neck. In some embodiments, the head and neck adenoid cystic carcinoma is adenoid cystic carcinoma of the salivary gland. In some embodiments, the adenoid cystic carcinoma is adenoid cystic carcinoma of the ovary. In some embodiments, the adenoid cystic carcinoma is adenoid cystic carcinoma of the prostate. In some embodiments, the adenoid cystic carcinoma is adenoid cystic carcinoma of the breast. In some embodiments, the adenoid cystic carcinoma is adenoid cystic carcinoma of the skin. In some embodiments, the adenoid cystic carcinoma is adenoid cystic carcinoma of the cervix. In a preferred embodiment, the present invention provides a human anti-B7-H4 antibody-drug conjugate (e.g., B7-H4-ADC) thereof for use in treating cancer ( e.g. , breast cancer, ovarian cancer, primary peritoneal cancer, fallopian tube cancer, endometrial cancer, lung cancer, bile duct cancer, gallbladder cancer, or head and neck cancer). In some embodiments, a composition is provided comprising any of the human anti-B7-H4 antibody-drug conjugates (e.g., B7-H4-ADCs) described herein. In some embodiments, a composition is provided comprising any of the human anti-B7-H4 antibody-drug conjugates ( e.g., B7-H4-ADCs) described herein for use in treating cancer (e.g., breast cancer, ovarian cancer, primary peritoneal cancer, fallopian tube cancer, endometrial cancer, lung cancer, bile duct cancer, gallbladder cancer, or head and neck cancer). In some embodiments, a composition is provided, comprising a human anti-B7-H4 antibody-drug conjugate ( e.g. , B7-H4-ADC) thereof described herein for use in treating cancer (e.g., breast cancer, ovarian cancer, primary peritoneal cancer, fallopian tube cancer, endometrial cancer, lung cancer, bile duct cancer, gall bladder cancer, or head and neck cancer). In some embodiments, a composition comprising a human anti-B7-H4 antibody-drug conjugate (e.g., B7-H4-ADC) thereof described herein is provided for use in the manufacture of a medicament for treating cancer ( e.g. , breast cancer, ovarian cancer, primary peritoneal cancer, fallopian tube cancer, endometrial cancer, lung cancer, bile duct cancer, gall bladder cancer, or head and neck cancer).

In certain exemplary embodiments, the present invention provides a method for treating cancer in cells, tissues, organs, animals or individuals. In certain exemplary embodiments, the present invention provides a method for treating solid tumors, such as breast cancer, ovarian cancer, primary peritoneal cancer, fallopian tube cancer, endometrial cancer, lung cancer, bile duct cancer, gallbladder cancer or head and neck cancer. In a specific exemplary embodiment, breast cancer, ovarian cancer, lung cancer, bile duct cancer and endometrial cancer are locally advanced or metastatic. In certain exemplary embodiments, the present invention provides a method for treating solid tumors, such as peritoneal cancer, fallopian tube cancer or gallbladder cancer. In some embodiments, the individual suffers from adenoid cystic carcinoma. In some embodiments, the individual has adenoid cystic carcinoma of the head and neck. In some embodiments, the individual has adenoid cystic carcinoma of the salivary glands. In some embodiments, the individual has adenoid cystic carcinoma of the ovaries. In some embodiments, the individual has adenoid cystic carcinoma of the prostate. In some embodiments, the individual has adenoid cystic carcinoma of the breast. In some embodiments, the individual has adenoid cystic carcinoma of the skin. In some embodiments, the individual has adenoid cystic carcinoma of the cervix. In certain exemplary embodiments, the present invention provides a method for treating a solid tumor, such as an ovarian tumor, a peritoneal tumor, a fallopian tube tumor, a HER2-negative breast tumor, a HER2-positive breast tumor, a triple-negative breast tumor, an endometrial tumor, non-small cell lung cancer, bile duct cancer, or gallbladder cancer.

In some embodiments, the individual has previously been 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 treatment. In some embodiments, the individual experienced disease progression after treatment. In some embodiments, the treatment previously administered to the individual was not an agent that targets B7-H4.

In some embodiments, the methods provided herein include detecting B7-H4 levels in cancer and administering a B7-H4-ADC to treat cancer. Certain breast cancers, ovarian cancers, lung cancers, bile duct cancers, and endometrial cancers display detectable levels of B7-H4 measured at the protein level (e.g., by immunoassay using one of the exemplary antibodies) or mRNA level. In certain embodiments, breast cancer, ovarian cancer, lung cancer, bile duct cancer, endometrial cancer, or head and neck cancer displays elevated levels of B7-H4 relative to non-cancerous tissue or cells of the same type from the same patient (e.g., breast, ovarian, lung, bile duct, endometrial cells, and cells from the head and neck). In other embodiments, breast cancer, ovarian cancer, lung cancer, bile duct cancer, or endometrial cancer display similar levels of B7-H4 relative to non-cancerous breast, ovarian, lung, bile duct, and endometrial cells of the same type (e.g., from the same patient).

Certain peritoneal cancers, fallopian tube cancers, and gall bladder cancers display detectable levels of B7-H4 measured at the protein (e.g., by immunoassay using one of the exemplary antibodies) or mRNA level. In certain embodiments, peritoneal cancer, fallopian tube cancer, or gall bladder cancer displays elevated levels of B7-H4 relative to non-cancerous tissue or cells of the same type (e.g., peritoneal, fallopian tube, or gall bladder cells), respectively, from the same patient. In other embodiments, peritoneal cancer, fallopian tube cancer, or gall bladder cancer displays similar levels of B7-H4 relative to non-cancerous peritoneal, fallopian tube, or gall bladder cells of the same type, e.g., from the same patient.

In some embodiments, B7-H4 protein is highly expressed in breast cancer, ovarian cancer, lung cancer, bile duct cancer, and endometrial cancer that are suitable for 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) are measured in breast cancer, ovarian cancer, lung cancer, bile duct cancer, endometrial cancer, and head and neck cancer from an individual before treatment is performed. 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 cancer cells express B7-H4. In some embodiments, B7-H4 expression is low or absent on myeloid immune cell subsets including monocytes, macrophages, and dendritic cells. In some embodiments, B7-H4 expression is low or absent on CD163+ macrophages.

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.

In some embodiments, cancer cells express B7-H4. In some embodiments, cancer cells do not express B7-H4. In some embodiments, cancer cells express B7-H4 at a level higher than that of non-diseased cells of the same cell type. In some embodiments, cancer cells express B7-H4 at a level comparable to or lower than that of non-diseased cells of the same cell type. A. Lung Cancer

Lung cancer remains the leading cause of cancer death in the United States, with an estimated 155,000 deaths in 2017. Curative intent treatment for patients with early-stage disease includes surgery, chemotherapy, radiation therapy, or a combination modality approach. However, the majority of patients are diagnosed with advanced disease, which is generally incurable. Non-small cell lung cancer (NSCLC) accounts for up to 80% of all lung cancers. Within the subtypes of NSCLC, squamous cell carcinoma (SCC/NSCLC) accounts for approximately 30% of NSCLC. Systemic therapies used in the metastatic setting of SCC/NSCLC have shown limited benefit, with the primary goal being to prolong survival and maintain quality of life for as long as possible while minimizing side effects attributable to treatment. First-line treatment for SCC/NSCLC patients whose tumors do not express high levels of PD-L1 includes platinum-based chemotherapy doublets without pemetrexed, anti-VEGF antibodies, or the anti-EGFR antibody necituzumab in combination with gemcitabine and cisplatin. Patients with at least 50% tumor cell PD-L1 staining receive first-line treatment with the anti-PD-1 inhibitor pembrolizumab. Patients with progression on initial combination chemotherapy regimens may receive anti-PD-1 or PD-L1 antibodies, and combination chemotherapy is considered for patients with disease progression after receiving PD-1/L1 inhibitors. New treatment categories that may provide meaningful benefit to patients with SCC/NSCLC are urgently needed.

The present invention provides methods for treating lung cancer using the anti-B7-H4 antibody-drug conjugates (e.g., B7-H4-ADC) described herein. In one aspect, the anti-B7-H4 antibody-drug conjugates (e.g., B7-H4-ADC) described herein are used in a method of treating lung cancer in an individual. The present invention also provides methods for treating lung cancer using the anti-B7-H4 antibody-drug conjugates (e.g., B7-H4-ADC) described herein in combination with an immune checkpoint inhibitor. In one aspect, the anti-B7-H4 antibody-drug conjugates (e.g., B7-H4-ADC) described herein in combination with an immune checkpoint inhibitor are used in a method of treating lung cancer in an individual. In some embodiments, a method of treating lung cancer with an anti-B7-H4 antibody-drug conjugate (e.g., B7-H4-ADC) described herein in combination with a PD-1 inhibitor (e.g., an anti-PD-1 antibody) is provided. In one aspect, an anti-B7-H4 antibody-drug conjugate (e.g., B7-H4-ADC) described herein in combination with a PD-1 inhibitor (e.g., an anti-PD-1 antibody) is used 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 embodiments herein, the lung cancer is non-squamous cell carcinoma. In some embodiments herein, the lung cancer is squamous cell carcinoma. In some embodiments herein, the lung cancer is lung adenocarcinoma. In some embodiments, lung cancer cells express B7-H4. In some embodiments, lung cancer cells do not express B7-H4. In some embodiments, lung cancer cells express B7-H4 at a level higher than that of non-diseased cells of the same cell type. In some embodiments, lung cancer cells express B7-H4 at a level comparable to or lower than that of non-diseased cells of the same cell type. B. Breast Cancer

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

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

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

Exemplary breast cancers are those that express B7-H4 in cells expressing the cancer (i.e., B7-H4 expressing cancers). In certain exemplary embodiments, the breast cancer is selected from the group consisting of carcinoma, sarcoma, phyllodes tumor, Paget's disease, and angiosarcoma. Breast cancer can 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).

In some embodiments, the individual suffers from breast cancer. In some embodiments, the individual suffers from estrogen receptor positive (ER+) breast cancer. In some embodiments, the individual suffers from estrogen receptor positive (ER-) breast cancer. In some embodiments, the individual suffers from progesterone receptor positive (PR+) breast cancer. In some embodiments, the individual suffers from progesterone receptor negative (PR-) breast cancer. In some embodiments, the individual suffers from hormone receptor positive (HR+) breast cancer. In some embodiments, the individual suffers from hormone receptor negative (HR-) breast cancer. In some embodiments, the individual suffers from HER2 gene overexpression (HER2+) breast cancer. In some embodiments, the individual suffers from HER2 gene wild-type breast cancer. In some embodiments, the individual suffers from HER2 gene underexpression (HER2-) breast cancer. In some embodiments, the individual has Group 1 (luminal A) (i.e., ER+/PR+/HER2-) breast cancer. In some embodiments, the individual has Group 2 (luminal B) (i.e., ER+/PR-/HER2+) breast cancer. In some embodiments, the individual has Group 3 (HER2+) (i.e., ER-/PR-/HER2+) breast cancer. In some embodiments, the individual has Group 4 (basal-like or triple negative (TN)) (i.e., ER-/PR-/HER2-) breast cancer.

Breast cancer can be further classified as grade 1, 2, or 3. Grade 1 or well-differentiated (scores 3, 4, or 5) breast cancers contain cells that grow slower and look more like normal breast tissue than higher-grade breast cancers. Grade 2 or moderately differentiated (scores 6, 7) breast cancers have cells that grow between grade 1 and 3 and look like grade 1 and 3 cells. Grade 3 or poorly differentiated (scores 8, 9) breast cancers have cells that look very different from normal cells and usually grow and spread faster than grade 1 or 2.

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

In some embodiments, breast cancer cells express B7-H4. In some embodiments, breast cancer cells do not express B7-H4. In some embodiments, breast cancer cells express B7-H4 at a level higher than that of non-diseased cells of the same cell type. In some embodiments, breast cancer cells express B7-H4 at a level comparable to or lower than that of non-diseased cells of the same cell type. C. Ovarian Cancer

The present invention provides methods of treating cancers, such as ovarian cancer, with antibody-drug conjugates. In some embodiments, the present 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 monomethyl auristatin. In some embodiments, the monomethyl auristatin is monomethyl auristatin E. In one aspect, the present invention provides methods of treating a condition associated with cells expressing B7-H4, such as cancer (e.g., ovarian cancer, such as locally advanced ovarian cancer or metastatic ovarian cancer). As a result, the present invention provides a method of treating an individual, such as an individual suffering from ovarian cancer, using an anti-B7-H4 antibody-drug conjugate described herein. The method comprises administering an effective amount of an anti-B7-H4 antibody-drug conjugate (e.g., B7-H4-ADC) to a subject in need thereof. In some embodiments, the cancer is an advanced cancer. In some embodiments, the advanced cancer is a metastatic cancer. In some embodiments, the cancer is unresectable. In some embodiments, the cancer is locally advanced. In some embodiments, the cancer is a recurrent cancer. In some embodiments, the subject has received a prior treatment with a standard of care therapy for the cancer and the prior treatment failed. In some embodiments, the subject has been previously treated with one or more therapeutic agents and has not responded to the treatment, wherein the one or more therapeutic agents are not an antibody-drug conjugate (e.g., B7-H4-ADC). In some embodiments, the subject has been previously treated with one or more therapeutic agents and has relapsed following treatment, wherein the one or more therapeutic agents are not an antibody-drug conjugate (e.g., B7-H4-ADC). In some embodiments, the subject has been previously treated with one or more therapeutic agents and has experienced disease progression during treatment, wherein the one or more therapeutic agents are an antibody-drug conjugate (e.g., B7-H4-ADC). In some embodiments, the subject is a human.

Exemplary ovarian cancers are those that express B7-H4 in cells expressing the cancer (i.e., B7-H4 expressing cancers). In certain exemplary embodiments, the ovarian cancer is selected from the group consisting of carcinoma, sarcoma, phyllodes tumor, Paget's disease, and angiosarcoma. In some embodiments, the ovarian cancer is an ovarian tumor. The ovarian cancer can be in situ or invasive/infiltrative.

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

Ovarian cancer can be further classified as grade 1, 2, or 3. Grade 1 or well-differentiated (scores 3, 4, or 5) ovarian cancers contain cells that grow more slowly and look more like normal ovarian tissue than higher-grade ovarian cancers. Grade 2 or moderately differentiated (scores 6, 7) ovarian cancers have cells that grow between grade 1 and 3 and look like cells. Grade 3 or poorly differentiated (scores 8, 9) ovarian cancers have cells that look very different from normal cells and usually grow and spread faster than grade 1 or 2.

In certain exemplary embodiments, ovarian cancer is incurable, unresectable, locally advanced or metastatic ovarian cancer. In some embodiments, ovarian cancer is ovarian serous cystadenocarcinoma (OV). In some embodiments, ovarian cancer is high-grade serous epithelial ovarian cancer.

In some embodiments, ovarian cells express B7-H4. In some embodiments, ovarian cancer cells do not express B7-H4. In some embodiments, ovarian cancer cells express higher levels of B7-H4 than non-diseased cells of the same cell type. In some embodiments, ovarian cancer cells express levels of B7-H4 that are comparable to or lower than non-diseased cells.

In some embodiments, an anti-B7-H4 antibody-drug conjugate described herein ( e.g. , B7-H4-ADC) is provided for use in treating cancer (e.g., breast cancer, ovarian cancer, primary peritoneal cancer, fallopian tube cancer, endometrial cancer, lung cancer, bile duct cancer, gall bladder cancer, or head and neck cancer). In some embodiments, an anti-B7-H4 antibody-drug conjugate (e.g., B7-H4-ADC) for treating cancer ( e.g. , breast cancer, ovarian cancer, primary peritoneal cancer, fallopian tube cancer, endometrial cancer, lung cancer, bile duct cancer, gallbladder cancer, or head and neck cancer) is provided, wherein the anti-B7-H4 antibody-drug conjugate (e.g., B7-H4-ADC) comprises a HCVR having at least about 95% (e.g., 95%, 97%, 98%, 99%, or 100%) homology or identity to SEQ ID NO: 11 and/or comprises a LCVR having at least about 95% (e.g., 95%, 97%, 98%, 99%, or 100%) homology or identity to SEQ ID NO: 12. In some embodiments, a B7-H4 antibody-drug conjugate (e.g., B7-H4-ADC) for treating cancer ( e.g. , breast cancer, ovarian cancer, primary peritoneal cancer, fallopian tube cancer, endometrial cancer, lung cancer, bile duct cancer, gallbladder cancer, or head and neck cancer) is provided, wherein the anti-B7-H4 antibody-drug conjugate (e.g., B7-H4-ADC) comprises a HCVR having at least about 95% (e.g., 95%, 97%, 98%, 99%, or 100%) homology or identity to SEQ ID NO: 11 and/or comprises a LCVR having at least about 95% (e.g., 95%, 97%, 98%, 99%, or 100%) homology or identity to SEQ ID NO: 12, and wherein the antibody is bound to vcMMAE, wherein the vcMMAE has the following structure: .

In some embodiments, use of an anti-B7-H4 antibody-drug conjugate (e.g., B7-H4-ADC) described herein for treating cancer ( e.g. , breast cancer, ovarian cancer, primary peritoneal cancer, fallopian tube cancer, endometrial cancer, lung cancer, bile duct cancer, gall bladder cancer, or head and neck cancer) is provided. In some embodiments, a use of an anti-B7-H4 antibody-drug conjugate (e.g., B7-H4-ADC) for treating cancer ( e.g. , breast cancer, ovarian cancer, primary peritoneal cancer, fallopian tube cancer, endometrial cancer, lung cancer, bile duct cancer, gallbladder cancer, or head and neck cancer) is provided, wherein the anti-B7-H4 antibody-drug conjugate (e.g., B7-H4-ADC) comprises a HCVR having at least about 95% (e.g., 95%, 97%, 98%, 99%, or 100%) homology or identity to SEQ ID NO: 11 and/or comprises a LCVR having at least about 95% (e.g., 95%, 97%, 98%, 99%, or 100%) homology or identity to SEQ ID NO: 12. In some embodiments, a use of a B7-H4 antibody-drug conjugate (e.g., B7-H4-ADC) for treating cancer ( e.g., breast cancer, ovarian cancer, primary peritoneal cancer, fallopian tube cancer, endometrial cancer, lung cancer, bile duct cancer, gallbladder cancer, or head and neck cancer) is provided, wherein the anti-B7-H4 antibody-drug conjugate (e.g., B7-H4-ADC) comprises a HCVR having at least about 95% (e.g., 95%, 97%, 98%, 99%, or 100%) homology or identity to SEQ ID NO: 11 and/or comprises a LCVR having at least about 95% (e.g., 95%, 97%, 98%, 99%, or 100%) homology or identity to SEQ ID NO: 12, and wherein the antibody binds to vcMMAE, wherein the vcMMAE has the following structure:

In some embodiments, use of an anti-B7-H4 antibody-drug conjugate (e.g., B7-H4-ADC) described herein in the manufacture of a medicament for treating cancer ( e.g. , breast cancer, ovarian cancer, primary peritoneal cancer, fallopian tube cancer, endometrial cancer, lung cancer, bile duct cancer, gall bladder cancer, or head and neck cancer) is provided. In some embodiments, use of an anti-B7-H4 antibody-drug conjugate (e.g., B7-H4-ADC) in the manufacture of a medicament for treating cancer ( e.g. , breast cancer, ovarian cancer, primary peritoneal cancer, fallopian tube cancer, endometrial cancer, lung cancer, bile duct cancer, gallbladder cancer, or head and neck cancer) is provided, wherein the anti-B7-H4 antibody-drug conjugate (e.g., B7-H4-ADC) comprises a HCVR having at least about 95% (e.g., 95%, 97%, 98%, 99%, or 100%) homology or identity to SEQ ID NO: 11 and/or comprises a LCVR having at least about 95% (e.g., 95%, 97%, 98%, 99%, or 100%) homology or identity to SEQ ID NO: 12. In some embodiments, use of a B7-H4 antibody-drug conjugate (e.g., B7-H4-ADC) in the manufacture of a medicament for treating cancer ( e.g. , breast cancer, ovarian cancer, primary peritoneal cancer, fallopian tube cancer, endometrial cancer, lung cancer, bile duct cancer, gallbladder cancer, or head and neck cancer) is provided, wherein the anti-B7-H4 antibody-drug conjugate (e.g., B7-H4-ADC) comprises a HCVR having at least about 95% (e.g., 95%, 97%, 98%, 99%, or 100%) homology or identity to SEQ ID NO: 11 and/or comprises a LCVR having at least about 95% (e.g., 95%, 97%, 98%, 99%, or 100%) homology or identity to SEQ ID NO: 12, and wherein the antibody binds to vcMMAE, wherein the vcMMAE has the following structure:

In some embodiments, the immune checkpoint inhibitor targets 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 a whole monoclonal antibody. In some embodiments, the immune checkpoint inhibitor is an anti-PD-1 antibody, such as one or more of: nivolumab, pembrolizumab, cemiprilimab, dotalimumab, and rivolimab. In some embodiments, the anti-PD-1 antibody is ^Keytruda® .

In some embodiments, the cancer is breast cancer, ovarian cancer, lung cancer, bile duct cancer, endometrial cancer, or head and neck cancer. In some embodiments, the cancer is peritoneal cancer, fallopian tube cancer, or gallbladder cancer. In a preferred embodiment, the cancer is selected from the group consisting of ovarian tumor, peritoneal tumor, fallopian tube tumor, HER2-negative breast tumor, HER2-positive breast tumor, triple-negative breast tumor, endometrial tumor, non-small cell lung cancer, bile duct cancer, and gallbladder cancer.

In some embodiments, the B7-H4-ADC is administered at a dose of about 0.75 mg/kg to about 2.4 mg/kg, based on the subject's weight. In some embodiments, the B7-H4-ADC is administered at a dose of 0.75 mg/kg to 2.4 mg/kg, based on the subject's 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, based on the subject's 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, based on the subject's weight. In some embodiments, the B7-H4-ADC is administered once. In some embodiments, the B7-H4-ADC is administered in multiple doses. In some embodiments, the B7-H4-ADC is administered once in a three-week period (Q3W). In some embodiments, the B7-H4-ADC is administered at a dose of about 0.75 mg/kg to about 1.5 mg/kg (e.g., a single dose), based on the subject's weight. In some embodiments, the B7-H4-ADC is administered at a dose (e.g., a 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, based on the subject's weight. In some embodiments, the B7-H4-ADC is administered at a dose (e.g., a single dose) of about 0.25 mg/kg/week to about 0.80 mg/kg/week, based on the subject's weight. In some embodiments, the B7-H4-ADC is administered at a dose (e.g., a 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, based on the subject's body weight. In some embodiments, the B7-H4-ADC is administered multiple times. In some embodiments, the B7-H4-ADC is administered twice over a three-week period (2Q3W). In some embodiments, the B7-H4-ADC is administered twice over a four-week period (2Q4W). In some embodiments, the B7-H4-ADC is administered three times over 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 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, depending on the subject'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 one 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, based on the subject's 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, based on the subject's 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, based on the subject's 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, based on the subject's 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, based on the subject's 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, about 1.69 mg/kg/week, or about 1.80 mg/kg/week, based on the subject's 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, based on the subject's weight. In some embodiments, the B7-H4-ADC is administered at a dosage 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, depending on the subject's weight. In some embodiments, 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), the upper limit of the subject's weight is 100 kg. In some embodiments, the subject's weight is actual weight. In some embodiments, the subject's weight is adjusted to an ideal 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 less than 5 days after the last dose.

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

In some embodiments, a method of treating a solid tumor in a subject is provided, the method comprising administering to the subject a B7-H4-ADC at a dose of about 0.75 mg/kg twice every three weeks (2Q3W), wherein the B7-H4-ADC comprises an anti-B7-H4 antibody conjugated to vcMMAE (valine-citrulline-monomethylauristatin 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 three complementary determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or an antigen-binding fragment thereof comprises three CDRs of SEQ ID NO: 12. In some embodiments, a method of treating a solid tumor in a subject comprises administering to the subject a B7-H4-ADC at a dose of about 0.75 mg/kg on about day 1, followed by a dose of about 0.75 mg/kg twice every three weeks (2Q3W) on about day 8. In some embodiments, the dose is determined based on the subject's weight. In some embodiments, the subject's weight is an actual weight. In some embodiments, the subject's weight is an adjusted ideal 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 of a 21 day cycle. In some embodiments, the B7-H4-ADC is administered about 7 days to about 14 days apart from one another. 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 cancer, lung cancer, bile duct cancer, gall bladder cancer, and head and neck cancer.

In some embodiments, a method of treating a solid tumor in a subject is provided, the method comprising administering to the subject a dose of about 1.0 mg/kg of a B7-H4-ADC twice every three weeks (2Q3W), wherein the B7-H4-ADC comprises an anti-B7-H4 antibody conjugated to vcMMAE (valine-citrulline-monomethylauristatin 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 three complementary determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or an antigen-binding fragment thereof comprises three CDRs of SEQ ID NO: 12. In some embodiments, a method of treating a solid tumor in a subject comprises administering to the subject a B7-H4-ADC at a dose of about 1.0 mg/kg on about day 1, followed by a dose of about 1.0 mg/kg twice every three weeks (2Q3W) on about day 8. In some embodiments, the dose is determined based on the subject's weight. In some embodiments, the subject's weight is an actual weight. In some embodiments, the subject's weight is an adjusted ideal 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 of a 21 day cycle. In some embodiments, the B7-H4-ADC is administered about 7 days to about 14 days apart from one another. 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 cancer, lung cancer, bile duct cancer, gall bladder cancer, and head and neck cancer.

In some embodiments, a method of treating a solid tumor in a subject is provided, the method comprising administering to the subject a dose of about 1.25 mg/kg of a B7-H4-ADC twice every three weeks (2Q3W), wherein the B7-H4-ADC comprises an anti-B7-H4 antibody conjugated to vcMMAE (valine-citrulline-monomethylauristatin 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 three complementary determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or an antigen-binding fragment thereof comprises three CDRs of SEQ ID NO: 12. In some embodiments, a method of treating a solid tumor in a subject comprises administering to the subject a B7-H4-ADC at a dose of about 1.25 mg/kg on about day 1, followed by a dose of about 1.25 mg/kg twice every three weeks (2Q3W) on about day 8. In some embodiments, the dose is determined based on the subject's weight. In some embodiments, the subject's weight is an actual weight. In some embodiments, the subject's weight is an adjusted ideal 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 of a 21 day cycle. In some embodiments, the B7-H4-ADC is administered about 7 days to about 14 days apart from one another. 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 cancer, lung cancer, bile duct cancer, gall bladder cancer, and head and neck cancer.

In some embodiments, a method of treating a solid tumor in a subject is provided, the method comprising administering to the subject a dose of about 1.5 mg/kg of a B7-H4-ADC twice every three weeks (2Q3W), wherein the B7-H4-ADC comprises an anti-B7-H4 antibody conjugated to vcMMAE (valine-citrulline-monomethylauristatin 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 three complementary determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or an antigen-binding fragment thereof comprises three CDRs of SEQ ID NO: 12. In some embodiments, a method of treating a solid tumor in a subject comprises administering to the subject a B7-H4-ADC at a dose of about 1.5 mg/kg on about day 1, followed by a dose of about 1.5 mg/kg twice every three weeks (2Q3W) on about day 8. In some embodiments, the dose is determined based on the subject's weight. In some embodiments, the subject's weight is an actual weight. In some embodiments, the subject's weight is an adjusted ideal 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 of a 21 day cycle. In some embodiments, the B7-H4-ADC is administered about 7 days to about 14 days apart from one another. 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 cancer, lung cancer, bile duct cancer, gall bladder cancer, and head and neck cancer.

In some embodiments, a method of treating a solid tumor in a subject is provided, the method comprising administering to the subject a dose of about 1.75 mg/kg of a B7-H4-ADC twice every three weeks (2Q3W), wherein the B7-H4-ADC comprises an anti-B7-H4 antibody conjugated to vcMMAE (valine-citrulline-monomethylauristatin 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 three complementary determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or an antigen-binding fragment thereof comprises three CDRs of SEQ ID NO: 12. In some embodiments, a method of treating a solid tumor in a subject comprises administering to the subject a B7-H4-ADC at a dose of about 1.75 mg/kg on about day 1, followed by a dose of about 1.75 mg/kg twice every three weeks (2Q3W) on about day 8. In some embodiments, the dose is determined based on the subject's weight. In some embodiments, the subject's weight is an actual weight. In some embodiments, the subject's weight is an adjusted ideal 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 of a 21 day cycle. In some embodiments, the B7-H4-ADC is administered about 7 days to about 14 days apart from one another. 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 cancer, lung cancer, bile duct cancer, gall bladder cancer, and head and neck cancer.

In some embodiments, a method of treating a solid tumor in a subject is provided, the method comprising administering to the subject a dose of about 2.0 mg/kg of a B7-H4-ADC twice every three weeks (2Q3W), wherein the B7-H4-ADC comprises an anti-B7-H4 antibody conjugated to vcMMAE (valine-citrulline-monomethylauristatin 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 three complementary determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or an antigen-binding fragment thereof comprises three CDRs of SEQ ID NO: 12. In some embodiments, a method of treating a solid tumor in a subject comprises administering to the subject a B7-H4-ADC at a dose of about 2.0 mg/kg on about day 1, followed by a dose of about 2.0 mg/kg twice every three weeks (2Q3W) on about day 8. In some embodiments, the dose is determined based on the subject's weight. In some embodiments, the subject's weight is an actual weight. In some embodiments, the subject's weight is an adjusted ideal 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 of a 21 day cycle. In some embodiments, the B7-H4-ADC is administered about 7 days to about 14 days apart from one another. 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 cancer, lung cancer, bile duct cancer, gall bladder cancer, and head and neck cancer.

In some embodiments, a method of treating a solid tumor in a subject is provided, the method comprising administering to the subject a dose of about 2.25 mg/kg of a B7-H4-ADC twice every three weeks (2Q3W), wherein the B7-H4-ADC comprises an anti-B7-H4 antibody conjugated to vcMMAE (valine-citrulline-monomethylauristatin 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 three complementary determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or an antigen-binding fragment thereof comprises three CDRs of SEQ ID NO: 12. In some embodiments, a method of treating a solid tumor in a subject comprises administering to the subject a B7-H4-ADC at a dose of about 2.25 mg/kg on about day 1, followed by a dose of about 2.25 mg/kg twice every three weeks (2Q3W) on about day 8. In some embodiments, the dose is determined based on the subject's weight. In some embodiments, the subject's weight is an actual weight. In some embodiments, the subject's weight is an adjusted ideal 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 of a 21 day cycle. In some embodiments, the B7-H4-ADC is administered about 7 days to about 14 days apart from one another. 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 cancer, lung cancer, bile duct cancer, gall bladder cancer, and head and neck cancer.

In some embodiments, a method of treating a solid tumor in a subject is provided, the method comprising administering to the subject a dose of about 2.4 mg/kg of a B7-H4-ADC twice every three weeks (2Q3W), wherein the B7-H4-ADC comprises an anti-B7-H4 antibody conjugated to vcMMAE (valine-citrulline-monomethylauristatin 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 three complementary determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or an antigen-binding fragment thereof comprises three CDRs of SEQ ID NO: 12. In some embodiments, a method of treating a solid tumor in a subject comprises administering to the subject a B7-H4-ADC at a dose of about 2.4 mg/kg on about day 1, followed by a dose of about 2.4 mg/kg twice every three weeks (2Q3W) on about day 8. In some embodiments, the dose is determined based on the subject's weight. In some embodiments, the subject's weight is an actual weight. In some embodiments, the subject's weight is an adjusted ideal 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 of a 21 day cycle. In some embodiments, the B7-H4-ADC is administered about 7 days to about 14 days apart from one another. 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 cancer, lung cancer, bile duct cancer, gall bladder cancer, and head and neck cancer.

In some embodiments, a method of treating a solid tumor in a subject is provided, the method comprising administering to the subject a B7-H4-ADC at a dose of about 0.75 mg/kg three times every four weeks (3Q4W), wherein the B7-H4-ADC comprises an anti-B7-H4 antibody conjugated to vcMMAE (valine-citrulline-monomethylauristatin 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 three complementary determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or an antigen-binding fragment thereof comprises three CDRs of SEQ ID NO: 12. In some embodiments, a method of treating a solid tumor in a subject comprises administering to the subject 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 based on the subject's weight. In some embodiments, the subject's weight is actual weight. In some embodiments, the subject's weight is adjusted ideal 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 of a 28-day cycle. In some embodiments, the B7-H4-ADC is administered about 7 days to about 14 days apart from 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 cancer, lung cancer, bile duct cancer, gall bladder cancer, and head and neck cancer.

In some embodiments, a method of treating a solid tumor in a subject is provided, the method comprising administering to the subject a B7-H4-ADC at a dose of about 1.0 mg/kg three times every four weeks (3Q4W), wherein the B7-H4-ADC comprises an anti-B7-H4 antibody conjugated to vcMMAE (valine-citrulline-monomethylauristatin 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 three complementary determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or an antigen-binding fragment thereof comprises three CDRs of SEQ ID NO: 12. In some embodiments, a method of treating a solid tumor in a subject comprises administering to the subject a B7-H4-ADC 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, followed by a dose of about 1.0 mg/kg on about day 15 three times every four weeks (3Q4W). In some embodiments, the dose is determined based on the subject's weight. In some embodiments, the subject's weight is an actual weight. In some embodiments, the subject's weight is an adjusted ideal 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 of a 28-day cycle. In some embodiments, the B7-H4-ADC is administered about 7 to about 14 days apart from one another. 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 cancer, lung cancer, bile duct cancer, gallbladder cancer, and head and neck cancer.

In some embodiments, a method of treating a solid tumor in a subject is provided, the method comprising administering to the subject a B7-H4-ADC at a dose of about 1.25 mg/kg three times every four weeks (3Q4W), wherein the B7-H4-ADC comprises an anti-B7-H4 antibody conjugated to vcMMAE (valine-citrulline-monomethylauristatin 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 three complementary determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or an antigen-binding fragment thereof comprises three CDRs of SEQ ID NO: 12. In some embodiments, a method of treating a solid tumor in a subject comprises administering to the subject 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 based on the subject's weight. In some embodiments, the subject's weight is actual weight. In some embodiments, the subject's weight is adjusted ideal 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 of a 28-day cycle. In some embodiments, the B7-H4-ADC is administered about 7 days to about 14 days apart from 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 cancer, lung cancer, bile duct cancer, gall bladder cancer, and head and neck cancer.

In some embodiments, a method of treating a solid tumor in a subject is provided, the method comprising administering to the subject a B7-H4-ADC at a dose of about 1.5 mg/kg three times every four weeks (3Q4W), 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 three complementary determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or antigen-binding fragment thereof comprises three CDRs of SEQ ID NO: 12. In some embodiments, a method of treating a solid tumor in a subject comprises administering to the subject a B7-H4-ADC 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 three times every four weeks (3Q4W). In some embodiments, the dose is determined based on the subject's weight. In some embodiments, the subject's weight is an actual weight. In some embodiments, the subject's weight is an adjusted ideal 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 of a 28-day cycle. In some embodiments, the B7-H4-ADC is administered about 7 to about 14 days apart from one another. 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 cancer, lung cancer, bile duct cancer, gallbladder cancer, and head and neck cancer.

In some embodiments, a method of treating a solid tumor in a subject is provided, the method comprising administering to the subject a B7-H4-ADC at a dose of about 1.75 mg/kg three times every four weeks (3Q4W), wherein the B7-H4-ADC comprises an anti-B7-H4 antibody conjugated to vcMMAE (valine-citrulline-monomethylauristatin 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 three complementary determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or an antigen-binding fragment thereof comprises three CDRs of SEQ ID NO: 12. In some embodiments, a method of treating a solid tumor in a subject comprises administering to the subject 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 based on the subject's weight. In some embodiments, the subject's weight is actual weight. In some embodiments, the subject's weight is adjusted ideal 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 of a 28-day cycle. In some embodiments, the B7-H4-ADC is administered about 7 days to about 14 days apart from 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 cancer, lung cancer, bile duct cancer, gall bladder cancer, and head and neck cancer.

In some embodiments, a method of treating a solid tumor in a subject is provided, the method comprising administering to the subject a B7-H4-ADC at a dose of about 2.0 mg/kg three times every four weeks (3Q4W), wherein the B7-H4-ADC comprises an anti-B7-H4 antibody conjugated to vcMMAE (valine-citrulline-monomethylauristatin 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 three complementary determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or an antigen-binding fragment thereof comprises three CDRs of SEQ ID NO: 12. In some embodiments, a method of treating a solid tumor in a subject comprises administering to the subject a B7-H4-ADC 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 three times every four weeks (3Q4W). In some embodiments, the dose is determined based on the subject's weight. In some embodiments, the subject's weight is an actual weight. In some embodiments, the subject's weight is an adjusted ideal 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 of a 28-day cycle. In some embodiments, the B7-H4-ADC is administered about 7 to about 14 days apart from one another. 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 cancer, lung cancer, bile duct cancer, gallbladder cancer, and head and neck cancer.

In some embodiments, a method of treating a solid tumor in a subject is provided, the method comprising administering to the subject a B7-H4-ADC at a dose of about 2.25 mg/kg three times every four weeks (3Q4W), wherein the B7-H4-ADC comprises an anti-B7-H4 antibody conjugated to vcMMAE (valine-citrulline-monomethylauristatin 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 three complementary determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or an antigen-binding fragment thereof comprises three CDRs of SEQ ID NO: 12. In some embodiments, a method of treating a solid tumor in a subject comprises administering to the subject 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 based on the subject's weight. In some embodiments, the subject's weight is actual weight. In some embodiments, the subject's weight is adjusted ideal 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 of a 28-day cycle. In some embodiments, the B7-H4-ADC is administered about 7 days to about 14 days apart from 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 cancer, lung cancer, bile duct cancer, gall bladder cancer, and head and neck cancer.

In some embodiments, a method of treating a solid tumor in a subject is provided, the method comprising administering to the subject a B7-H4-ADC at a dose of about 2.4 mg/kg three times every four weeks (3Q4W), wherein the B7-H4-ADC comprises an anti-B7-H4 antibody conjugated to vcMMAE (valine-citrulline-monomethylauristatin 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 three complementary determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or an antigen-binding fragment thereof comprises three CDRs of SEQ ID NO: 12. In some embodiments, a method of treating a solid tumor in a subject comprises administering to the subject a B7-H4-ADC 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 three times every four weeks (3Q4W). In some embodiments, the dose is determined based on the subject's weight. In some embodiments, the subject's weight is an actual weight. In some embodiments, the subject's weight is an adjusted ideal 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 of a 28-day cycle. In some embodiments, the B7-H4-ADC is administered about 7 to about 14 days apart from one another. 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 cancer, lung cancer, bile duct cancer, gallbladder cancer, and head and neck cancer.

In some embodiments, a method of treating a solid tumor in a subject is provided, the method comprising administering to the subject a B7-H4-ADC at a dose of about 0.75 mg/kg twice every four weeks (2Q4W), wherein the B7-H4-ADC comprises an anti-B7-H4 antibody conjugated to vcMMAE (valine-citrulline-monomethylauristatin 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 three complementary determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or an antigen-binding fragment thereof comprises three CDRs of SEQ ID NO: 12. In some embodiments, a method of treating a solid tumor in a subject comprises administering to the subject a B7-H4-ADC at a dose of about 0.75 mg/kg on about day 1, followed by a dose of about 0.75 mg/kg twice every four weeks (2Q4W) on about day 15. In some embodiments, the dose is determined based on the subject's weight. In some embodiments, the subject's weight is an actual weight. In some embodiments, the subject's weight is an adjusted ideal 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 about day 15 of a 28-day cycle. In some embodiments, the B7-H4-ADC is administered about 14 days apart from 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 cancer, lung cancer, bile duct cancer, gallbladder cancer, and head and neck cancer.

In some embodiments, a method of treating a solid tumor in a subject is provided, the method comprising administering to the subject a B7-H4-ADC at a dose of about 1.0 mg/kg twice every four weeks (2Q4W), wherein the B7-H4-ADC comprises an anti-B7-H4 antibody conjugated to vcMMAE (valine-citrulline-monomethylauristatin 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 three complementary determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or an antigen-binding fragment thereof comprises three CDRs of SEQ ID NO: 12. In some embodiments, a method of treating a solid tumor in a subject comprises administering to the subject a B7-H4-ADC at a dose of about 1.0 mg/kg on about day 1, followed by a dose of about 1.0 mg/kg twice every four weeks (2Q4W) on about day 15. In some embodiments, the dose is determined based on the subject's weight. In some embodiments, the subject's weight is an actual weight. In some embodiments, the subject's weight is an adjusted ideal 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 about day 15 of a 28-day cycle. In some embodiments, the B7-H4-ADC is administered about 14 days apart from one another. 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 cancer, lung cancer, bile duct cancer, gallbladder cancer, and head and neck cancer.

In some embodiments, a method of treating a solid tumor in a subject is provided, the method comprising administering to the subject a B7-H4-ADC at a dose of about 1.25 mg/kg twice every four weeks (2Q4W), wherein the B7-H4-ADC comprises an anti-B7-H4 antibody conjugated to vcMMAE (valine-citrulline-monomethylauristatin 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 three complementarity determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or an antigen-binding fragment thereof comprises three CDRs of SEQ ID NO: 12. In some embodiments, a method of treating a solid tumor in a subject comprises administering to the subject a B7-H4-ADC at a dose of about 1.25 mg/kg on about day 1, followed by a dose of about 1.25 mg/kg twice every four weeks (2Q4W) on about day 15; wherein the B7-H4-ADC comprises an anti-B7-H4 antibody conjugated to vcMMAE (valine-citrulline-monomethylauristatin E). In some embodiments, the dose is determined according to the subject's weight. In some embodiments, the subject's weight is actual weight. In some embodiments, the subject's weight is adjusted ideal 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 about day 15 of a 28-day cycle. In some embodiments, the B7-H4-ADC is administered about 14 days apart from 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 cancer, lung cancer, bile duct cancer, gallbladder cancer, and head and neck cancer.

In some embodiments, a method of treating a solid tumor in a subject is provided, the method comprising administering to the subject a B7-H4-ADC at a dose of about 1.5 mg/kg twice every four weeks (2Q4W), wherein the B7-H4-ADC comprises an anti-B7-H4 antibody conjugated to vcMMAE (valine-citrulline-monomethylauristatin 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 three complementary determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or an antigen-binding fragment thereof comprises three CDRs of SEQ ID NO: 12. In some embodiments, a method of treating a solid tumor in a subject comprises administering to the subject a B7-H4-ADC at a dose of about 1.5 mg/kg on about day 1, followed by a dose of about 1.5 mg/kg twice every four weeks (2Q4W) on about day 15. In some embodiments, the dose is determined based on the subject's weight. In some embodiments, the subject's weight is an actual weight. In some embodiments, the subject's weight is an adjusted ideal 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 about day 15 of a 28-day cycle. In some embodiments, the B7-H4-ADC is administered about 14 days apart from one another. 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 cancer, lung cancer, bile duct cancer, gall bladder cancer, and head and neck cancer.

In some embodiments, a method of treating a solid tumor in a subject is provided, the method comprising administering to the subject a B7-H4-ADC at a dose of about 1.75 mg/kg twice every four weeks (2Q4W), wherein the B7-H4-ADC comprises an anti-B7-H4 antibody conjugated to vcMMAE (valine-citrulline-monomethylauristatin 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 three complementary determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or an antigen-binding fragment thereof comprises three CDRs of SEQ ID NO: 12. In some embodiments, a method of treating a solid tumor in a subject comprises administering to the subject a B7-H4-ADC at a dose of about 1.75 mg/kg on about day 1, followed by a dose of about 1.75 mg/kg twice every four weeks (2Q4W) on about day 15. In some embodiments, the dose is determined based on the subject's weight. In some embodiments, the subject's weight is an actual weight. In some embodiments, the subject's weight is an adjusted ideal 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 about day 15 of a 28-day cycle. In some embodiments, the B7-H4-ADC is administered about 14 days apart from 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 cancer, lung cancer, bile duct cancer, gallbladder cancer, and head and neck cancer.

In some embodiments, a method of treating a solid tumor in a subject is provided, the method comprising administering to the subject a B7-H4-ADC at a dose of about 2.0 mg/kg twice every four weeks (2Q4W), wherein the B7-H4-ADC comprises an anti-B7-H4 antibody conjugated to vcMMAE (valine-citrulline-monomethylauristatin 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 three complementary determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or an antigen-binding fragment thereof comprises three CDRs of SEQ ID NO: 12. In some embodiments, a method of treating a solid tumor in a subject comprises administering to the subject a B7-H4-ADC at a dose of about 2.0 mg/kg on about day 1, followed by a dose of about 2.0 mg/kg twice every four weeks (2Q4W) on about day 15. In some embodiments, the dose is determined based on the subject's weight. In some embodiments, the subject's weight is an actual weight. In some embodiments, the subject's weight is an adjusted ideal 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 about day 15 of a 28-day cycle. In some embodiments, the B7-H4-ADC is administered about 14 days apart from one another. 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 cancer, lung cancer, bile duct cancer, gall bladder cancer, and head and neck cancer.

In some embodiments, a method of treating a solid tumor in a subject is provided, the method comprising administering to the subject a B7-H4-ADC at a dose of about 2.25 mg/kg twice every four weeks (2Q4W), wherein the B7-H4-ADC comprises an anti-B7-H4 antibody conjugated to vcMMAE (valine-citrulline-monomethylauristatin 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 three complementary determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or an antigen-binding fragment thereof comprises three CDRs of SEQ ID NO: 12. In some embodiments, a method of treating a solid tumor in a subject comprises administering to the subject a B7-H4-ADC at a dose of about 2.25 mg/kg on about day 1, followed by a dose of about 2.25 mg/kg twice every four weeks (2Q4W) on about day 15. In some embodiments, the dose is determined based on the subject's weight. In some embodiments, the subject's weight is an actual weight. In some embodiments, the subject's weight is an adjusted ideal 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 about day 15 of a 28-day cycle. In some embodiments, the B7-H4-ADC is administered about 14 days apart from 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 cancer, lung cancer, bile duct cancer, gallbladder cancer, and head and neck cancer.

In some embodiments, a method of treating a solid tumor in a subject is provided, the method comprising administering to the subject a B7-H4-ADC at a dose of about 2.4 mg/kg twice every four weeks (2Q4W), wherein the B7-H4-ADC comprises an anti-B7-H4 antibody conjugated to vcMMAE (valine-citrulline-monomethylauristatin 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 three complementary determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or an antigen-binding fragment thereof comprises three CDRs of SEQ ID NO: 12. In some embodiments, a method of treating a solid tumor in a subject comprises administering to the subject a B7-H4-ADC at a dose of about 2.4 mg/kg on about day 1, followed by a dose of about 2.4 mg/kg twice every four weeks (2Q4W) on about day 15. In some embodiments, the dose is determined based on the subject's weight. In some embodiments, the subject's weight is an actual weight. In some embodiments, the subject's weight is an adjusted ideal 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 about day 15 of a 28-day cycle. In some embodiments, the B7-H4-ADC is administered about 14 days apart from one another. 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 cancer, lung cancer, bile duct cancer, gall bladder cancer, and head and neck cancer.

In some embodiments, a method of treating a solid tumor in a subject is provided, the method comprising administering to the subject 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-H4 antibody conjugated to vcMMAE (valine-citrulline-monomethylauristatin 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 three complementary determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or an antigen-binding fragment thereof comprises three CDRs of SEQ ID NO: 12. In some embodiments, a method of treating a solid tumor in a subject comprises administering a B7-H4-ADC to the subject 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 based on the subject's weight. In some embodiments, the subject's weight is an actual weight. In some embodiments, the subject's weight is an adjusted ideal weight. In some embodiments, the B7-H4-ADC is administered on about day 1, on about day 22, or on about day 43. In some embodiments, the B7-H4-ADC is administered on about day 1 of a 21 day cycle. In some embodiments, the B7-H4-ADC is administered about 21 days apart from 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 cancer, lung cancer, bile duct cancer, gallbladder cancer, and head and neck cancer.

In some embodiments, a method of treating a solid tumor in a subject is provided, the method comprising administering to the subject 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 vcMMAE (valine-citrulline-monomethylauristatin 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 three complementary determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or an antigen-binding fragment thereof comprises three CDRs of SEQ ID NO: 12. In some embodiments, a method of treating a solid tumor in a subject comprises administering a B7-H4-ADC to the subject 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 based on the subject's weight. In some embodiments, the subject's weight is an actual weight. In some embodiments, the subject's weight is an adjusted ideal weight. In some embodiments, the B7-H4-ADC is administered on about day 1, on about day 22, or on about day 43. In some embodiments, the B7-H4-ADC is administered on about day 1 of a 21 day cycle. In some embodiments, the B7-H4-ADC is administered about 21 days apart from 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 cancer, lung cancer, bile duct cancer, gallbladder cancer, and head and neck cancer.

In some embodiments, a method of treating a solid tumor in a subject is provided, the method comprising administering to the subject 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 vcMMAE (valine-citrulline-monomethylauristatin 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 three complementary determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or an antigen-binding fragment thereof comprises three CDRs of SEQ ID NO: 12. In some embodiments, a method of treating a solid tumor in a subject comprises administering a B7-H4-ADC to the subject 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 based on the subject's weight. In some embodiments, the subject's weight is an actual weight. In some embodiments, the subject's weight is an adjusted ideal 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 of a 21 day cycle. In some embodiments, the B7-H4-ADC is administered about 21 days apart from 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 cancer, lung cancer, bile duct cancer, gallbladder cancer, and head and neck cancer.

In some embodiments, a method of treating a solid tumor in a subject is provided, the method comprising administering to the subject 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-H4 antibody conjugated to vcMMAE (valine-citrulline-monomethylauristatin 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 three complementary determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or an antigen-binding fragment thereof comprises three CDRs of SEQ ID NO: 12. In some embodiments, a method of treating a solid tumor in a subject comprises administering a B7-H4-ADC to the subject 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 based on the subject's weight. In some embodiments, the subject's weight is an actual weight. In some embodiments, the subject's weight is an adjusted ideal weight. In some embodiments, the B7-H4-ADC is administered on about day 1, on about day 22, or on about day 43. In some embodiments, the B7-H4-ADC is administered on about day 1 of a 21 day cycle. In some embodiments, the B7-H4-ADC is administered about 21 days apart from 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 cancer, lung cancer, bile duct cancer, gallbladder cancer, and head and neck cancer.

In some embodiments, a method of treating a solid tumor in a subject is provided, the method comprising administering to the subject 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 vcMMAE (valine-citrulline-monomethylauristatin 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 three complementary determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or an antigen-binding fragment thereof comprises three CDRs of SEQ ID NO: 12. In some embodiments, a method of treating a solid tumor in a subject comprises administering a B7-H4-ADC to the subject 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 based on the subject's weight. In some embodiments, the subject's weight is an actual weight. In some embodiments, the subject's weight is an adjusted ideal weight. In some embodiments, the B7-H4-ADC is administered on about day 1, on about day 22, or on about day 43. In some embodiments, the B7-H4-ADC is administered on about day 1 of a 21 day cycle. In some embodiments, the B7-H4-ADC is administered about 21 days apart from 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 cancer, lung cancer, bile duct cancer, gallbladder cancer, and head and neck cancer.

In some embodiments, a method of treating a solid tumor in a subject is provided, the method comprising administering to the subject 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 vcMMAE (valine-citrulline-monomethylauristatin 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 three complementary determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or an antigen-binding fragment thereof comprises three CDRs of SEQ ID NO: 12. In some embodiments, a method of treating a solid tumor in a subject comprises administering a B7-H4-ADC to the subject 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 based on the subject's weight. In some embodiments, the subject's weight is an actual weight. In some embodiments, the subject's weight is an adjusted ideal weight. In some embodiments, the B7-H4-ADC is administered on about day 1, on about day 22, or on about day 43. In some embodiments, the B7-H4-ADC is administered on about day 1 of a 21 day cycle. In some embodiments, the B7-H4-ADC is administered about 21 days apart from 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 cancer, lung cancer, bile duct cancer, gallbladder cancer, and head and neck cancer.

In some embodiments, a method of treating a solid tumor in a subject is provided, the method comprising administering to the subject 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-H4 antibody conjugated to vcMMAE (valine-citrulline-monomethylauristatin 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 three complementary determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or an antigen-binding fragment thereof comprises three CDRs of SEQ ID NO: 12. In some embodiments, a method of treating a solid tumor in a subject comprises administering a B7-H4-ADC to the subject 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 based on the subject's weight. In some embodiments, the subject's weight is an actual weight. In some embodiments, the subject's weight is an adjusted ideal weight. In some embodiments, the B7-H4-ADC is administered on about day 1, on about day 22, or on about day 43. In some embodiments, the B7-H4-ADC is administered on about day 1 of a 21 day cycle. In some embodiments, the B7-H4-ADC is administered about 21 days apart from 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 cancer, lung cancer, bile duct cancer, gallbladder cancer, and head and neck cancer.

In some embodiments, a method of treating a solid tumor in a subject is provided, the method comprising administering to the subject 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 vcMMAE (valine-citrulline-monomethylauristatin 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 three complementary determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or an antigen-binding fragment thereof comprises three CDRs of SEQ ID NO: 12. In some embodiments, a method of treating a solid tumor in a subject comprises administering a B7-H4-ADC to the subject 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 based on the subject's weight. In some embodiments, the subject's weight is an actual weight. In some embodiments, the subject's weight is an adjusted ideal weight. In some embodiments, the B7-H4-ADC is administered on about day 1, on about day 22, or on about day 43. In some embodiments, the B7-H4-ADC is administered on about day 1 of a 21 day cycle. In some embodiments, the B7-H4-ADC is administered about 21 days apart from 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 cancer, lung cancer, bile duct cancer, gallbladder cancer, and head and neck cancer.

In some embodiments, the methods provided herein utilize a dosage determined according to the individual's weight. In some embodiments, the individual's weight is the actual weight. In some embodiments, the individual's weight is the adjusted ideal body weight (AIBW). In some embodiments, the dosage is adjusted for individuals who experience a ≥10% weight change relative to baseline. In some embodiments, the dosage is adjusted according to the AIBW. In some embodiments, when the individual's actual weight is higher than their ideal weight, the dosage is adjusted. In some embodiments, when the individual's actual weight is lower than their ideal weight, the dosage is adjusted. In some embodiments, the AIBW is calculated based on the individual's gender, height, and actual weight. Calculation of ideal body weight and AIBW is known in the art and is 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(11):1795-801; and Yeary et al ., Hosp Pharm. 2020 Dec;55(6):400-404, the contents of which are incorporated by reference.

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 targets but is not limited to PD-1, PD-L1, CTLA-4, LAG3, TIM-3, TIGIT, VISTA, TIM1, or BTLA. In some embodiments, the immune checkpoint inhibitor targets 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 the following: an antibody that binds to PD-1, an antibody that binds to PD-L1, an antibody that binds to CTLA-4, an antibody that binds to LAG3, an antibody that binds to TIM-3, an antibody that binds to TIGIT, an antibody that binds to VISTA, an antibody that binds to TIM-1, or an antibody that binds to BTLA. In some embodiments, the immune checkpoint inhibitor targets one or more of PD-1, PD-L1, CTLA-4, or TIGIT. In some embodiments, the immune checkpoint inhibitor targets PD-1. In some embodiments, the immune checkpoint inhibitor is one or more of the following: an antibody that binds to PD-1, an antibody that binds to PD-L1, an antibody that binds to CTLA-4, or an antibody that binds to TIGIT. In some embodiments, the immune checkpoint inhibitor is 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 the following: nivolumab, pembrolizumab, cemiplimab, dotalimumab, and rivulimab. 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 PD-L1 inhibitor (e.g., an anti-PD-L1 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® .

In some embodiments, a method of treating a solid tumor in a subject is provided, the method comprising administering to the subject a B7-H4-ADC at a dose of about 1.5 mg/kg AiBW twice every four weeks (2Q4W) and administering pembrolizumab at a dose of about 400 mg once every six weeks (Q6W), wherein the B7-H4-ADC comprises an anti-B7-H4 antibody conjugated to vcMMAE (valine-citrulline-monomethylauristatin 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 three complementary determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or an antigen-binding fragment thereof comprises SEQ ID NO: 12 of three CDRs. In some embodiments, a method of treating a solid tumor in a subject comprises administering to the subject a B7-H4-ADC at a dose of about 1.5 mg/kg on about day 1, followed by a dose of about 1.5 mg/kg twice every four weeks (2Q4W) 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 about day 15 of a 28-day cycle. In some embodiments, the B7-H4-ADC is administered about 14 days apart from 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 less than 5 days apart from the last dose. In some embodiments, pembrolizumab is administered starting on about day 1. In some embodiments, pembrolizumab is administered about 42 days apart from each other. In some embodiments, 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 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 is administered in combination with the B7-H4-ADC, pembrolizumab is administered first, followed by administration of the B7-H4-ADC. In some embodiments, pembrolizumab is administered at least 30 minutes prior to administration of the B7-H4-ADC. In some embodiments, pembrolizumab is administered to the individual at a dose of about 200 mg every three weeks (Q3W) until the individual is able to resume treatment on a Q6W schedule. In some embodiments, the solid tumor is triple negative breast cancer (TNBC). In some embodiments, the individual has 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.

In some embodiments, a method of treating a solid tumor in a subject is provided, the method comprising administering to the subject a B7-H4-ADC at a dose of about 1.75 mg/kg AiBW twice every four weeks (2Q4W) and administering pembrolizumab at a dose of about 400 mg once every six weeks (Q6W), wherein the B7-H4-ADC comprises an anti-B7-H4 antibody conjugated to vcMMAE (valine-citrulline-monomethylauristatin 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 three complementary determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or an antigen-binding fragment thereof comprises SEQ ID NO: 12 of three CDRs. In some embodiments, a method of treating a solid tumor in a subject comprises administering to the subject a B7-H4-ADC at a dose of about 1.75 mg/kg on about day 1, followed by a dose of about 1.75 mg/kg twice every four weeks (2Q4W) 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 about day 15 of a 28-day cycle. In some embodiments, the B7-H4-ADC is administered about 14 days apart from 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 less than 5 days apart from the last dose. In some embodiments, pembrolizumab is administered starting on about day 1. In some embodiments, pembrolizumab is administered about 42 days apart from each other. In some embodiments, 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 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 is administered in combination with the B7-H4-ADC, pembrolizumab is administered first, followed by administration of the B7-H4-ADC. In some embodiments, pembrolizumab is administered at least 30 minutes prior to administration of the B7-H4-ADC. In some embodiments, pembrolizumab is administered to the individual at a dose of about 200 mg every three weeks (Q3W) until the individual is able to resume treatment on a Q6W schedule. In some embodiments, the solid tumor is triple negative breast cancer (TNBC). In some embodiments, the individual has 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.

In some embodiments, a method of treating a solid tumor in a subject is provided, the method comprising administering to the subject a B7-H4-ADC at a dose of about 1.5 mg/kg AiBW twice every four weeks (2Q4W) and administering pembrolizumab at a dose of about 400 mg once every six weeks (Q6W), wherein the B7-H4-ADC comprises an anti-B7-H4 antibody conjugated to vcMMAE (valine-citrulline-monomethylauristatin 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 three complementary determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or an antigen-binding fragment thereof comprises SEQ ID NO: 12 of three CDRs. In some embodiments, a method of treating a solid tumor in a subject comprises administering to the subject a B7-H4-ADC at a dose of about 1.5 mg/kg on about day 1, followed by a dose of about 1.5 mg/kg twice every four weeks (2Q4W) 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 about day 15 of a 28-day cycle. In some embodiments, the B7-H4-ADC is administered about 14 days apart from 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 less than 5 days from the last dose. In some embodiments, the B7-H4-ADC is administered 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 is administered in combination with the B7-H4-ADC, pembrolizumab is administered first, followed by the B7-H4-ADC. In some embodiments, pembrolizumab is administered at least 30 minutes prior to administration of the B7-H4-ADC. In some embodiments, pembrolizumab is administered starting on about day 1. In some embodiments, pembrolizumab is administered about 42 days apart from each other. In some embodiments, pembrolizumab is administered up to about 1 dose, up to about 2 doses, up to about 3 doses, or up to about 4 doses. In some embodiments, pembrolizumab is administered to the individual at a dose of about 200 mg every three weeks (Q3W) until the individual is able to resume treatment on a Q6W schedule. In some embodiments, the solid tumor is triple negative breast cancer (TNBC). In some embodiments, the TNBC is neoadjuvant therapy and postoperative residual disease.

In some embodiments, a method of treating a solid tumor in a subject is provided, the method comprising administering to the subject a B7-H4-ADC at a dose of about 1.75 mg/kg AiBW twice every four weeks (2Q4W) and administering pembrolizumab at a dose of about 400 mg once every six weeks (Q6W), wherein the B7-H4-ADC comprises an anti-B7-H4 antibody conjugated to vcMMAE (valine-citrulline-monomethylauristatin 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 three complementary determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or an antigen-binding fragment thereof comprises SEQ ID NO: 12 of three CDRs. In some embodiments, a method of treating a solid tumor in a subject comprises administering to the subject a B7-H4-ADC at a dose of about 1.75 mg/kg on about day 1, followed by a dose of about 1.75 mg/kg twice every four weeks (2Q4W) 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 about day 15 of a 28-day cycle. In some embodiments, the B7-H4-ADC is administered about 14 days apart from 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 less than 5 days from the last dose. In some embodiments, the B7-H4-ADC is administered 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 is administered in combination with the B7-H4-ADC, pembrolizumab is administered first, followed by the B7-H4-ADC. In some embodiments, pembrolizumab is administered at least 30 minutes prior to administration of the B7-H4-ADC. In some embodiments, pembrolizumab is administered starting on about day 1. In some embodiments, pembrolizumab is administered about 42 days apart from each other. In some embodiments, pembrolizumab is administered up to about 1 dose, up to about 2 doses, up to about 3 doses, or up to about 4 doses. In some embodiments, pembrolizumab is administered to the individual at a dose of about 200 mg every three weeks (Q3W) until the individual is able to resume treatment on a Q6W schedule. In some embodiments, the solid tumor is triple negative breast cancer (TNBC). In some embodiments, the TNBC is neoadjuvant therapy and postoperative residual disease.

In some embodiments, the methods described herein for treating a solid tumor in an individual further comprise 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 (according to American Society for Clinical Oncology [ASCO]/CAP [College of American Pathologists] criteria, based on the most recent biopsy available); 3) TNBC (according to ASCO/CAP criteria, based on the most recent biopsy available); 4) endometrial cancer (Part C: up to 10 individuals with endometrial carcinosarcoma may be enrolled in a single therapy dose expansion cohort); 5) NSCLC (SqCC, AC); 6) cholangiocarcinoma or gallbladder cancer; or 7) ACC. In some embodiments, the individual has disease that is recurrent or refractory or intolerant to SOC therapy and, in the judgment of the investigator, should not have appropriate SOC treatment options. If a SOC therapy is available but has not yet been administered, the reason why the therapy is inappropriate must be documented. In some embodiments, the individual provides archival tumor tissue from the 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 can be accessed by minimally invasive procedures that do not represent a significant risk). In some embodiments, the individual provides archival tumor tissue from the most recent biopsy collected within 12 months. In some embodiments, the individual meets one or more of the following criteria: 1) age 18 years or older; 2) Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1; 3) measurable disease according to RECIST version 1.1 at baseline; 4) the following baseline laboratory test results: a) absolute neutrophil count (ANC) ≥1500/μL; b) hemoglobin (Hgb) ≥9 g/dL; c) platelet count ≥100,000/μL; d) serum bilirubin ≤1.5 × upper limit of normal (ULN) or ≤3 × ULN for individuals 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 (if applicable) or 24-hour creatinine clearance (CrCl) ≥45 mL/min/1.73 ^m2 ; and ALT and AST ≤3 × ULN (≤5 × ULN if there is evidence of malignant disease involving the liver); 5) Individuals of reproductive potential who 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 [β-hCG]) result within 7 days before the first dose of SGN-B7H4V. Individuals with a false positive result and documented non-pregnancy were eligible to participate; b) must agree not to attempt pregnancy during the study and for at least 2 months after the last dose of SGN-B7H4V; c) must agree not to breastfeed or donate eggs, beginning at the time of informed consent and continuing until 2 months after the last dose of SGN B7H4V; d) must continue to use at least 2 acceptable methods of birth control (contraception), at least 1 of which must be highly effective, starting at the time of informed consent and continuing until the last dose of SGN B7H4V for at least 2 months after the date of the study; and/or 6) individuals who can conceive a pregnancy and meet the following conditions: a) must agree not to donate sperm from the time of informed consent and continue for the duration of the study and for at least 4 months after the final dose of the study treatment; b) if sexual activity with a person of childbearing potential could result in pregnancy, must continue to use at least 2 acceptable birth control methods (contraception), at least 1 of which must be highly effective from the time of informed consent and continue for at least 4 months after the final dose of the study treatment; c) if sexual activity with a person who is pregnant or breastfeeding, must continue to use condoms from the time of informed consent and continue for at least 4 months after the final dose of the study treatment. In some embodiments, the subject has TNBC that is relapsed or refractory or intolerant to SOC therapy as specified below: 1) treated with at least 1 and no more than 3 prior lines of systemic chemotherapy in the setting of locally advanced unresectable or metastatic TNBC; 2) if the subject subsequently develops locally advanced unresectable or metastatic disease within 12 months after completion of adjuvant or neoadjuvant therapy, adjuvant or neoadjuvant therapy for earlier disease will count as 1 line of systemic chemotherapy; 3) received a PD-(L)1 inhibitor if eligible based on biomarker status and consistent with SOC; 4) treatment with a topoisomerase-1 (TOPO-1) inhibitor-based ADC (if available) has been discussed. If the subject has received treatment with a TOPO-1 inhibitor-based ADC, it will be counted as 1 line of systemic chemotherapy; and/or 5) hormonal therapy will not be considered as a prior line of systemic chemotherapy.

In some embodiments, the methods of treating a solid tumor in an individual described herein further include 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 cancer, squamous NSCLC, bile duct cancer or gallbladder cancer, 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, individuals suitable for such treatment as described herein meet one or more of the following criteria: 1) have received treatment with platinum-based chemotherapy and are considered to have platinum-resistant disease, which is defined as disease that has radiographic progression within 6 months after completing at least 4 cycles of platinum-containing therapy; 2) the individual does not have primary platinum-refractory disease, which is defined as disease that has not responded or has progressed within 3 months after the last dose of first-line platinum-containing chemotherapy; 3) must have received a regimen containing bevacizumab; and 4) if the individual qualifies based on biomarker status and is 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, an individual who is suitable for such treatment as described herein meets one or more of the following criteria: 1) treated with at least 1 and no more than 3 prior lines of systemic chemotherapy in the setting of locally advanced unresectable or metastatic TNBC; 2) adjuvant or neoadjuvant therapy for earlier disease will count as 1 line of systemic chemotherapy if the individual subsequently develops locally advanced unresectable or metastatic disease within 12 months after completion of adjuvant or neoadjuvant therapy; 1) prior systemic chemotherapy; 2) if eligible based on biomarker status and consistent with the SOC, treatment must include a PD-(L)1 inhibitor; 3) treatment with a TOPO-1 inhibitor-based ADC has been discussed (if available); 4) if the individual has received treatment with a TOPO-1 inhibitor-based ADC, it will count as 1 line of systemic chemotherapy; and 5) 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, an individual who is suitable for such treatment as described herein meets one or more of the following criteria: 1) treated with endocrine therapy. Individuals must have progressed and are no longer eligible for endocrine therapy, as assessed by the investigator; 2) treated with a cyclin D-dependent kinase (CDK) 4/6 inhibitor, unless CDK is not indicated for safety reasons, as assessed by the investigator. 4/6 inhibitor therapy is not suitable; 3) treated with at least 1 and no more than 3 prior lines of systemic chemotherapy in the locally advanced unresectable or metastatic HR+/HER2- breast setting; 4) if the individual subsequently develops locally advanced unresectable or metastatic disease within 12 months after completion of adjuvant or neoadjuvant therapy, adjuvant or neoadjuvant therapy for early stage disease will count as 1 line of systemic chemotherapy; 5) treatment with a TOPO-1 inhibitor-based ADC has been discussed (if available); 6) if the individual 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 cancer. In some embodiments, individuals suitable for such treatment as described herein meet one or more of the following criteria: 1) must have received at least 1 line of systemic therapy; 2) must have received prior PD-1 inhibitors and/or a combination of pembrolizumab and lenvatinib if appropriate based on biomarker status (including but not limited to microsatellite instability [MSI] and mismatch repair deficiency [dMMR] status) and available based on local SOC; and 3) must have received at least 1 prior platinum-based regimen. In some embodiments, the individual has squamous NSCLC. In some embodiments, individuals suitable for such treatment as described herein meet the following criteria: Locally advanced recurrent/metastatic disease must have received prior treatment with platinum-based therapy alone or in combination and a PD-(L)1 inhibitor if indicated by the local SOC. In some embodiments, the individual has cholangiocarcinoma or gallbladder cancer. In some embodiments, individuals suitable for such treatment as described herein meet one or more of the following criteria: 1) must have received at least 1 line of systemic therapy; 2) if appropriate based on 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 mutation burden [TMB-H] status) and available based on local SOC, the individual must have received approved targeted therapy; and 3) liver involvement is allowed. In some embodiments, the individual has adenoid cystic carcinoma. In some embodiments, individuals suitable for such treatments described herein meet 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 carry genomic mutations/alterations and have access to approved targeted therapies based on local SOC must have received approved and available targeted therapies. In some embodiments, individuals suitable for such treatments described herein are required to provide fresh pre-treatment biopsy, on-treatment biopsy on Day 15 of Cycle 1, and end-of-treatment (EOT) biopsy.

In some embodiments, the methods of treating a solid tumor in an individual described herein further comprise administering pembrolizumab. In some embodiments, the methods of treating a solid tumor in an individual described herein further comprise selecting an individual suitable for such treatment. In some embodiments, the solid tumor is triple negative breast cancer (TNBC). In some embodiments, the individual has PD-L1 positive (combined positive score (CPS) ≥ 10) TNBC. In some embodiments, individuals suitable for such treatment described herein meet one or more of the following criteria: 1) Must have histologically or cytologically confirmed locally advanced unresectable or metastatic TNBC (according to ASCO/CAP criteria, based on the most recent available biopsy). Subjects must have CPS ≥ 10 by local testing; 2) locally advanced unresectable or metastatic TNBC with no prior treatment. Subjects treated in a curative setting were eligible if it had been ≥ 6 months since completion of self-curative treatment; and 3) provided archival tumor tissue from the most recent biopsy collected within 12 months or a fresh pre-treatment biopsy.

In some embodiments, the methods of treating a solid tumor in an individual described herein further comprise administering pembrolizumab. In some embodiments, the methods of treating a solid tumor in an individual described herein further comprise selecting an individual suitable for such treatment. In some embodiments, the solid tumor is triple negative breast cancer (TNBC). In some embodiments, the individual has PD-L1 negative (CPS <10) TNBC. In some embodiments, individuals suitable for such treatment described herein meet one or more of the following criteria: 1) Must have histologically or cytologically confirmed locally advanced unresectable or metastatic TNBC (according to ASCO/CAP criteria, based on the most recent available biopsy). Subjects must have CPS < 10 by local testing; 2) locally advanced unresectable or metastatic TNBC with no prior treatment. Subjects treated in a curative setting were eligible if it had been ≥6 months since completion of spontaneous curative treatment; and 3) provided archival tumor tissue from the most recent biopsy collected within 12 months or a fresh pre-treatment biopsy.

In some embodiments, the methods of treating a solid tumor in an individual described herein further comprise administering pembrolizumab. In some embodiments, the methods of treating a solid tumor in an individual described herein further comprise selecting an individual suitable for such treatment. In some embodiments, the solid tumor is triple negative breast cancer (TNBC). In some embodiments, the TNBC is neoadjuvant therapy and postoperative residual disease. In some embodiments, individuals suitable for such treatment described herein meet one or more of the following criteria: 1) Must have histologically or cytologically confirmed TNBC (according to ASCO/CAP criteria, based on the most recently available biopsy); 2) must have stage I-III disease with evidence of residual disease in the breast and/or axillary lymph nodes after definitive surgical resection following neoadjuvant therapy; 3) must have adequate resection and surgical removal of all clinically significant disease in the breast and/or lymph nodes; 4) for locally advanced unresectable or metastatic TNBC, with or without immuno-CPIs 5) radiation therapy (if indicated) must have been administered prior to the start of study treatment; 6) provision of archival tumor tissue from the most recent biopsy collected within 12 months or a fresh pre-treatment biopsy; and 7) left ventricular ejection fraction (LVEF) ≥50% based on echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan within 28 days prior to the start of study treatment.

In some embodiments, the methods described herein for treating a solid tumor in an individual further include excluding an individual who is not suitable for such treatment. In some embodiments, an individual who is not suitable for the treatment methods described herein meets one or more of the following criteria: 1) a history of another malignant tumor within 3 years prior to the first dose of study drug, or any evidence of residual disease from a previously diagnosed malignant tumor. Exceptions are malignant tumors with negligible risk of metastasis or death (e.g., 5-year OS ≥90%), such as adequately treated cervical carcinoma in situ, non-melanoma skin cancer, 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 were eligible to participate provided that they were clinically stable for at least 4 weeks prior to study entry following treatment of brain metastases, did not have new or enlarging brain metastases, and were off corticosteroid prescription for symptoms related to brain metastases for at least 7 days prior to the first dose of study drug; 3) carcinomatous meningitis; 4) prior exposure to agents containing MMAE or targeting B7H4; 5) pre-existing neuropathy ≥ Grade 2 according to the 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 was allowed; 7) Uncontrolled diabetes, defined as Hgb A1c ≥8% or Hgb A1c between 7 and <8% with associated diabetic symptoms not otherwise explained (polyuria or thirst); 8) Positive for hepatitis B based on surface antigen expression and/or positive anti-hepatitis B core (HBc) total antibody titer. Active hepatitis C infection (based on positive polymerase chain reaction [PCR] or receiving antiviral therapy for hepatitis C within the past 6 months). Individuals with treated hepatitis C infection are permitted if a sustained virologic response for 12 weeks has been documented; 9) known to be positive for human immunodeficiency virus; 10) a history of documented cerebrovascular 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) Class III or IV congestive heart failure according to New York Heart Association criteria; 12) ≥ Grade 2 active or uncontrolled lung disease;13) Active autoimmune disease that required systemic treatment (i.e., use of disease-modifying agents, corticosteroids, or immunosuppressive drugs) within the past 2 years. Replacement therapy (e.g., thyroid hormone, insulin, or physiologic corticosteroid replacement for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is permitted;14) Corneal disease or injury requiring treatment or active monitoring;15) Parts A and D only: Use of strong cytochrome P450 3A within 14 days prior to the start of study treatment (CYP3A) inhibitors or inducers; 16) Receipt of vaccines containing live or attenuated viruses within 30 days before the first dose of study drug; 17) Chemotherapy, immunotherapy, biologics, and/or other approved or investigational anti-cancer treatments 4 weeks before the start of study treatment (for all parts), or before the start of study treatment if the underlying disease has progressed on treatment 18) Partial radiation therapy or major surgery not completed within 2 weeks prior to the start of study treatment; 19) Individuals who are breastfeeding, pregnant, or planning to become pregnant from the time of informed consent until 2 months after the last dose of SGN-B7H4V and until 4 months after the last dose of pembrolizumab (for Parts D and E); 20) Individuals with known SGN Allergy to any formulation of the drug or other treatment to be administered; 21) Estimated life expectancy < 12 weeks; 22) Other serious potential medical conditions that the investigator believes will impair the individual's ability to accept or tolerate the planned treatment and follow-up; 23) Related to previous treatment and has not recovered to baseline or > Any toxicity of Grade 1, excluding alopecia and well-controlled immune-mediated endocrine toxicity (e.g. Grade 2 hypothyroidism) caused by previous immunotherapy CPI use; 24) individuals who are familially or financially dependent on the sponsor, the sponsor's legal representative, the clinical research organization or the investigators; and/or 25) in Germany only, individuals submitted to the institution pursuant to an order issued by a judicial or administrative authority.

In some embodiments, the methods of treating a solid tumor in an individual described herein further include administering pembrolizumab. In some embodiments, the methods of treating a solid tumor in an individual described herein further include excluding individuals who are not suitable for such treatment. In some embodiments, individuals who are not suitable for the treatment methods described herein meet one or more of the following criteria: 1) have received prior treatment with a PD-1 inhibitor, anti-PD(L)1 or anti-PD L2 agent, or an agent directed against another stimulatory or co-inhibitory T cell receptor (e.g., CTLA4, OX40, CD137) and discontinued that treatment due to a Grade 3 or higher IMAE; 2) have been diagnosed with immunodeficiency within 7 days prior to the first dose of study drug or are receiving long-term systemic corticosteroid therapy (more than 10 doses per day); mg of prednisone equivalents) or any other form of immunosuppressive therapy; 3) have undergone allogeneic tissue/solid organ transplantation; 4) have a history of (non-infectious) pneumonitis/interstitial lung disease requiring steroids or currently have pneumonitis/interstitial lung disease; and 4) have received >30 Gy lung radiation therapy within 6 months after the first dose of study drug.

In some embodiments, the methods of treating a solid tumor in an individual described herein further comprise administering pembrolizumab. In some embodiments, the solid tumor is triple negative breast cancer (TNBC). In some embodiments, the individual has 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 neoadjuvant therapy and postoperative residual disease. In some embodiments, individuals who are not suitable for the treatment methods described herein meet one or more of the following criteria: 1) have received prior therapy with a PD-1 inhibitor, anti-PD(L)1 or anti-PD L2 agent, or an agent directed against another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA4, OX40, CD137) and discontinued that therapy due to a Grade 3 or higher IMAE; 2) have been diagnosed with immunodeficiency within 7 days prior to the first dose of study drug or are receiving long-term systemic corticosteroid therapy (more than 10 doses per day); mg of prednisone equivalents) or any other form of immunosuppressive therapy; 3) have undergone allogeneic tissue/solid organ transplantation; 4) have a history of (non-infectious) pneumonitis/interstitial lung disease requiring steroids or currently have pneumonitis/interstitial lung disease; and 4) have received >30 Gy lung radiation therapy within 6 months after the first dose of study drug.

In some embodiments, the methods of treating a solid tumor in an individual described herein further comprise administering pembrolizumab. In some embodiments, the TNBC is neoadjuvant therapy and post-operative residual disease. In some embodiments, individuals who are not suitable for the treatment methods described herein meet one or more of the following criteria: 1) have received prior adjuvant therapy; 2) have evidence of local or distant recurrence; and 3) have a known germline BRCA1 or BRCA2 mutation.

In some embodiments, the methods of treating a solid tumor in an individual as described herein further include treating an individual who experiences an infusion-related reaction. In some embodiments, the individual is administered with pre-medication. In some embodiments, pre-medication is not administered before the first dose of B7-H4-ADC. In some embodiments, pre-medication is an antihistamine (e.g., diphenhydramine 50 mg IV or equivalent and famotidine 40 mg IV or equivalent). In some embodiments, pre-medication is a corticosteroid (e.g., hydrocortisone 100 mg IV or equivalent). In some embodiments, pre-medication is an antipyretic (e.g., 500 to 1000 mg oral acetaminophen).

In some embodiments, the methods of treating a solid tumor in an individual described herein further comprise administering granulocyte colony stimulating factor (G-CSF). In some embodiments, administration of G-CSF is indicated if the individual meets one or more of the following criteria: 1) treatment of febrile neutropenia, and 2) experience Grade 4 neutropenia in any cycle or any grade of febrile neutropenia must receive prophylactic G-CSF in all subsequent cycles. In some embodiments, administration of G-CSF is prophylactic. In some embodiments, administration of G-CSF begins 1 to 3 days after administration of B7-H4-ADC. In some embodiments, pegfilgrastim is used. In some embodiments, if pegfilgrastim is used, administration should not be performed within 14 days prior to or on the day of B7-H4-ADC administration. In some embodiments, daily G-CSF is used. In some embodiments, administration of G-CSF should not be performed within 24 hours prior to or on the day of B7-H4-ADC administration and treatment should continue until ANC ≥ 1500/µL.

In some embodiments, a method of treating a solid tumor in an individual is provided, the method 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 cancer, lung cancer, bile duct cancer, gallbladder cancer, and head and neck cancer. In some embodiments, the ovarian cancer is high-grade serous ovarian cancer (HGSOC). In some embodiments, the breast cancer is 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 non-small cell lung cancer (NSCLC). In some embodiments, the NSCLC is squamous cell lung cancer or adenocarcinoma. In some embodiments, the head and neck cancer is adenoid cystic carcinoma (ACC). In some embodiments, the individual has no history of another malignant tumor within three years before the first dose of study drug, or no evidence of residual disease from a previously diagnosed malignant tumor. In some embodiments, the diagnosed malignant tumor is an exception, wherein the exception is a negligible risk of metastasis or death (e.g., 5-year overall survival rate ≥ 90%). In some embodiments, the exception is selected from the group consisting of: adequately treated in situ cervical cancer, non-melanoma skin cancer, localized prostate cancer, ductal carcinoma in situ, and stage I uterine cancer. In some embodiments, the individual does not have known active central nervous system metastases. In some embodiments, the subject has treated brain metastases and is clinically stable for at least four weeks prior to study entry after treatment of brain metastases, does not have new or enlarged brain metastases, and has been off a corticosteroid prescription for symptoms associated with brain metastases for at least 7 days prior to the first dose of study drug. In some embodiments, the subject does not have carcinomatous meningitis. In some embodiments, the subject has not previously received an agent containing MMAE or an agent targeting B7-H4. In some embodiments, the subject does not have pre-existing neuropathy of ≥ Grade 2 according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0.

In some embodiments, a method of treating high-grade serous ovarian cancer (HGSOC) in a subject is provided, the method comprising administering a B7-H4 ADC to the subject. In some embodiments, the HGSOC is selected from the group consisting of epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer. In some embodiments, the subject has platinum-resistant or refractory disease, wherein the platinum-resistant or refractory disease has progressed. In some embodiments, progression is evidenced by radiographic progression. In some embodiments, progression is evidenced by relapse within 6 months during or after prior platinum-containing chemotherapy. In some embodiments, the subject has received a regimen containing bevacizumab. In some embodiments, the subject has received a poly ADP ribose polymerase (PARP) inhibitor. In some embodiments, the subject has no history of another malignancy within three years prior to the first dose of study drug, or no evidence of residual disease from a previously diagnosed malignancy. In some embodiments, the diagnosed malignancy is an exception, wherein the exception is a negligible risk of metastasis or death (e.g., 5-year overall survival rate ≥ 90%). In some embodiments, the exception is selected from the group consisting of adequately treated cervical carcinoma in situ, non-melanoma skin cancer, localized prostate cancer, ductal carcinoma in situ, and stage I uterine cancer. In some embodiments, the subject does not have known active central nervous system metastases. In some embodiments, the subject has treated brain metastases and is clinically stable for at least four weeks prior to study entry after treatment of brain metastases, does not have new or enlarged brain metastases, and has been off a corticosteroid prescription for symptoms associated with brain metastases for at least 7 days prior to the first dose of study drug. In some embodiments, the subject does not have carcinomatous meningitis. In some embodiments, the subject has not previously received an agent containing MMAE or an agent targeting B7-H4. In some embodiments, the subject does not have pre-existing neuropathy of ≥ Grade 2 according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0.

In some embodiments, a method of treating HER2-negative/HR-positive breast cancer in an individual is provided, the method comprising administering a B7-H4-ADC to the individual. In some embodiments, a method of treating triple-negative breast cancer (TNBC) in an individual is provided, the method 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 embodiments, the prior therapy is a taxane. In some embodiments, the taxane is administered as a single agent or in combination. In some embodiments, the individual has further received therapy with a cyclin D-cyclin-dependent kinase (CDK) 4/6 inhibitor and at least one prior hormone therapy, unless contraindicated. In some embodiments, the individual has received a PARP inhibitor, a PD(L)1 inhibitor, and/or a phosphoinositide 3-kinase (PI3K) inhibitor. In some embodiments, the individual has HER2-negative/HR-positive breast cancer and triple-negative breast cancer (TNBC). In some embodiments, lenvatinib govitecan may be provided to individuals with HER2-negative/HR-positive breast cancer and triple-negative breast cancer (TNBC). In some embodiments, the individual has no history of another malignant tumor within three years prior to the first dose of study drug, or has no evidence of residual disease from a previously diagnosed malignant tumor. In some embodiments, a diagnosed malignancy is an exception, wherein the exception is a negligible risk of metastasis or death (e.g., 5-year overall survival rate ≥ 90%). In some embodiments, the exception is selected from the group consisting of adequately treated cervical cancer in situ, non-melanoma skin cancer, localized prostate cancer, ductal carcinoma in situ, and stage I uterine cancer. In some embodiments, the subject does not have known active central nervous system metastases. In some embodiments, the subject has treated brain metastases and is clinically stable for at least four weeks prior to study entry after treatment of brain metastases, does not have new or enlarged brain metastases, and has discontinued a corticosteroid prescription for symptoms related to brain metastases for at least 7 days prior to the first dose of study drug. In some embodiments, the subject does not have carcinomatous meningitis. In some embodiments, the subject has not previously received an agent containing MMAE or an agent targeting B7-H4. In some embodiments, the subject does not have a pre-existing neuropathy of ≥ grade 2 according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 5.0.

In some embodiments, a method of treating endometrial cancer in an individual is provided, the method 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 biomarker status. In some embodiments, the biomarker status includes, but is not limited to, microsatellite instability (MSI) and deficient mismatch repair (dMMR) status. In some embodiments, the individual has received prior PD-1 inhibitors or a combination of pembrolizumab and lenvatinib. In some embodiments, the individual has received prior PD-1 inhibitors and a combination of pembrolizumab and lenvatinib. In some embodiments, the subject has no history of another malignancy within three years prior to the first dose of study drug, or no evidence of residual disease from a previously diagnosed malignancy. In some embodiments, the diagnosed malignancy is an exception, wherein the exception is a negligible risk of metastasis or death (e.g., 5-year overall survival rate ≥ 90%). In some embodiments, the exception is selected from the group consisting of adequately treated cervical carcinoma in situ, non-melanoma skin cancer, localized prostate cancer, ductal carcinoma in situ, and stage I uterine cancer. In some embodiments, the subject does not have known active central nervous system metastases. In some embodiments, the subject has treated brain metastases and is clinically stable for at least four weeks prior to study entry after treatment of brain metastases, does not have new or enlarged brain metastases, and has been off a corticosteroid prescription for symptoms associated with brain metastases for at least 7 days prior to the first dose of study drug. In some embodiments, the subject does not have carcinomatous meningitis. In some embodiments, the subject has not previously received an agent containing MMAE or an agent targeting B7-H4. In some embodiments, the subject does not have pre-existing neuropathy of ≥ Grade 2 according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0.

In some embodiments, a method of treating squamous NSCLC in a subject is provided, the method comprising administering a B7-H4-ADC to the subject. In some embodiments, the subject has locally advanced recurrent or metastatic disease. In some embodiments, the subject with locally advanced recurrent or metastatic disease has received prior treatment with a platinum-based therapy or a PD(L)1 inhibitor. In some embodiments, the subject has received prior treatment with a platinum-based therapy and a PD(L)1 inhibitor. In some embodiments, the subject has no history of another malignancy within three years prior to the first dose of study drug, or has no evidence of residual disease from a previously diagnosed malignancy. In some embodiments, a diagnosed malignancy is an exception, wherein the exception is a negligible risk of metastasis or death (e.g., 5-year overall survival rate ≥ 90%). In some embodiments, the exception is selected from the group consisting of adequately treated cervical cancer in situ, non-melanoma skin cancer, localized prostate cancer, ductal carcinoma in situ, and stage I uterine cancer. In some embodiments, the subject does not have known active central nervous system metastases. In some embodiments, the subject has treated brain metastases and is clinically stable for at least four weeks prior to study entry after treatment of brain metastases, does not have new or enlarged brain metastases, and has discontinued a corticosteroid prescription for symptoms related to brain metastases for at least 7 days prior to the first dose of study drug. In some embodiments, the subject does not have carcinomatous meningitis. In some embodiments, the subject has not previously received an agent containing MMAE or an agent targeting B7-H4. In some embodiments, the subject does not have a pre-existing neuropathy of ≥ grade 2 according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 5.0.

In some embodiments, a method of treating bile duct cancer in an individual is provided, the method comprising administering a B7-H4-ADC to the individual. In some embodiments, a method of treating gallbladder cancer in an individual is provided, the method comprising administering a B7-H4-ADC to the individual. In some embodiments, the individual has received at least one line of systemic therapy. In some embodiments, a biomarker status is used to assess the individual. 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 an approved targeted therapy. In some embodiments, the subject has liver involvement. In some embodiments, the subject has no history of another malignant tumor within three years before the first dose of study drug, or no evidence of residual disease from a previously diagnosed malignant tumor. In some embodiments, the diagnosed malignant tumor is an exception, wherein the exception is a negligible risk of metastasis or death (e.g., 5-year overall survival rate ≥ 90%). In some embodiments, the exception is selected from the group consisting of: adequately treated cervical cancer in situ, non-melanoma skin cancer, localized prostate cancer, ductal carcinoma in situ, and stage I uterine cancer. In some embodiments, the subject does not have known active central nervous system metastases. In some embodiments, the subject has treated brain metastases and is clinically stable for at least four weeks prior to study entry after treatment of brain metastases, does not have new or enlarged brain metastases, and has been off a corticosteroid prescription for symptoms associated with brain metastases for at least 7 days prior to the first dose of study drug. In some embodiments, the subject does not have carcinomatous meningitis. In some embodiments, the subject has not previously received an agent containing MMAE or an agent targeting B7-H4. In some embodiments, the subject does not have pre-existing neuropathy of ≥ Grade 2 according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0.

In some embodiments, a method of treating adenoid cystic carcinoma (ACC) of the head and neck in a subject is provided, the method comprising administering a B7-H4-ADC to the subject. In some embodiments, the subject has locally advanced recurrent or metastatic disease. In some embodiments, the subject with locally advanced recurrent or metastatic disease has received at least one line of systemic therapy. In some embodiments, the subject has a tumor that carries a genomic mutation/alteration and for which an approved targeted therapy is available. In some embodiments, the subject has received an approved targeted therapy. In some embodiments, the subject has no history of another malignant tumor within three years prior to the first dose of study drug, or has no evidence of residual disease from a previously diagnosed malignant tumor. In some embodiments, a diagnosed malignancy is an exception, wherein the exception is a negligible risk of metastasis or death (e.g., 5-year overall survival rate ≥ 90%). In some embodiments, the exception is selected from the group consisting of adequately treated cervical cancer in situ, non-melanoma skin cancer, localized prostate cancer, ductal carcinoma in situ, and stage I uterine cancer. In some embodiments, the subject does not have known active central nervous system metastases. In some embodiments, the subject has treated brain metastases and is clinically stable for at least four weeks prior to study entry after treatment of brain metastases, does not have new or enlarged brain metastases, and has discontinued a corticosteroid prescription for symptoms related to brain metastases for at least 7 days prior to the first dose of study drug. In some embodiments, the subject does not have carcinomatous meningitis. In some embodiments, the subject has not previously received an agent containing MMAE or an agent targeting B7-H4. In some embodiments, the subject does not have a pre-existing neuropathy of ≥ grade 2 according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 5.0.

In some embodiments, the methods provided herein further comprise determining the level of B7-H4 expression in the solid tumor. In some embodiments, the expression level is determined by immunohistochemistry (IHC). In some embodiments, greater than 25% of the solid tumors have 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 than 50%, greater than 55%, greater than 60%, greater than 65%, greater than 70%, greater than 75%, greater than 80%, greater than 85%, greater than 90%, greater than 91%, greater than 92%, greater than 93%, greater than 94%, greater than 95%, greater than 96%, greater than 97%, greater than 98%, or greater than 99% of the solid tumor cells express B7-H4. In some embodiments, greater than 25% of the solid tumor cells express B7-H4. In some embodiments, greater than 50% of the solid tumor cells express B7-H4. D. Treatment Outcomes

In one embodiment of the methods or uses or products for use provided herein, the response to treatment with an antibody-drug conjugate as described herein ( e.g. , B7-H4-ADC) is assessed by measuring the size of tumors arising from cancer ( e.g. , breast cancer, ovarian cancer, primary peritoneal cancer, fallopian tube cancer, endometrial cancer, lung cancer, bile duct cancer, gall bladder cancer, or head and neck cancer). In one embodiment of the methods or uses or products for use provided herein, the response to treatment with a combination of B7-H4-ADC and a PD-1 inhibitor (e.g., an anti-PD1 antibody) is assessed by measuring the size of tumors arising from cancer ( e.g. , breast cancer, ovarian cancer, primary peritoneal cancer, fallopian tube cancer, endometrial cancer, lung cancer, bile duct cancer, gall bladder cancer, or head and neck cancer).

In some embodiments, the cancer is selected from peritoneal cancer, fallopian tube cancer, and gallbladder cancer. In a preferred embodiment, the cancer is selected from the group consisting of ovarian tumor, peritoneal tumor, fallopian tube tumor, HER2 negative breast tumor, HER2 positive breast tumor, triple negative breast tumor, endometrial tumor, non-small cell lung cancer, bile duct cancer, and gallbladder cancer. In one embodiment, the size of the 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 an antibody-drug conjugate described herein (e.g., B7-H4-ADC). In one embodiment, the size of a tumor derived from cancer is reduced by at least about 10%-80%. In one embodiment, the size of a tumor derived from cancer is reduced by at least about 20%-80%. In one embodiment, the size of a tumor derived from cancer is reduced by at least about 30%-80%. In one embodiment, the size of a tumor derived from cancer is reduced by at least about 40%-80%. In one embodiment, the size of a tumor derived from cancer is reduced by at least about 50%-80%. In one embodiment, the size of a tumor derived from cancer is reduced by at least about 60%-80%. In one embodiment, the size of a tumor derived from cancer is reduced by at least about 70%-80%. In one embodiment, the size of a tumor derived from cancer is reduced by at least about 80%. In one embodiment, the size of a tumor derived from cancer is reduced by at least about 85%. In one embodiment, the size of a tumor derived from cancer is reduced by at least about 90%. In one embodiment, the size of a tumor derived from cancer is reduced by at least about 95%. In one embodiment, the size of a tumor derived from cancer is reduced by at least about 98%. In one embodiment, the size of a tumor derived from cancer is reduced by at least about 99%. In one embodiment, the size of a tumor derived from 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 cancer prior to administration of an antibody-drug conjugate described herein (e.g., B7-H4-ADC). In one embodiment, the size of a tumor derived from cancer is reduced by at least 10%-80%. In one embodiment, the size of a tumor derived from cancer is reduced by at least 20%-80%. In one embodiment, the size of a tumor derived from cancer is reduced by at least 30%-80%. In one embodiment, the size of a tumor derived from cancer is reduced by at least 40%-80%. In one embodiment, the size of a tumor derived from cancer is reduced by at least 50%-80%. In one embodiment, the size of a tumor derived from cancer is reduced by at least 60%-80%. In one embodiment, the size of a tumor derived from cancer is reduced by at least 70%-80%. In one embodiment, the size of a tumor derived from cancer is reduced by at least 80%. In one embodiment, the size of a tumor derived from cancer is reduced by at least 85%. In one embodiment, the size of a tumor derived from cancer is reduced by at least 90%. In one embodiment, the size of a tumor arising from cancer is reduced by at least 95%. In one embodiment, the size of a tumor arising from cancer is reduced by at least 98%. In one embodiment, the size of a tumor arising from cancer is reduced by at least 99%. In one embodiment, the size of a tumor arising from cancer is reduced by 100%. In one embodiment, the size of a tumor arising from cancer is measured by magnetic resonance imaging (MRI). In one embodiment, the size of a tumor arising from cancer is measured by computed tomography (CT). In one embodiment, the size of a tumor arising from cancer is measured by positron emission tomography (PET). In one embodiment, the size of a tumor arising from cancer is measured by ultrasound. In some embodiments, the tumor cells express B7-H4. In some embodiments, tumor cells do not express B7-H4. In some embodiments, tumor cells express B7-H4 at a level higher than that of non-diseased cells of the same cell type. In some embodiments, tumor cells express B7-H4 at a level comparable to or lower than that of non-diseased cells of the same cell type.

In one embodiment of the methods or uses or products for use provided herein, the response to treatment with an antibody-drug conjugate described herein (e.g., B7-H4-ADC) promotes regression of a tumor derived from a 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, the tumor derived from the cancer is regressed 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 prior to administration of the antibody-drug conjugate described herein (e.g., B7-H4-ADC).

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

In some embodiments, administration of B7-H4-ADC induces upregulation of expression of one or more interferons and/or one or more type I interferon response genes. In some embodiments, the interferons are CXCL10 and/or CXCL1. In some embodiments, the type I interferon response genes are IFIT2 and/or MX1 . In some embodiments, administration of B7-H4-ADC induces upregulation of expression of CXCL10 and/or CXCL1 . In some embodiments, administration of B7-H4-ADC induces upregulation of expression of IFIT2 and/or MX1 . In some embodiments, administration of B7-H4-ADC induces activation of immune cells. In some embodiments, administration of B7-H4-ADC induces recruitment of immune cells to tumors.

In some embodiments, administration of B7-H4-ADC induces immunogenic cell death (ICD). In some embodiments, administration of B7-H4-ADC induces cancer cells to release ATP. In some embodiments, administration of B7-H4-ADC induces exposure of calcein on the surface of cancer cells.

In some embodiments, administration of B7-H4-ADC promotes the recruitment of innate immune cells and/or adaptive immune cells to tumors. In some embodiments, administration of B7-H4-ADC promotes the recruitment of innate immune cells and/or adaptive immune cells to tumors, and wherein the recruited immune cells are tumor-infiltrating. In some embodiments, the innate immune cells comprise antigen presenting cells, including macrophages (such as CD68+ macrophages) or dendritic cells (such as CD11c+ 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, tumor cells express B7-H4. In some embodiments, tumor cells do not express B7-H4. In some embodiments, tumor cells express B7-H4 at a level higher than that of non-diseased cells of the same cell type. In some embodiments, tumor cells express B7-H4 at a level comparable to or lower than that of non-diseased cells of the same cell type.

In some embodiments, administration of a B7-H4 ADC induces an anti-tumor immune response in an individual. In some embodiments, the anti-tumor immune response is determined by changes in local inflammatory markers at the tumor site. In some embodiments, the anti-tumor response is measured by changes in interleukin expression, interferon expression, recruitment of pro-inflammatory immune cells, changes in the expression levels of cell cycle markers, or changes in the levels of transcripts associated with inflammation.

In some embodiments, administration of a B7-H4 ADC induces up-regulation of expression of one or more interleukins and/or one or more type I interferon response genes. In some embodiments, administration of a B7-H4-ADC induces up-regulation of expression of CXCL10 , CXCL9 , CXCL1 , IFIT2 , and/or MX1 . In some embodiments, expression is determined by qPCR.

In some embodiments, administration of B7-H4-ADC promotes the recruitment of innate immune cells and/or adaptive immune cells to tumor sites. In some embodiments, the innate immune cells and/or adaptive immune cells are tumor infiltrating cells. In some embodiments, administration of ADC results in the recruitment of dendritic cells to tumor sites. In some embodiments, the dendritic cells express CD11c. In some embodiments, administration of ADC results in the recruitment of macrophages to tumor sites. In some embodiments, administration of ADC results in the recruitment of cells expressing CD86 to tumor sites. In some embodiments, the presence or absence of cells is determined by immunohistochemistry. In some embodiments, administration of B7-H4-ADC promotes the recruitment of CD11c+ dendritic cells, CD68+ macrophages, and/or cells expressing CD86 to tumor sites.

In some embodiments, administration of the ADC results in increased gene expression of one or more genes associated with inflammation at the tumor site. In some embodiments, administration of the B7-H4-ADC results in increased expression of genes associated with responsiveness to anti-PD-1 agents. In some embodiments, administration of the ADC results in increased expression of CXCL9 . In some embodiments, administration of the ADC results in increased expression of CXCL9 , CXCL10 , IFIT2 , IFIT3 , and/or MX1 .

In some embodiments, administration of the ADC results in increased expression of dendritic cell and macrophage markers. In some embodiments, administration of the ADC results in increased expression of ITGAX , BATF3 , and CD68 .

In some embodiments, the administration of the ADC results in an increase in the expression of MHC class II molecules. In some embodiments, the administration of the ADC results in an increase in the expression of HLA-DP, HLA-DM, HLA-DOA, HLA-DOB, HLA-DQ and/or HLA-DR.

In some embodiments, administration of the ADC results in increased expression of a co-stimulatory molecule. In some embodiments, administration of the ADC results in increased expression of CD80 , CD86 , and/or ICOSL .

In some embodiments, administration of the ADC results in increased expression of ITGAX , BATF3 , CD68 , CD80 , CD86 and/or ICOSL .

In some embodiments, administration of the ADC results in 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 immunohistochemistry.

In some embodiments, administration of the ADC results in an inflammatory gene expression signature. In some embodiments, the expression levels of Cd27, Cxcr6, Lag3, Nkg7, Pdcd1Ig2, Ccl5, Cd274, Cmk131, Cxcl9, Psmb10 and/or STAT1 are increased.

In some embodiments, administration of B7-H4-ADC results in changes in the expression of markers of cell division and/or cell cycle progression. In some embodiments, the levels of Ki67, CD163, CD206, ChiL3 and/or granzyme B positive cells at the tumor site are altered.

In some embodiments, the vcMMAE B7-H4 ADCs provided herein trigger a more effective response than ADCs with other microtubule inhibitor drugs. In some embodiments, the vcMMAE B7-H4 ADCs provided herein trigger a more effective immune response than ADCs comprising the same antibody bound to DM1 or DM4. In some embodiments, a lower amount of vcMMAE B7-H4 ADC is required to trigger an immune response than an ADC comprising the same antibody bound to DM1 or DM4. IV. Pharmaceutical Compositions and Formulations

For therapeutic uses, the antibody-drug conjugate (e.g., B7-H4-ADC) is combined with a pharmaceutically acceptable carrier. In some embodiments according to any B7-H4-ADC composition described herein (e.g., a composition comprising a B7-H4-ADC), the composition comprises a pharmaceutically acceptable carrier. In some embodiments according to any B7-H4-ADC composition 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 carriers" means buffers, carriers and excipients that are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reaction or other problems or complications and commensurate with a reasonable benefit/risk ratio. The carrier should be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient. Pharmaceutically acceptable carriers include buffers, solvents, dispersion media, coatings, isotonic agents and absorption delaying agents and the like, which are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is known in the art.

In some embodiments, a B7-H4-ADC composition 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)-1 receptor and blocks its interaction with PD-L1 and PD-L2, thereby releasing inhibition of PD-1 pathway-mediated immune responses (including anti-tumor immune responses). In some embodiments, pembrolizumab is a 100 mg/4 mL (25 mg/mL) solution in a single-use vial. In some embodiments, pembrolizumab is for intravenous (IV) injection. In some embodiments, pembrolizumab is a sterile, preservative-free, clear to slightly opalescent and colorless to slightly yellowish solution. In some embodiments, pembrolizumab requires dilution for IV infusion. In some embodiments, a pembrolizumab vial contains 4 mL of solution containing 100 mg of pembrolizumab. In some embodiments, each 1 mL of solution contains 25 mg of pembrolizumab and is formulated in L-histidine, polysorbate, sucrose, and WFI (water for injection) USP. In some embodiments, the pembrolizumab is ^Keytruda® .

In some embodiments, pembrolizumab comprises QVQLVQSGVEVKKPGASVKVSCKASGYTFTNYYMYWVRQAPGQGLEWMGGINPSNGGTNFNEKFKNRVTLTTDSSTTTAYMELKSLQFDDTAVYYCARRDYRFDMGFDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDK RVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSS IEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK The heavy chain sequence of (SEQ ID NO: 93).

In some embodiments, pembrolizumab comprises the light chain sequence of EIVLTQSPATLSLSPGERATLSCRASKGVSTSGYSYLHWYQQKPGQAPRLLIYLASYLESGVPARFSGSGSGTDFTLTISSLEPEDFAVYYCQHSRDLPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 94).

Therefore, the antibody-drug conjugate (e.g., B7-H4-ADC) composition of the present invention may include at least one of any suitable excipients, such as but not limited to diluents, binders, stabilizers, buffers, salts, lipophilic solvents, preservatives, adjuvants or the like. Pharmaceutically acceptable excipients are preferred. Non-limiting examples and methods for 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, 18th edition, Mack Publishing Co. (Easton, Pa.) 1990. Pharmaceutically acceptable carriers can be routinely selected to be appropriate for the mode of administration, solubility and/or stability of the antibody molecule, fragment or variant composition as known in the art or as described herein.

Pharmaceutical excipients and/or additives suitable for use in the antibody molecule compositions according to the present invention are known in the art, for example, as listed in "Remington: The Science & Practice of Pharmacy," 19th edition, Williams & Williams, (1995) and "Physician's Desk Reference," 52nd edition, Medical Economics, Montvale, N.J. (1998).

Pharmaceutical compositions containing an antibody-drug conjugate (e.g., B7-H4-ADC) as disclosed herein can be presented in dosage unit form and can be prepared by any suitable method. The 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. The 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 . Components of formulations suitable for parenteral administration include sterile diluents such as water for injection, saline solutions, nonvolatile oils, polyethylene glycols, glycerol, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as EDTA; buffers such as acetates, citrates or phosphates; and agents for regulating tonicity such as sodium chloride or dextrose.

For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL ^™ (BASF, Parsippany, NJ) 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, polyols (e.g., glycerol, propylene glycol and liquid polyethylene glycol) and suitable mixtures thereof.

The pharmaceutical formulation is preferably sterile. Sterilization can be achieved by any suitable method, such as filtration through a sterile filter membrane. In the case of freeze-dried composition, filtration sterilization can be performed before or after freeze-drying and reconstitution.

The compositions of the invention may be in a variety of forms. Such forms include, for example, liquid, semisolid and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, and liposomes. The specific form depends on the intended mode of administration and therapeutic application. In exemplary embodiments, the 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 formulation is administered by intravenous infusion or injection. In another preferred embodiment, the formulation is administered by intramuscular or subcutaneous injection.

As used herein, the phrase "parenteral administration" or "administered parenterally" means modes of administration other than enteral and topical administration, usually by injection, and includes, but is not limited to, intravenous, intramuscular, subcutaneous, intraarterial, intrathecal, intracapsular, intraorbital, intravitreal, intracardiac, intradermal, intraperitoneal, transtracheal, inhalation, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal injection and infusion.

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

The present invention provides a kit comprising packaging material and at least one vial containing a solution of at least one antibody-drug conjugate (e.g., B7-H4-ADC) and a specified buffer and/or preservative, optionally in an aqueous diluent. The concentration of preservative used in the formulation is a concentration sufficient to produce an antimicrobial effect. Such concentration depends on the preservative selected and is readily determined by a skilled artisan.

Various delivery systems can be used to administer the antibody-drug conjugate to a subject. In certain exemplary embodiments, the antibody-drug conjugate (e.g., B7-H4-ADC) is administered 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 will be infused over 2 hours).

Any of the above formulations can be stored in liquid or frozen form, and the preservation process can be carried out separately as appropriate. In some embodiments, the above formulations are lyophilized, that is, they are lyophilized separately. In some embodiments, the above formulations are subjected to a preservation process, such as lyophilization, and then reconstituted with a suitable liquid (e.g., water). Lyophilization means that the composition has been freeze-dried under vacuum. Lyophilization is usually accomplished by freezing a particular formulation to separate the solute from the solvent. Then, the solvent is removed by sublimation (i.e., primary drying) and then by desorption (i.e., secondary drying).

In some embodiments, the lyophilized formulation comprises an antibody-drug conjugate described herein (e.g., B7-H4-ADC). 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.

The formulations of the invention can be used with the methods described herein or other methods for treating a disease. Antibody-drug conjugate (e.g., B7-H4-ADC) formulations can be further diluted prior to administration to a subject. In some embodiments, the formulations will be diluted with saline and kept in an IV bag or syringe prior to administration to a subject. V. Articles of manufacture and kits

In another aspect, an article of manufacture or kit is provided, comprising an antibody-drug conjugate (e.g., B7-H4-ADC) described herein. The article of manufacture or kit may further comprise instructions for using the antibody-drug conjugate (e.g., B7-H4-ADC) described herein in the methods of the invention. Thus, in certain embodiments, the article of manufacture or kit comprises instructions for using the anti-B7-H4 antibody-drug conjugate ( e.g. , B7-H4-ADC) described herein in a method for treating cancer (e.g., breast cancer, ovarian cancer, primary peritoneal cancer, fallopian tube cancer, endometrial cancer, lung cancer, bile duct cancer, gallbladder cancer, or head and neck cancer) in a subject, the methods comprising administering to the subject an effective amount of the anti-B7-H4 antibody-drug conjugate (e.g., B7-H4-ADC) described herein. In one aspect, an article of manufacture or kit is provided, comprising an antibody-drug conjugate (e.g., B7-H4-ADC) described herein and an immune checkpoint inhibitor (e.g., anti-PD1 antibody). In some embodiments, the immune checkpoint inhibitor is pembrolizumab. The article of manufacture or kit may further comprise instructions for using the antibody-drug conjugate (e.g., B7-H4-ADC) and immune checkpoint inhibitor (e.g., anti-PD1 antibody) described herein in the methods of the invention. In certain embodiments, the article of manufacture or kit comprises instructions for using an antibody-drug conjugate ( e.g. , B7-H4-ADC) and an immune checkpoint inhibitor (e.g., anti-PD1 antibody) described herein in a method for treating cancer (e.g., breast cancer, ovarian cancer, primary peritoneal cancer, fallopian tube cancer, endometrial cancer, lung cancer, bile duct cancer, gallbladder cancer, or head and neck cancer) in a subject, the methods comprising administering to the subject an effective amount of an anti-B7-H4 antibody-drug conjugate (e.g., B7-H4-ADC) and an effective amount of an immune checkpoint inhibitor (e.g., anti-PD1 antibody). In some embodiments, the immune checkpoint inhibitor is pembrolizumab. In some embodiments, the cancer is locally advanced cancer. In some embodiments, the cancer is 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 using an antibody-drug conjugate ( e.g., B7-H4-ADC) described herein in a method for treating a cancer (e.g., breast cancer, ovarian cancer, primary peritoneal cancer, fallopian tube cancer, endometrial cancer, lung cancer, bile duct cancer, gallbladder cancer, or head and neck cancer) in a subject, the methods comprising administering to the subject an effective amount of an anti-B7-H4 antibody-drug conjugate (e.g., B7-H4-ADC) described herein. 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 cancer 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, bile duct cancer, and endometrial cancer. In some embodiments herein, the cancer is selected from peritoneal cancer, fallopian tube cancer, and gallbladder cancer. In a preferred embodiment, the cancer is selected from the group consisting of ovarian tumor, peritoneal tumor, fallopian tube tumor, HER2-negative breast tumor, HER2-positive breast tumor, triple-negative breast tumor, endometrial tumor, non-small cell lung cancer, bile duct carcinoma and gallbladder cancer.

The article of manufacture or kit may further comprise a container. Suitable containers include, for example, bottles, vials ( e.g. , dual chamber vials), syringes (e.g., single chamber 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.

The article of manufacture or kit may further comprise a label or package insert on or associated with the container that may indicate instructions for reconstitution and/or use of the formulation. The label or package insert may further indicate that the formulation may be used or intended for subcutaneous, intravenous ( e.g., intravenous infusion), or other modes of administration for treating a cancer as described herein ( e.g. , breast cancer, ovarian cancer, primary peritoneal cancer, fallopian tube cancer, endometrial cancer, lung cancer, bile duct cancer, gallbladder cancer, or head and neck cancer) in a subject. The label or package insert may further indicate that the formulation can be used or is intended for subcutaneous administration, intravenous administration ( 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 a subject. The label or package insert may indicate that the formulation can be used or is intended for subcutaneous administration, intravenous administration ( e.g., intravenous infusion), or other modes of administration for treating breast cancer, ovarian cancer, lung cancer, bile duct cancer, endometrial cancer, peritoneal cancer, fallopian tube cancer, or gallbladder cancer as described herein in a subject. The container holding the formulation can be a single-use vial or a multiple-use vial, which allows for repeated administration of the reconstituted formulation. The article of manufacture or kit may further comprise a second container comprising a suitable diluent. The article of manufacture or kit may further comprise other materials that may be desirable from a commercial, therapeutic, and user perspective, including other buffers, diluents, filters, needles, syringes, and package inserts with instructions for use. In some embodiments, the second agent comprises an immune checkpoint inhibitor (e.g., an anti-PD1 antibody).

The articles of manufacture or kits herein optionally further include a container comprising a second agent, wherein an anti-B7-H4 antibody-drug conjugate described herein (e.g., B7-H4-ADC) is the first agent, and the article or kit further includes instructions on a label or package insert for treating a subject with an effective amount of the second agent. In some embodiments, the label or package insert indicates that the first and second agents are to be administered sequentially or simultaneously, as described herein. In some embodiments, the label or package insert indicates that the first agent is to be administered prior to administration of the second agent. In some embodiments, the label or package insert indicates that the second agent is to be administered prior to administration of the first agent.

The articles of manufacture or kits herein optionally further include a container comprising a second agent, wherein the second agent is used to eliminate or reduce the severity of one or more adverse events, wherein the antibody-drug conjugate described herein (e.g., B7-H4-ADC) is the first agent, and the article or kit further includes instructions on the label or package insert for treating the subject with an effective amount of the second agent. In some embodiments, the label or package insert indicates that the first and second agents are to be administered sequentially or simultaneously, as described herein. In some embodiments, the label or package insert indicates that the first agent is to be administered prior to the administration of the second agent. In some embodiments, the label or package insert indicates that the second agent is to be administered prior to the first agent.

In some embodiments, the antibody-drug conjugates (e.g., B7-H4-ADC) described herein are present as a lyophilized powder in a container. In some embodiments, the lyophilized powder is in a hermetically sealed container (e.g., a vial, an ampoule, or a sachet) indicating the amount of active agent. In the case of administration of the drug by injection, for example, an ampoule of sterile water for injection or saline solution may be provided, as appropriate, as part of the kit so that the ingredients can be mixed prior to administration. If necessary, such kits may further include one or more of a variety of known pharmaceutical components, such as a container with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be apparent to those skilled in the art. The kit may also include printed instructions, either as an insert or as a label, indicating the amounts of the components to be administered, directions for administration, and/or directions for mixing the components.

In this specification, where compositions and kits are described as having, including or comprising particular components, or where processes and methods are described as having, including or comprising particular steps, it is contemplated that there are additional compositions and kits of the invention consisting essentially of or consisting of said components, and there are processes and methods according to the invention consisting essentially of or consisting of said processing and method steps.

It will be apparent to those skilled in the art that other suitable modifications and adaptations of the methods described herein may be made using appropriate equivalents without departing from the scope of the embodiments disclosed herein. Having now described certain embodiments in detail, such embodiments will be more clearly understood by reference to the following examples, which are included for illustrative purposes only and are not intended to be limiting. All patents, patent applications, and references described herein are incorporated by reference in their entirety for all purposes. Examples Example 1: Phase 1 Study of SGN-B7H4V in Advanced Solid Tumors

This is a Phase 1, open-label, multicenter, dose escalation, dose and schedule optimization, and dose expansion study designed to evaluate the safety, tolerability, pharmacokinetics (PK), and antitumor activity of SGN B7H4V in adults with selected advanced solid tumors. SGN-B7H4V is a human IgG1 anti-B7-H4 antibody conjugated to the microtubule disruptor monomethyl auristatin E (vcMMAE) via a protease-cleavable peptide linker vcPAB. The anti-B7-H4 antibody includes a heavy chain variable region comprising the sequence of SEQ ID NO: 11 and a light chain variable region comprising the sequence of SEQ ID NO: 12. The study included dose escalation (Part A), dose and schedule optimization (Part B), and dose expansion (Part C), with multiple disease-specific groups and one biological group in the dose expansion. The overall study design is shown in Figure 1. Part A - Dose Escalation Group

The dose escalation portion of this trial (Part A) is being conducted in approximately 90 subjects to evaluate the safety and tolerability of a single dose of SGN B7H4V and to identify a maximum tolerated dose (MTD) and/or a recommended dose and a recommended schedule, and to assess antitumor activity and PK, anti-drug antibody (ADA), pharmacodynamic, and biomarker profiles. Dose escalation is performed based on the modified toxicity probability internal (mTPI) approach. If the MTD is not reached, safety, PK, pharmacodynamic, and biomarker analyses, as well as preliminary antitumor activity, are used to determine the recommended dose.

SGN-B7H4V is administered by IV infusion. The initial dosing schedule to be evaluated is 2Q3W (Table 8), with a starting dose level of 0.75 mg/kg and planned dose escalation levels up to 2.4 mg/kg as indicated in Table 9. If investigation of lower and/or intermediate dose levels is recommended, the mTPI dose escalation rules continue to apply. Note: In each new dose escalation group, subjects receive their initial dose at least 1 day apart.

Alternative schedules were evaluated by dose escalation during Part A (see Table 8). The sponsor, in consultation with the SMC, selected the open enrollment schedule based on available data on safety, dose-limiting toxicities (DLTs), PK, and initial antitumor activity.

The dose levels available for evaluation in the alternate schedule are specified in Table 9. In terms of dose strength (mg/kg/week), the starting dose level in the alternate schedule will be no higher than the highest dose level considered tolerated in the initial schedule. For example, if 1.5 mg/kg (1.00 mg/kg/week dose strength) is the highest dose currently considered tolerated in the initial schedule, the maximum starting dose would be 1.25 mg/kg for the Day 1, Day 8, Day 15 q28 (3Q4W) schedule (0.94 mg/kg/week) and would be 2.0 mg/kg for the Day 1, Day 15 q28 (2Q4W) schedule (1.00 mg/kg/week). Table 8: Initial and Alternative Therapy Schedules Schedule Name Schedule Cycle length (days) Treatment days Schedule intensity Day 1 Day 8 Day 15 (Infusion/week) Initial schedule 2Q Day 1, Day 8, Day 21 twenty one X X - 0.67 Alternative 3Q Day 1, Day 8, Day 15q28 days 28 X X X 0.75 schedule 2Q Day 1, Day 15, Day 28 28 X - X 0.50 Q3W Day 1q21 days twenty one X - - 0.33 Table 9 : Planned dose levels Dosage level (mg/kg) Dose strength at planned dose levels for each schedule (mg/kg/week) Initial schedule Alternative Schedule 2Q3W Day 1, Day 8, Day 21 3Q4W Day 1, Day 8, Day 15q28 2Q4W Day 1, Day 15, Day 28 Q3W Day 1q21 Day 0.75 0.50 0.56 0.38 0.25 1.0 0.67 0.75 0.50 0.33 1.25 0.83 0.94 0.63 0.42 1.5 1.00 1.13 0.75 0.50 1.75 1.17 1.31 0.88 0.58 2.0 1.33 1.50 1.00 0.67 2.25 1.50 1.69 1.13 0.75 2.4 1.60 1.80 1.20 0.80 Dose-limiting toxicity

DLTs were assessed during the dose escalation period in Part A. The DLT assessment period was Cycle 1 (21 or 28 days, depending on the schedule).

A DLT was defined as any of the following events that occurred during the DLT assessment period and were assessed by the investigator to be clinically significant and related to SGN-B7H4V treatment. • Grade 5 toxicities with no clear relationship to disease progression or external causes • ≥ Grade 3 non-hematologic, non-laboratory treatment-related adverse events (Ae), with the following exceptions: ○ Grade 3 fatigue that resolves within 72 hours with or without intervention ○ Grade 3 nausea, vomiting, diarrhea, or constipation that resolves within 72 hours with or without intervention ○ Grade 3 infusion-related reactions (IRRs) that resolve within 24 hours to ≤ Grade 1 with or without intervention without sequelae and without hospitalization other than observation NOTE: If a ≥ Grade 3 IRR occurs in ≥20% of subjects (i.e., 2 or more of the first 10 subjects), all subsequent subjects will require upfront medication and/or infusion method modifications and the regimen will be modified. • Grade 3 or 4 non-hematologic laboratory abnormality if: ○ The abnormality persists for >72 hours, or ○ The abnormality meets the definition of potential drug-induced liver injury (DILI), or ○ ≥ Grade 3 transaminase (alanine aminotransferase and/or aspartate aminotransferase) elevation• Grade 4 anemia or thrombocytopenia• Grade 4 hematologic toxicity (other than anemia/thrombocytopenia) persisting for >7 days• Grade 3 thrombocytopenia with clinically significant bleeding• ≥ Grade 3 febrile neutropenia• Dose delay of ≥14 days due to toxicityPart B - Dose and Schedule Optimization Group

After dose escalation, if there is sufficient evidence to support evaluation of a dosing regimen in dose expansion (Part C) based on dose escalation (Part A), Part B is omitted. Otherwise, if more than one dose and schedule are identified as candidates for a recommended dosing regimen, dose and schedule optimization is performed. Part B, if present, further evaluates selected doses from selected schedules identified in Part A in parallel groups of 10 subjects. Enroll up to a total of 40 subjects in 4 groups. The doses and schedules used for evaluation in Part B are selected by the sponsor in consultation with the Safety Monitoring Committee (SMC) and are equal to or lower than the MTD of any of the evaluated schedules. Participants in Part B were randomly assigned to different doses and schedules with equal probability.

Groups are defined based on the selected disease type, with each disease type evaluated in a separate group for each selected dose and schedule. If disease-specific groups are used, randomization to dose and schedule occurs separately within each disease type.

The best recommended dosing schedule will be determined based on safety, PK, preliminary antitumor activity, and relevant pharmacodynamic and biomarker data from Parts A and B for further evaluation in Part C disease-specific expansion cohorts. Part C - Expansion Cohorts

To further characterize the safety, tolerability, PK, and antitumor activity of SGN-B7H4V, approximately 270 additional individuals are enrolled in 6 expansion cohorts and one biological cohort. The expansion cohorts enroll individuals with selected tumor types. Dosing, schedule, and disease settings for the expansion cohorts are determined by the sponsor in consultation with the SMC and may vary between cohorts.

The dose expansion registration group includes:

Disease-Specific Cohorts : Approximately 240 subjects (up to 40 subjects per cohort) will be treated at the MTD or recommended dose in disease-specific expansion cohorts to further characterize the safety, tolerability, PK, and antitumor activity of SGN-B7H4V. For each disease-specific cohort, an interim analysis will be conducted after 15 subjects are evaluable for response. Enrollment will continue uninterrupted during the interim analysis period. Futility analyses will be performed using the predicted probability of success (PpoS) approach, where success is defined as the posterior probability of a response rate greater than the background rate greater than 0.70. If an estimated PpoS <10% is given for interim data, the sponsor will evaluate all data and decide in consultation with the SMC whether to continue enrollment in the cohort.

Biological Cohort : Up to approximately 30 additional individuals will be enrolled into the Biological Cohort. This cohort enrolls one or more tumor types from those individuals who are eligible for Part C and consent to protocol-specified research examinations. Individuals in the Biological Cohort will be asked to provide additional tissue to enable biomarker studies of SGN-B7H4V to compare pre- and post-treatment tumor samples to characterize the clinical mechanism of action (MOA) at the recommended dose and the relevance of sensitivity/resistance mechanisms. Dosing and Administration

Initially, SGN-B7H4V will be administered by IV infusion 2Q3W. Alternative dosing schedules may be evaluated during Part B (see Table 8). In any case, doses of SGN-B7H4V to be administered will be separated by no less than 5 days.

For dose levels up to and including 1.75 mg/kg, weight-based dosing is based on the individual’s actual weight at baseline or per institutional standards. For dose levels of 2.0 mg/kg and above (i.e., 2.0, 2.25, and 2.4 mg/kg), the upper weight limit for dose calculations is 100 kg. If indicated, SMC may have recommended adjusted ideal body weight (AIBW) dosing. Adjust dose for individuals who experience a ≥10% weight change from baseline. Measure individual weight during all relevant assessment windows as described in the event timeline. Additional dose adjustments for weight change are permitted per institutional standards. Rounding to the nearest milligram is permitted within 5% of the nominal dose. Weight limit for dosing

As PK, pharmacodynamic, and clinical activity data evolve, weight-capped IV dosing is implemented for dose levels up to and including 1.75 mg/kg, based on SMC recommendations. In contrast to weight-based dosing, where the total dose is calculated without an individual weight cap, weight-capped dosing limits the weight to be used in total dose calculations. The upper limit used in dosing calculations is defined based on emerging data.

For dose levels of 2.0 mg/kg and above (i.e., 2.0, 2.25, and 2.4 mg/kg), an upper weight limit of 100 kg is required.

For example, if the upper weight limit is 100 kg, individuals weighing ≥100 kg use a weight of 100 kg to calculate the total dose to be administered. In individuals weighing <100 kg, the individual's actual weight is used to calculate the total dose to be administered .

AIBW provides an adjustment to ideal body weight (IBW) if an individual's actual total body weight (TBW) is above or below their IBW. Because the AIBW is calculated using the individual's sex, height, and TBW, the percentage adjustment to the total dose depends on the target body mass index (BMI) group. Patient Selection CriteriaIndividuals must provide written informed consent1. Individuals must have one of the following histologically or cytologically confirmed locally advanced unresectable or metastatic solid tumor types: • High-grade serous epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer • HER2-negative, HR-positive breast cancer • Triple-negative breast cancer (TNBC) • Endometrial cancer • Non-small cell lung cancer (NSCLC) (squamous cell carcinoma (SqCC), adenocarcinoma (AC)) • Biliary duct cancer or gallbladder cancer • Adenoid cystic carcinoma (ACC) of the head and neck 2. Previous treatment: a. Part A and B: Subjects must have disease that is relapsed or refractory or intolerant to standard of care (SOC) therapy and should not have appropriate SOC treatment options in the investigator’s judgment. If a SOC therapy is available but not administered, the reason why that therapy is inappropriate must be documented. b. Section C: Subjects must have disease that is relapsed or refractory or intolerant to SOC therapy as specified below, unless contraindicated: • High-grade serous ovarian cancer (epithelial ovarian, primary peritoneal, or fallopian tube cancer): Subjects must have platinum-resistant or platinum-refractory disease, defined as disease that has progressed during or within 6 months of prior platinum-containing chemotherapy, has evidence of radiographic progression, or has relapsed. If eligible, subjects must have received a regimen containing bevacizumab. Must have received a poly ADP ribose polymerase (PARP) inhibitor if eligible based on biomarker status and consistent with SOC. • Advanced HER2-negative, HR-positive breast cancer or TNBC (per the American Society of Clinical Oncology [ASCO]/American College of Pathologists 2018 guidelines). ○ Individuals must have received one or more prior lines of therapy for locally advanced or metastatic disease. Prior therapy must have included a taxane administered as a single agent or in combination. ○ Individuals with HR-positive disease must have additionally received therapy with a cyclin D-dependent kinase (CDK) 4/6 inhibitor and at least 1 prior hormonal therapy unless contraindicated. ○ Must have received a PARP inhibitor, PD-(L)1 inhibitor, and/or phosphoinositide 3-kinase (PI3K) inhibitor if eligible based on biomarker status and consistent with SOC. ○ For individuals with TNBC and HER2-negative, HR-positive breast cancer, golenvatinib has been discussed by the investigator as a treatment option when applicable. • Endometrial cancer : individuals must have received at least 1 line of systemic therapy ○ Must have received prior PD 1 inhibitor and/or pembrolizumab in combination with lenvatinib if appropriate based on biomarker status (including but not limited to microsatellite instability [MSI] and mismatch repair deficiency [dMMR] status) and available based on local SOC. • Squamous NSCLC ○ Subjects with locally advanced recurrent/metastatic disease must have received prior treatment with platinum-based therapy alone or in combination and a PD(L)1 inhibitor if indicated by the local SOC. • Cholangiocarcinoma or gallbladder cancer ○ Subjects must have received at least 1 line of systemic therapy. ○ Subjects must have received an approved targeted therapy if appropriate based on 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 based on local SOC○ Liver involvement and head and neck ACC are allowed○ Subjects with locally advanced recurrent/metastatic disease must have received at least 1 line of systemic therapy.○ Subjects whose tumors harbor genomic mutations/alterations and for whom an approved targeted therapy is available based on local SOC must have received an approved and available targeted therapy. 3. Tumor tissue needs to be registered. • For Part A and Part B, archival tumor tissue from the most recent biopsy collected within 24 months of enrollment is required (if available). For all individuals in Part C, archival tumor tissue from the most recent biopsy collected within 12 months of enrollment is required (if available). If archival tissue is not available for individuals in Part A, Part B, and Part C, a fresh pre-treatment biopsy must be submitted (appropriate lesions can be accessed by minimally invasive procedures that do not present a significant risk). • For the Part C biological group, an intra-treatment biopsy on Day 15 of Cycle 1 and an end-of-treatment (EOT) biopsy are also required. 4. Age 18 years or older 5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 6. Measurable disease according to RECIST version 1.1 at baseline 7. The following baseline laboratory test results: • Absolute neutrophil count (ANC) ≥1500/µL • Hemoglobin (Hgb) ≥9 g/dL • Platelet count ≥100,000/μL • Serum bilirubin ≤1.5 × upper limit of normal (ULN) or ≤3 × ULN for individuals with Gilbert’s disease • Estimated glomerular filtration rate (eGFR) ≥45 mL/min/1.73 ^m2 using the Modification of Diet in Renal Disease (MDRD) equation, if applicable • ALT and AST ≤3 × ULN (≤5 × ULN if there is evidence of malignant disease involving the liver) Exclusion 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 negligible risk of metastasis or death (e.g., 5-year OS ≥90%), such as adequately treated cervical carcinoma in situ, non-melanoma skin cancer, localized prostate cancer, ductal carcinoma in situ, or stage I uterine cancer. 2. Known active central nervous system metastasis. Subjects with previously treated brain metastases were eligible to participate provided that they were clinically stable for at least 4 weeks prior to study entry following treatment of brain metastases, did not have new or enlarging brain metastases, and were off prescription corticosteroids for symptoms related to brain metastases for at least 7 days prior to the first dose of study drug. 3. Carcinomatous meningitis 4. Prior exposure to agents containing MMAE or targeting B7H4 5. Pre-existing neuropathy of ≥ Grade 2 according to the 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 was permitted. 7. Uncontrolled diabetes, defined as Hgb A1c ≥8% or Hgb A1c between 7 and <8% with associated diabetic symptoms not otherwise explained (polyuria or thirst) 8. Positive for hepatitis B based on surface antigen expression and/or positive anti-hepatitis B core (HBc) total antibody titer. Active hepatitis C infection (based on positive polymerase chain reaction [PCR] or receipt of antiviral therapy for hepatitis C within the past 6 months). Individuals with treated hepatitis C infection are permitted if a sustained virologic response has been documented for 12 weeks. 9. Known HIV positive10. History of documented cerebrovascular 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 first dose of SGN B7H4V11. Class III or IV congestive heart failure according to New York Heart Association criteria12. Active or uncontrolled lung disease ≥ Grade 2 not related to underlying malignancy13. Active uncontrolled autoimmune disease14. Corneal disease or injury requiring treatment or active monitoring15. Use of strong cytochrome P450 3A within 14 days prior to initiation of study treatment during Part A (CYP3A) inhibitors or inducers 16. Receipt of vaccines containing live or attenuated viruses within 30 days before the first dose of study drug 17. Chemotherapy, immunotherapy, biologics, and/or other approved or investigational anti-cancer treatments that were not completed within 4 weeks prior to the start of study treatment, or within 2 weeks prior to the start of study treatment if the underlying disease has progressed on treatment. 18. Localized radiation therapy or major surgery not completed 2 weeks prior to the start of study treatment 19. Subjects who are breastfeeding, pregnant, or planning to become pregnant from the time of informed consent until 2 months after the last dose of study drug 20. Known allergy to any formulation contained in the drug formulation of SGN B7H4V 21. Estimated life expectancy < 12 weeks 22. Other serious potential medical conditions that the investigator believes will impair the subject's ability to receive or tolerate the planned treatment and follow-up 23. Any toxicity related to previous therapy that has not recovered to baseline or > Grade 1, except for alopecia Management of Treatment-Emergent Adverse Events Dose Modifications

Table 10 describes the recommended dose modifications for study treatment-related toxicities. If an individual experiences an AE that is ≥ Grade 3 and possibly related to SGN-B7H4V treatment, the individual needs to obtain approval from the medical supervisor to continue study treatment. Table 10: Recommended dose modifications for SGN-B7H4V-related toxicities toxicity Level 1 Level 2 Level ^3a Level ^4b Peripheral neuropathy Continue at same dose level Withhold until toxicity resolves to ≤ Grade 1; then resume treatment at the next lower dose level If, after evaluating the individual, the investigator and medical monitor agree that the benefit-risk assessment remains favorable, dosing is withheld until toxicity resolves to ≤ Grade 1 and then treatment is resumed at the next lower dose ^levelc , otherwise treatment is withheld. Stop treatment Non-hematological (except peripheral neuropathy and hyperglycemia)d Continue at same dose level Continue at same dose level Withhold dose until toxicity resolves to ≤ Grade 1 or baseline, then resume treatment at next lower dose levelc Unless the Medical Supervisor and the Treatment Investigator agree to continue treatment, then stop treatment. If treatment is continued, stop the dose until toxicity resolves to ≤ Grade 1 or baseline, then resume treatment at the next lower dose level. If AE recurs and is > Grade 3, stop treatment. Hematology Continue at same dose level Continue at same dose level Withhold dose until toxicity resolves to ≤ Grade 1 or baseline (without transfusion), then resume treatment at same dose level or consider reducing by one dose level c. For asymptomatic anemia, withhold dose until toxicity resolves to ≤ Grade 2 or baseline (without transfusion), then resume treatment at same dose level or consider reducing by one dose level c. Withhold until toxicity resolves to ≤ Grade 1 or baseline, then resume treatment at one dose level or permanently discontinue. Neutropenia Continue at same dose level Continue at same dose level Withhold dose until toxicity resolves to ≤ Grade 2, then resume treatment at same dose level. Consider growth factor support for treatment of Grade 3 neutropenia. Consider prophylactic growth factor support for subsequent cycles. If neutropenia recurs, consider dose reduction in consultation with the Medical Supervisor or discontinue treatment at the discretion of the Investigator. Withhold dose until toxicity resolves to ≤ Grade 2, then resume treatment at same dose level. Strongly consider growth factor support for treatment of Grade 4 neutropenia. Strongly consider prophylactic growth factor support for subsequent cycles. If neutropenia recurs, consider dose reduction in consultation with the Medical Supervisor or discontinue treatment at the discretion of the Investigator. Febrile neutropenia N/A N/A Treatment of febrile neutropenia requires growth factor support. Withhold dose until febrile neutropenia resolves and neutrophil counts return to ≤ Grade 1 or baseline, then resume treatment by 1 dose level reduction or permanently discontinue. Prophylactic growth factor support is required for all subsequent cycles. If febrile neutropenia recurs despite growth factor support, consider further dose reductions or discontinuation. Keratitis Continue at same dose level Withhold dose until toxicity resolves to ≤ Grade 1, then resume prophylaxis at same dose level. Refer for ophthalmologic consultation. If Grade 2 event recurs, continue prophylaxis and reduce dose to next lower dose level. Withhold dose until toxicity resolves to ≤ Grade 1, then resume prophylaxis at the next lower dose level. Refer for ophthalmologic consultation. If Grade 2 event recurs, continue prophylaxis and reduce dose to the next lower dose level. If Grade 3 keratitis recurs, discontinue treatment. Withhold dose until toxicity resolves to ≤ Grade 1, then resume prophylaxis at the next lower dose level. Refer for ophthalmologic consultation. If Grade 2 event recurs, continue prophylaxis and reduce dose to the next lower dose level. If ≥ Grade 3 event recurs, withhold treatment. For Grade 4 keratitis events that do not improve within 4 weeks, resume treatment only after discussion with and approval of the medical supervisor. Hyperglycemia Withhold dosing for blood glucose >250 mg/dL or >13.9 mmol/L or Grade 3 or 4 hyperglycemia requiring new or additional insulin. Consider hospitalization for Grade 3 or 4 hyperglycemia with dehydration and/or acidosis. Resume dosing at the same dosing level once elevated blood glucose has improved to ≤250 mg/dL or ≤13.9 mmol/L and the individual is clinically and metabolically stable. NOTE: For subjects at or below dose level 2, resume treatment at 50% of the most recently administered dose. NOTE: If a subject has two dose reductions for the same AE (other than neutropenia) and this AE recurs, treatment must be permanently discontinued (i.e., a third dose reduction is prohibited). NOTE: In consultation with the Medical Supervisor, the Investigator may take more conservative actions than those recommended in the table. a Following the occurrence of a Grade ≥ 3 AE that may be related to SGN-B7H4V treatment, the Medical Supervisor must be consulted prior to continuing study treatment. b For all grades of febrile neutropenia, follow the dose modification instructions for Grade 4 hematologic toxicity. c If Grade 3 (or Grade 4 for neutropenia) toxicity recurs despite dose reduction, dosing frequency may be reduced in consultation with the Medical Supervisor. d If an individual experiences a Grade 4 IRR, hypersensitivity reaction, or anaphylaxis, study drug must be permanently discontinued. ObjectivesPrimary Objectives1 . Evaluate the safety and tolerability of SGN-B7H4V in subjects with advanced solid tumors2. Identify the maximum tolerated dose ( MTD ) of SGN-B7H4V in subjects with advanced solid tumors3. Identify the recommended dose and schedule of SGN-B7H4VSecondary Objectives1 . Evaluate the pharmacokinetics (PK) of SGN-B7H4V2. Evaluate the immunogenicity of SGN-B7H4V3. Evaluate the anti-tumor activity of SGN-B7H4VExploratory Objectives1 . Evaluate biomarkers associated with response, toxicity, pharmacodynamics, PK/pharmacodynamic relationships, or resistance to SGN-B7H4V2. Evaluation of the Effect of SGN-B7H4V on Health-Related Quality of Life (HRQoL) in Metastatic Breast Cancer from an Individual Perspective Example 2: Determination of Antitumor Efficacy in Part A

Determination of antitumor efficacy was based on objective response assessments according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, and the investigator's treatment decision was based on these assessments. Clinical responses of progressive disease (PD), stable disease (SD), partial response (PR), or complete response (CR) were determined at each assessment. Progressive disease included PD according to RECIST v1.1 and clinical disease progression according to the investigator.

41 subjects were treated with 0.75 mg/kg, 1.0 mg/kg, 1.25 mg/kg, 1.25 mg/kg (AiBW), or 1.5 mg/kg (AiBW) of SGN-B7H4V on days 1 and 8 of a 21-day treatment cycle (2Q3W). The 41 subjects were diagnosed with the following advanced solid tumors: ovarian cancer; HR-positive, HER2-negative breast cancer; triple-negative breast cancer, endometrial cancer, cholangiocarcinoma, non-small lung cancer, gallbladder cancer, and adenoid cystic carcinoma of the head and neck. As shown in Figure 2A, a reduction in the sum of tumor diameters compared to the sum at baseline was confirmed in half of the subjects administered SGN-B7H4V. At each dose level, at least nine subjects had a minimum 30% reduction in sum of tumor diameters (SoD). For all subjects with at least a 30% reduction in SoD, the change in tumor size from baseline was sustained, confirming a durable response up to 67 weeks from the first dose in the 2Q3W regimen (Figure 2B).

45 subjects were treated with SGN-B7H4V at 1.25 mg/kg, 1.5 mg/kg, 1.5 mg/kg (AiBW), 1.75 mg/kg AiBW, or 2.0 mg/kg AiBW on days 1 and 15 of a 28-day treatment cycle (2Q4W). The 45 subjects were diagnosed with the following advanced solid tumors: ovarian cancer; HR-positive, HER2-negative breast cancer; triple-negative breast cancer, endometrial cancer, cholangiocarcinoma, non-small lung cancer, gallbladder cancer, and adenoid cystic carcinoma of the head and neck. As shown in Figure 3A, approximately half of the subjects given SGN-B7H4V showed a decrease in tumor SOD compared to the sum at baseline. For subjects with reduced SoD, the change in tumor size from baseline was sustained, confirming a durable response up to 54 weeks from the first dose in the 2Q4W regimen (Figure 3B). Example 3: Cancer Expressing B7-H4

Immunohistochemistry was used to assess the intensity of B7-H4 expression in whole tumor sections. Tumor sections were collected from individuals diagnosed with one of the following cancers: ovarian cancer, triple-negative breast cancer (TNBC), HR-positive breast cancer, endometrioid carcinoma, cholangiocarcinoma, and non-small cell lung cancer (NSCLC - both squamous and adenocarcinoma subtypes). Sections were scored based on IHC intensity (score 3 is the highest intensity). As shown in Figure 4, B7-H4 expression was observed in scored tumor sections from individuals diagnosed with ovarian cancer, TNBC, HR-positive breast cancer, endometrioid carcinoma, cholangiocarcinoma, and NSCLC. Example 4: Antitumor activity of SGN-B7H4V in triple-negative breast cancer

Subjects were treated with 0.75 mg/kg, 1.0 mg/kg, 1.25 mg/kg, 1.25 mg/kg (AiBW), 1.5 mg/kg (AiBW), and 1.75 mg/kg (AiBW) of SGN-B7H4V on days 1 and 8 of a 21-day treatment cycle (2Q3W). Different subjects were treated with 1.25 mg/kg, 1.5 mg/kg (AiBW), and 1.75 mg/kg (AiBW) of SGN-B7H4V on days 1 and 15 of a 28-day treatment cycle (2Q4W). In addition, several subjects were given 1.5 mg/kg (AiBW) of SGN-B7H4V on days 1 and 8 of a 21-day treatment cycle (2Q3W) for dose expansion to further characterize the safety, tolerability, PK, and antitumor activity of SGN-B7H4V against triple-negative breast cancer (TNBC) tumors. 42 subjects were diagnosed with advanced solid tumors of TNBC. As shown in Figure 5, more than half of the subjects given SGN-B7H4V showed a reduction in tumor SoD compared to the sum at baseline.

Further analysis was performed to determine the response rate to SGN-B7H4V based on the B7H4 expression of the individual's tumor. Overall, 21.4% of the individuals responded to SGN-B7H4V (Table 11). For individuals with greater than 25% of tumor cells expressing B7H4, 35% responded to SGN-B7H4V (Table 11). For individuals with greater than 50% of tumor cells expressing B7H4, 38% responded to SGN-B7H4V (Table 11). Table 11: Response Rate Based on B7H4 Expression All newcomers N=42 B7H4 performance＞25% N=16 B7H4 performance＞50% N=15 21.4% 35% 38% Example 5: Antitumor activity of SGN-B7H4V in HR+ Her2- breast cancer

Subjects were treated with 0.75 mg/kg, 1.0 mg/kg, 1.25 mg/kg, 1.25 mg/kg (AiBW), and 1.5 mg/kg (AiBW) of SGN-B7H4V on days 1 and 8 of a 21-day treatment cycle (2Q3W). Different subjects were treated with 1.25 mg/kg, 1.5 mg/kg, 1.5 mg/kg (AiBW), and 1.75 mg/kg (AiBW) of SGN-B7H4V on days 1 and 15 of a 28-day treatment cycle (2Q4W). In addition, several subjects were given 1.5 mg/kg (AiBW) of SGN-B7H4V on Day 1 and Day 8 of a 21-day treatment cycle (2Q3W) for dose expansion to further characterize the safety, tolerability, PK, and antitumor activity of SGN-B7H4V against HR+ Her2- breast cancer tumors. 24 subjects were diagnosed with advanced solid tumors of HR+ Her2- breast cancer. As shown in Figure 6, approximately half of the subjects given SGN-B7H4V showed a decrease in tumor SOD compared to the sum at baseline. Example 6: Phase 1 Study of SGN-B7H4V in Combination with Pembrolizumab in Advanced Solid Tumors

This is a Phase 1, open-label, multicenter, dose escalation, dose and schedule optimization, and dose expansion study designed to evaluate the safety, tolerability, PK, and antitumor activity of SGN-B7H4V monotherapy and the combination of SGN-B7H4V and pembrolizumab in adults with selected advanced solid tumors. The study will include dose escalation (Part A), dose optimization (Part B), and monotherapy dose expansion (Part C), with multiple 6 disease-specific groups and one biological group in the dose expansion. The study will also include a combination safety run-in (Part D) and combination dose expansion (Part E). The overall study design is shown in Figure 1. Event timeline Table 12: 21-day medication schedule: 2Q3W (Day 1, Day 8, q21 days), Q3W (Day 1, q21 days) program Filter Baseline Treatment period, 21-day cycle (up to 28 days before D1) (up to 7 days before D1) D1 (± 1 d, cycle＞1) D8 (± 1 d) D15 (± 1 d) SGN-B7H4V ^injection Day 1, Day 8, 21-day schedule ^{X X} Day 1q21 day schedule ^X d Cycle 1 during Part A: Keep subjects under observation for 4 hours after completion of infusion. If the first infusion is well tolerated and no IRR occurs, the observation period for subsequent infusions may be shortened according to institutional standards. Cycle 1 during Parts B and C: The observation period after the Cycle 1 Day 1 infusion and subsequent infusions should be applied according to institutional standards. If IRR occurs, the SMC may recommend an extended observation period. Table 13: 28-day schedule: 2Q4W (Day 1, Day 15 q28 days), 3Q4W (Day 1, Day 8, Day 15 q28 days) [Selected AEs, except for Group E3] program Filter Baseline Treatment period, 28-day cycle (up to 28 days before D1) (up to 7 days before D1) D1 (± 1 d, cycle＞1) D8 (± 1 d) D15 (± 1 d) D22 (± 1 d), 1st and 2nd cycles only SGN-B7H4V ^injection Day 1, Day 15, and Day 28 schedule X ^e X ^e Day 1, Day 8, Day 15q28 Day Schedule X ^e X ^e X ^e Pembrolizumab administration (parts D and E only) ^d Q6W (every 6 weeks from C1D1) up to 24 ^months d SGN-B7H4V is intended to be administered until PD, unacceptable toxicity, withdrawal of consent, death, or study termination, whichever occurs first. Part D and Part E only: Pembrolizumab is intended to be administered for up to 24 months, or until PD, unacceptable toxicity, withdrawal of consent, death, or study termination, whichever occurs first. In the case of delayed pembrolizumab administration, once pembrolizumab dosing is resumed, the medical supervisory consultation site may consider administering pembrolizumab 200 mg Q3W until the subject is able to resume treatment on a Q6W schedule. e Cycle 1 during Part A: Keep subjects for a 4-hour observation period after completion of infusion. If the first infusion is well tolerated and no IRRs occur, the observation period for subsequent infusions may be shortened per institutional standards. Cycle 1 during Part B, Part C, Part D, and Part E: The observation period after the Cycle 1 Day 1 infusion and subsequent infusions should be applied according to institutional standards. If IRR occurs, the SMC may recommend an extended observation period. Table 14: 28-day schedule: 2Q4W (Day 1, Day 15q28) [Part E Group E3 only] program Filter Baseline Treatment period, cycles 1-8 (28-day cycle) (up to 28 days before D1) (up to 7 days before D1) D1 (± 1 d, cycle＞1) D8 (± 1 d, cycle＞1) D15 (± 1 d) D22 (± 1 d), 1st and 2nd cycles only SGN-B7H4V cast ^c Day 1, Day 15, and 28-day schedule ^{X X} Pembrolizumab ^{administrationc} Q6W (every 6 weeks starting from C1D1) up to a total of 4 ^doses c SGN-B7H4V is intended to be administered for up to 8 cycles (16 doses) or until unacceptable toxicity, withdrawal of consent, death, or study termination, whichever occurs first. Pembrolizumab is intended to be administered at 400 mg Q6W for up to 4 doses or until unacceptable toxicity, withdrawal of consent, death, or study termination, whichever occurs first. In the case of delayed pembrolizumab administration, once pembrolizumab dosing is resumed, the medical supervisory consultation site may consider administering pembrolizumab 200 mg Q3W until the individual is able to resume treatment on a Q6W schedule. d The observation period following the Cycle 1 Day 1 infusion and subsequent infusions should be applied according to institutional standards. If an IRR occurs, the SMC may recommend an extended observation period. Table 15: 28-day schedule: 2Q4W (Day 1, Day 15q28), 3Q4W (Day 1, Day 8, Day 15q28) [Parts A, B, and C] Cycle Research Day time window Relative time ^a PK ADA Biomarkers Plasma Streck PBMC1 Whole blood (PAX gene) ^ECGb Tumor biopsy serum Plasma 2 Filter -28 to 1 N/A N/A N/A X Cycle 1 and Cycle 2 Day 1 ^Before medication Within 24 hours Infusion starts X X X X X X X X EOI Within 15 minutes End of infusion X X 2 h ± 15 min X 4 h ± 30 min X X X Day 2 ^24h ± 4 h End of infusion X X X Day 3 48h ± 4 h End of infusion X Day 4 72h ± 24 ^hours End of infusion X X Day 8 Before medication Within 4 hours Infusion starts ^{X X} X ^f,g X ^f,g EOI Within 15 minutes End of infusion ^X 2 h ± 15 min ^X 4 h ± 30 min ^X Day 15 Before medication Within 4 hours Infusion starts X X X X ^g X ^g X EOI Within 15 minutes End of infusion X ^Day 29 672h ± 72 h Cycle starts X X 3rd cycle, 4th cycle, 6th cycle, 8th cycle and every 4th cycle thereafter (e.g. 12th cycle, 16th cycle, etc.) Day 1 Before medication Within 4 hours Infusion starts X X ^{X X X} X ^l X ^l EOI Within 15 minutes End of infusion X EOT X X X X X X X X ADA = anti-drug antibodies; ECG = electrocardiogram; EOI = end of infusion; EOT = end of treatment; h = hours; min = minutes; N/A = not applicable; PBMC = peripheral blood mononuclear cells; PK = pharmacokinetics. a For reference points specifying relative times, “start of infusion” and “end of infusion” refer to the start/end of the most recent SGN-B7H4V infusion. b PK-matched ECGs were collected in triplicate for up to approximately the first 30 subjects treated at US sites. Unless otherwise specified, PK-matched ECGs should be obtained within 30 minutes prior to PK blood collection (e.g., within 15 minutes after end of infusion) and prior to ADA and biomarker sample collection. d The predose collection window for Cycle 1, Day 1 was 24 hours. e Day 4 collection should not be performed within 4 hours of Day 3 collection. f If SGN-B7H4V is not administered at this visit (e.g., the subject is not dosed on Day 8 on a 2Q4W schedule), samples should still be collected within ± 24 hours of the visit date. g Cycle 1 only. For Day 15, collect on or within 5 days of Cycle 1 Day 15 (i.e., Cycle 1 Days 15 to 21). h If SGN-B7H4V is not administered at this visit (e.g., the subject is not dosed on Day 8 on a 2Q4W schedule), do not collect PK samples at this time point. i Day 29 sample collection is required only if there is a ≥1 day delay in SGN-B7H4V AE-related dosing at the end of Cycle 1 or Cycle 2 or if SGN-B7H4V is discontinued during Cycle 1 or Cycle 2. Day 29 sample is not collected if new anticancer therapy is administered before Day 29. j Cycles 3-6 only. k Cycle 3 only. l Cycles 3-4 only. Table 16: 28-Day Schedule: 2Q4W (Day 1, Day 15q28) [Part D and Part E] Cycle Cycle Day time window Relative time SGN-B7H4V Pembrolizumab Plasma 2 ctDNA Tumor biopsy (selected individuals only) PK ADA PK ADA Filter -28 to 1 N/A N/A N/A X Cycle 1 and Cycle 2 Day 1 Before medication Within 4 hours First infusion begins X ^b,d X ^b,d X ^b,c,d X ^{b,c,d Xb Xb} End of infusion Within 15 minutes SGN-B7H4V infusion ended X End of pembrolizumab infusion ^X Day 15 Before medication Within 4 hours First infusion begins Xd ^,e X ^{c,d X} X End of infusion Within 15 minutes SGN-B7H4V infusion ended X ^e End of pembrolizumab infusion ^X Day 29 336h ±72 h End of last infusion X ^g X ^g X ^g X ^g The 3rd, 4th, 7th and every 3rd cycle thereafter (e.g. the 10th, 13th, etc.) Day 1 Before medication Within 4 hours First infusion begins ^{X X} X ^c,d X ^{c,d X} X ⁱ End of infusion Within 15 minutes SGN-B7H4V infusion ended X ^e End of pembrolizumab infusion ^X Cycle 8 Day 1 Before medication Within 4 hours SGN-B7H4V infusion started X ⁱ Treatment completed X X X X X X ^i,j X Visit ^X AE = adverse event; ADA = anti-drug antibodies; ctDNA = circulating tumor DNA; EOT = end of treatment; h = hour; min = minute; N/A = not applicable; PBMC = peripheral blood mononuclear cells; PK = pharmacokinetics. b The collection window for Cycle 1, Day 1, pre-dose administration was -4 hours. c If the individual did not receive pembrolizumab on that day for any reason, no sample was collected at this time. (For example, according to the Q6W dosing schedule, pembrolizumab is administered on Day 1 of Cycle 1, followed by Day 15 of Cycle 2, not administered during Cycle 3, administered on Day 1 of Cycle 4, followed by Day 15 of Cycle 5, not administered during Cycle 6, and this pattern is repeated. Therefore, PK and/or ADA samples of pembrolizumab are only collected on Day 15 of Cycle 1, Day 1 of Cycle 2, Day 1 of Cycle 3, etc. In addition, if the subject is receiving a reduced dose of pembrolizumab (200 mg Q3W) or after pembrolizumab cessation, PK and ADA samples of pembrolizumab are not collected at this time point.) d Predose PK and ADA samples for SGN-B7H4V and pembrolizumab should be collected simultaneously within 4 hours prior to the start of the first infusion. e If the subject has not been administered SGN-B7H4V that day, samples will not be collected at this time point. f If the subject has not been administered SGN-B7H4V that day, samples should still be collected within ± 24 hours of the visit date. g Day 29 sample collection is only required if there is a ≥1 day delay in AE-related doses of SGN-B7H4V at the end of Cycle 1 or Cycle 2 or if SGN-B7H4V is discontinued during Cycle 1 or Cycle 2. If a new anticancer therapy is administered before Day 29, a Day 29 sample will not be collected. h Plasma 2 samples are not required after Cycle 7 Day 1, except for Cycle 13 Day 1. i ctDNA samples collected on Cycle 4 Day 1, Cycle 8 Day 1, and at EOT. j Cohort E3 only: if ctDNA sample is collected on Cycle 8 Day 1, then ctDNA sample is not collected at EOT k Cohort E3 only: ctDNA samples collected at each follow-up visit until relapse. The first follow-up visit will occur 3 months (± 4 weeks) after the last dose of SGN-B7H4V or 3 months (± 4 weeks) after the last dose of pembrolizumab, whichever occurs last. Subsequent follow-up will be conducted every 3 months (± 4 weeks) for 2 years from the previous follow-up, and then every 6 months (± 4 weeks) until disease recurrence. Dosage and Administration of SGN-B7H4V

Initially, SGN-B7H4V will be administered by IV infusion 2Q3W. Alternative dosing schedules may be evaluated during Part B ( see Table 8). In any case, doses of SGN-B7H4V should be administered no less than 5 days apart.

For dose levels up to and including 1.75 mg/kg, weight-based dosing is based on the individual's actual weight at baseline or per institutional standards. For dose levels of 2.0 mg/kg and above (i.e., 2.0, 2.25, and 2.4 mg/kg), the upper weight limit for dose calculations is 100 kg. SMC may recommend AIBW dosing when indicated. Dosing must be adjusted for individuals who experience an actual weight change of ≥10% from baseline. Individual weight must be measured during all relevant assessment windows. Other dose adjustments for actual weight change are permitted per institutional standards. Rounding to the nearest milligram is permitted within 5% of the nominal dose.

Infusion duration will vary depending on the infusion administration method and dose. Initially, SGN-B7H4V should be infused over a minimum of 30 minutes. The SMC may recommend or request a longer or shorter infusion duration after reviewing the aggregated individual data.

If an individual does not tolerate the infusion, the duration of the infusion may be increased for that individual; the duration of the infusion may also be increased for subsequent infusions at the discretion of the investigator in consultation with the medical supervisor. Conversely, if the individual tolerates the continuous infusion without experiencing an IRR > Grade 1, the duration of the infusion may be shortened (i.e., administered at a faster rate) at the discretion of the investigator in consultation with the medical supervisor, which may be dose-group specific. Fixed Infusion Rate  

If a fixed infusion rate is implemented based on SMC recommendations, the dose is administered at a fixed rate rather than over a fixed time.

For example, for a fixed infusion rate of 50 mg/hour, a dose of 100 mg would be infused over 2 hours . As clinical experience with administration at a fixed infusion rate evolves, the rate may be increased or decreased based on accumulated safety data and/or recommendations of the SMC.   

As PK, pharmacodynamic, and clinical activity data evolve, weight-capped IV dosing may be implemented for dose levels up to and including 1.75 mg/kg, based on SMC recommendations. In contrast to weight-based dosing, where the total dose is calculated without an individual weight cap, weight-capped dosing limits the weight to be used in total dose calculations. The upper limit to be used in dose calculations will be defined based on emerging data.

For dose levels of 2.0 mg/kg and above (i.e., 2.0, 2.25, and 2.4 mg/kg), an upper weight limit of 100 kg is required.

For example, if the upper weight limit is 100 kg, individuals weighing ≥100 kg will use a weight of 100 kg to calculate the total dose to be administered. In individuals weighing <100 kg, the individual's actual weight is used to calculate the total dose to be administered .   

AIBW provides an adjustment to ideal body weight (IBW) if the individual's actual total body weight (TBW) is above or below their IBW (Devine, 1974). Because the AIBW is calculated using the individual's sex, height, and TBW, the percentage adjustment to the total dose will depend on the target body mass index (BMI) group. Dose Modifications for SGN-B7H4V

Dose reductions or dosing interval extensions for toxicity (including DLT) may be considered on a per-individual basis in consultation with the medical supervisor. Dose modifications for toxicity (including DLT) may be permitted on a per-individual basis in consultation with the medical supervisor ( see Table 17). For subjects treated at the lowest dose level, the dose may be reduced to 50% of the most recently administered dose, the dosing frequency may be reduced (e.g., initial 2Q3W dosing may be changed to Q3W), or the subject may discontinue treatment.

Individuals who experience AEs that meet criteria for permanent discontinuation of SGN-B7H4V treatment may not be able to resume treatment, including at a lower or modified dose.

Subjects who experience a DLT in Cycle 1 of Part A or Part D should not receive further treatment with SGN-B7H4V and pembrolizumab (if applicable) unless toxicity is adequately managed and in consultation with the Medical Supervisor. The type and severity of the observed AEs will be considered to inform the decision. If a subject continues treatment after a DLT and the same DLT recurs, treatment must be permanently discontinued.

Growth factor and transfusion support are discouraged during the DLT period in Parts A and D unless medically indicated; individuals who receive growth factor (e.g., G-CSF or GM-CSF) or transfusion support for reasons other than DLT during this period may not be evaluated for DLT. Growth factor support to prevent or treat cytopenias in subsequent cycles should be considered. Despite the use of growth factors, discontinuation or dose reduction to 1 dose level below the current dose may be considered for individuals with recurrent Grade 4 neutropenia.

If a subject has a clinically significant unresolved treatment-emergent adverse event (TEAE) on the next scheduled dosing day during Cycle 1 or thereafter, the next dose may be delayed for up to 7 days. Delays for other reasons or lasting >7 days must be discussed with the medical supervisor. Subjects who require a dose delay of >7 days due to an unresolved TEAE may be dosed at a reduced dose in subsequent cycles or may have their dosing frequency reduced in consultation with the medical supervisor. For the combination group, if SGN-B7H4V is delayed due to a TEAE or other reason, the pembrolizumab dosing day may be adjusted to coincide with SGN-B7H4V dosing in consultation with the medical supervisor. If the TEAE is clearly related to SGN-B7H4V alone and the SGN-B7H4V dose will be eliminated, pembrolizumab may be administered at regularly scheduled visits. If SGN-B7H4V or pembrolizumab is discontinued before the remaining dose, therapy may be continued with the remaining dose until it has been administered for the allowed duration of treatment or until the treatment discontinuation criteria are met, whichever occurs first.

During the dosing delay period, a combined metabolic panel (CMP) and CBC should be collected at least weekly. If an individual has two dose reductions for the same AE (other than neutropenia) and the AE recurs, treatment must be permanently discontinued (i.e., a third dose reduction is prohibited).

Once the dose has been reduced, it cannot be increased further.

Table 17 describes the recommended dose modifications for study treatment-related toxicities. If an individual experiences an AE that is ≥ Grade 3 and possibly related to SGN-B7H4V treatment, the individual needs to obtain approval from the medical supervisor to continue study treatment. Table 17: Recommended dose modifications for SGN-B7H4V-related toxicities toxicity Level 1 Level 2 Level ^3a Level 4 Peripheral neuropathy Continue at same dose level Withhold until toxicity resolves to ≤ Grade 1; then resume treatment at the next lower dose level If, after evaluating the individual, the investigator assesses the benefit-risk assessment to be favorable, the dose is withheld until toxicity resolves to ≤ Grade 1 and then treatment is resumed at the next lower dose ^levelc , otherwise treatment is withheld. Stop treatment Non-hematological (except peripheral neuropathy and hyperglycemia) ^d Continue at same dose level Continue at same dose level Withhold dose until toxicity resolves to ≤ Grade 1 or baseline, then resume treatment at next lower dose ^levelc Unless the Medical Supervisor and the Treatment Investigator agree to continue treatment, then stop treatment. If treatment is continued, stop the dose until toxicity resolves to ≤ Grade 1 or baseline, then resume treatment at the next lower dose level. If AE recurs and is > Grade 3, stop treatment. Hematology (anemia, lymphocytopenia, thrombocytopenia) Continue at same dose level Continue at same dose level Withhold dose until toxicity resolves to ≤ Grade 1 or baseline (without transfusion), then resume treatment at same dose level or consider reducing by one dose level ^c . For asymptomatic anemia, withhold dose until toxicity resolves to ≤ Grade 2 or baseline (without transfusion), then resume treatment at same dose level or consider reducing by one dose level ^c . Withhold until toxicity resolves to ≤ Grade 1 or baseline, then resume treatment at one dose level or permanently discontinue. Neutropenia Continue at same dose level Continue at same dose level Withhold dose until toxicity resolves to ≤ Grade 1, then resume treatment at same dose level. Consider growth factor support for treatment of Grade 3 neutropenia. Consider prophylactic growth factor support for subsequent cycles. If neutropenia recurs, consider dose reduction in consultation with the Medical Supervisor or discontinue ^treatment at the discretion of the Investigatorc. Withhold dose until toxicity resolves to ≤ Grade 1, then resume treatment at same dose level. Strongly consider growth factor support for treatment of Grade 4 neutropenia. Strongly consider prophylactic growth factor support for subsequent cycles. If neutropenia recurs, consider dose reduction in consultation with the medical supervisor or discontinue ^treatment at the discretion of the investigatorc. Febrile ^neutropeniab N/A N/A Treatment of febrile neutropenia requires growth factor support. Withhold dose until febrile neutropenia resolves and neutrophil counts return to ≤ Grade 1 or baseline, then resume treatment by 1 dose level reduction or permanently discontinue. Prophylactic growth factor support is required for all subsequent cycles. If febrile neutropenia recurs despite growth factor support, consider further dose reductions or discontinuation. Keratitis Continue at same dose level Withhold dose until toxicity resolves to ≤ Grade 1, then resume prophylaxis at same dose level. Refer for ophthalmologic consultation. If Grade 2 event recurs, continue prophylaxis and reduce dose to next lower dose level. Withhold dose until toxicity resolves to ≤ Grade 1, then resume prophylaxis at the next lower dose level. Refer for ophthalmologic consultation. If Grade 2 event recurs, continue prophylaxis and reduce dose to the next lower dose level. If Grade 3 keratitis recurs, discontinue treatment. Withhold dose until toxicity resolves to ≤ Grade 1, then resume prophylaxis at the next lower dose level. Refer for ophthalmologic consultation. If Grade 2 event recurs, continue prophylaxis and reduce dose to the next lower dose level. If ≥ Grade 3 event recurs, withhold treatment. For Grade 4 keratitis events that do not improve within 4 weeks, resume treatment only after discussion with and approval of the medical supervisor. Hyperglycemia Continue at same dose level Continue at same dose level For Grade 3 or 4 hyperglycemia with blood glucose >250 mg/dL or >13.9 mmol/L or requiring new or additional insulin, withhold dose. Consider hospitalization for Grade 3 or 4 hyperglycemia with dehydration and/or acidosis. Resume dosing at the same dose level once elevated blood glucose has improved to ≤250 mg/dL or ≤13.9 mmol/L and the individual is clinically and metabolically stable. For recurrent Grade 3 hyperglycemia, consider dose reduction in consultation with medical supervisor. Withhold dose until elevated blood glucose has improved to ≤250 mg/dL or ≤13.9 mmol/L and the individual is clinically and metabolically stable. Consider hospitalization for Grade 4 hyperglycemia with dehydration and/or acidosis. Reduce dose to next lower dose level to resume therapy. For recurrent Grade 4 hyperglycemia, withhold therapy. a The medical supervisor must be consulted before continuing study treatment following a Grade ≥ 3 AE that may be related to SGN-B7H4V treatment. b For all grades of febrile neutropenia, follow the dose modification instructions for Grade 4 hematologic toxicity. c If Grade 3 (or Grade 4 for neutropenia) toxicity recurs despite dose reduction, the dosing frequency may be reduced in consultation with the medical supervisor. d If an individual experiences a Grade 4 IRR, hypersensitivity reaction, or anaphylaxis, study drug must be permanently discontinued. NOTE: If an individual has had two dose reductions for the same AE (other than neutropenia) and the AE recurs, treatment must be permanently discontinued (i.e., a third dose reduction is prohibited). NOTE: In consultation with the Medical Supervisor, the Investigator may take a more conservative action than that recommended in the table. Dosing and Administration of Pembrolizumab

Pembrolizumab will be supplied as a 100 mg/4 mL (25 mg/mL) solution in a single-use vial. Pembrolizumab for injection is a sterile, preservative-free, clear to slightly opalescent, colorless to slightly yellowish solution that requires dilution for IV infusion. Each vial contains 4 mL of solution containing 100 mg of pembrolizumab. Each 1 mL of solution contains 25 mg of pembrolizumab and is formulated in L-histidine, polysorbate, sucrose, and WFI (Water for Injection) USP.

Part D and Part E only: Pembrolizumab will be administered by IV infusion at 400 mg Q6W. In the event of delayed pembrolizumab administration, once pembrolizumab dosing is resumed, the medical oversight consultation site may consider administering pembrolizumab 200 mg Q3W until the individual is able to resume treatment on a Q6W schedule. Sites should make every effort to target infusion timing as close to 30 minutes as possible. However, given the variability of infusion pumps between sites, a ±10 minute window is allowed (i.e., an infusion time of 30 minutes ±10 min). In combination with SGN-B7H4V, pembrolizumab will be administered first, followed by SGN-B7H4V.

Unless otherwise indicated, pembrolizumab should be administered according to prescribing information or institutional guidelines. Dosage Modifications for Pembrolizumab

For the combination group, if SGN-B7H4V is delayed due to TEAEs or other reasons, the pembrolizumab dosing day may be adjusted to coincide with SGN-B7H4V dosing in consultation with the medical supervisor. If the TEAE is clearly related to SGN-B7H4V alone and the SGN-B7H4V dose will be eliminated, pembrolizumab may be administered at a regularly scheduled visit.

In cases where pembrolizumab dosing is delayed, once pembrolizumab dosing is resumed, the medical advisory site may consider administering pembrolizumab 200 mg Q3W until the individual is able to resume treatment on a Q6W schedule.

If SGN-B7H4V or pembrolizumab is discontinued before the remaining dose, therapy may be continued with the remaining dose until it has been administered for the allowed duration of treatment or until the treatment discontinuation criteria are met, whichever occurs first. Section A - Dose Escalation Groups

The dose escalation portion of this trial (Part A) will be conducted in approximately 120 subjects to evaluate the safety and tolerability of a single dose of SGN-B7H4V and identify the MTD and/or recommended dose and recommended schedule, and to evaluate antitumor activity and PK, ADA, pharmacodynamics, and biomarker characteristics. Dose escalation is performed according to the modified toxicity probability internal (mTPI) method (see , e.g., Ji et al. , Clin Trials , 2010;7(6):653-63). If the MTD is not reached, safety, PK, pharmacodynamics, and biomarker analyses and preliminary antitumor activity will be used to determine the recommended dose.

SGN-B7H4V will be administered by IV infusion. The initial dosing schedule to be evaluated is 2Q3W ( see Table 8), with a starting dose level of 0.75 mg/kg and planned dose escalation levels up to 2.4 mg/kg as indicated in Table 9. The SMC may recommend studies of lower and/or intermediate dose levels, in which case the mTPI dose escalation rules will continue to apply. Note: In each new dose escalation group, subjects will receive their initial dose at least 1 day apart.

Alternative schedules may be evaluated via dose escalation during Part A ( see Table 8 and Figure 1). The sponsor, in consultation with the SMC, will select the open enrollment schedule based on available data on safety, DLTs, PK, and initial antitumor activity.

The dose levels available for evaluation in the alternate schedule are specified in Table 9. In terms of dose strength (mg/kg/week), the starting dose level in the alternate schedule will not be higher than the highest dose level in the initial schedule that is currently considered tolerable by SMC review. For example, if 1.5 mg/kg (1.00 mg/kg/week dose strength) is the highest dose currently considered tolerable by SMC review in the initial schedule, the maximum starting dose will be 1.25 mg/kg for the Day 1, Day 8, Day 15 q28 (3Q4W) schedule (0.94 mg/kg/week) and will be 2.0 mg/kg for the Day 1, Day 15 q28 (2Q4W) schedule (1.00 mg/kg/week). Dose-limiting toxicity

Dose-limiting toxicity (DLT) will be evaluated during the dose escalation period in Part A. The DLT evaluation period will be the first cycle (21 days or 28 days, depending on the schedule).

A DLT was defined as any of the following events that occurred during the DLT evaluation period and were assessed by the investigator as clinically significant and related to SGN-B7H4V treatment. • Grade 5 toxicities with no clear relationship to disease progression or external causes • ≥ Grade 3 non-hematologic, non-laboratory treatment-related AEs, with the following exceptions: ○ Grade 3 fatigue that resolves within 72 hours with or without intervention ○ Grade 3 nausea, vomiting, diarrhea, or constipation that resolves within 72 hours with or without intervention ○ Grade 3 infusion-related reactions (IRRs) that resolve within 24 hours to ≤ Grade 1 with or without intervention without sequelae and without hospitalization other than observation NOTE: If a ≥ Grade 3 IRR occurs in ≥20% of subjects (i.e., 2 or more of the first 10 subjects), all subsequent subjects will require upfront medication and/or infusion regimen modification as recommended by the SMC and the regimen will be modified. • Grade 3 or 4 non-hematologic laboratory abnormality if: ○ The abnormality persists for >72 hours, or ○ The abnormality meets the definition of potential drug-induced liver injury (DILI), or ○ ≥ Grade 3 elevation of transaminases (ALT and/or AST) • Grade 4 anemia or thrombocytopenia • Grade 4 hematologic toxicity (other than anemia/thrombocytopenia) persisting for >7 days • Grade 3 thrombocytopenia with clinically significant bleeding • ≥ Grade 3 febrile neutropenia • Dosing delayed ≥14 days due to toxicity Section B - Optimization Group Dosing and Schedule Optimization

Following dose escalation, if there is sufficient evidence to support evaluation of a dosing regimen in dose expansion (Part C) based on dose escalation (Part A), Part B will be omitted. Otherwise, if more than one dose and schedule are identified as candidates for a recommended dosing regimen, dose and schedule optimization will be performed. Part B, if present, will further evaluate selected doses from the selected schedules identified in Part A in parallel groups of 10 subjects. Up to a total of 40 subjects may be enrolled in 4 groups. The doses and schedules used for evaluation in Part B will be selected by the sponsor in consultation with the SMC and may be equal to or lower than the MTD of any of the evaluated schedules. Participants in Part B will be randomly assigned to different doses and schedules with equal probability.

Groups can also be defined based on selected disease types, with each disease type being evaluated in a separate group for each selected dose and schedule ( see Figure 7B, Part B). If disease-specific groups are used, randomization to dose and schedule will be performed separately within each disease type.

The best recommended dosing regimen will be determined based on safety, PK, preliminary antitumor activity, and relevant pharmacodynamic and biomarker data from Part A and (if conducted) Part B, for further evaluation in the Part C disease-specific monotherapy expansion cohort. 2Q4W Monotherapy Optimization for TNBC

Based on the comparable safety profile and preliminary efficacy at both dose levels, SGN-B7H4V 1.5 mg/kg AiBW 2Q4W and 1.75 mg/kg AiBW 2Q4W have been identified as potential dose levels for further development. To further evaluate these dose levels, a randomized dose-optimization cohort of approximately 40 subjects will be initiated in subjects with locally advanced unresectable or metastatic TNBC. Part C - Monotherapy Expansion Cohort

To further characterize the safety, tolerability, PK, and antitumor activity of SGN-B7H4V, approximately 270 additional individuals may be enrolled in up to 6 monotherapy expansion cohorts and one biological cohort. The monotherapy expansion cohorts will enroll individuals with selected tumor types. Dosing, schedule, and disease settings for the monotherapy expansion cohorts will be determined by the sponsor in consultation with the SMC and may vary between cohorts.

The following groups can be enrolled in dose expansion:

Disease-Specific Monotherapy Cohorts : Approximately 240 subjects (up to 40 subjects per cohort) will be treated in disease-specific expansion cohorts at the maximum tolerated dose (MTD) or recommended dose to further characterize the safety, tolerability, PK, and antitumor activity of SGN-B7H4V. For each disease-specific cohort, an interim analysis will be performed after approximately 15 subjects are evaluable for response. Enrollment may continue uninterrupted during the interim analysis. Futility analyses will be performed using the predicted probability of success (PPoS) approach ( see , e.g., Lee and Liu, Clin Trials , 2008, 5(2):93-106), where success is defined as the posterior probability of a response rate greater than the background rate greater than 0.70. If the estimated PPoS given in the interim data is <10%, the sponsor will evaluate all the data and decide in consultation with the SMC whether to continue to be enrolled in the group.

Biological Cohort : Up to approximately 30 additional individuals may be enrolled into the Biological Cohort. This cohort will enroll one or more tumor types from those individuals who are eligible for Part C and consent to the protocol-specified research examinations. Individuals in the Biological Cohort will be asked to provide additional tissue to enable biomarker studies of SGN-B7H4V to compare pre- and post-treatment tumor samples to characterize the clinical mechanism of action (MOA) at the recommended dose and the relevance of sensitivity/resistance mechanisms. Part D - Combination Safety Lead-in

Part D is designed to evaluate the safety and tolerability of the combination of SGN-B7H4V and pembrolizumab in TNBC. Approximately 6 to 12 individuals with previously untreated locally advanced unresectable or metastatic TNBC will be enrolled in Part D. The initial dose level to be evaluated is 1.5 mg/kg AiBW 2Q4W, followed by 1.75 mg/kg AiBW 2Q4W.

The first 6 subjects will be enrolled in Part D. Subjects will receive SGN-B7H4V on a 2Q4W schedule, starting at 1.5 mg/kg AiBW, and pembrolizumab at a dose of 400 mg every 6 weeks (SGN-B7H4V and pembrolizumab administered together starting on Day 1). The Sponsor, in consultation with the SMC, will assess the safety and tolerability of SGN-B7H4V and pembrolizumab after 6 subjects have completed study treatment for the first 28 days and are confirmed evaluable for DLT. Subjects will be considered evaluable for DLT if they receive at least 75% of the planned SGN-B7H4V and pembrolizumab doses during the first 28 days of study treatment and meet the criteria. • If 0 or 1 of the initial 6 subjects experience a DLT, 6 additional subjects will be enrolled to receive SGN-B7H4V 1.75 mg/kg AiBW 2Q4W with pembrolizumab. • If 2 or more of the initial 6 subjects experience a DLT, the sponsor in consultation with the SMC will review the data to determine next steps. Dose-Limiting Toxicity

DLTs will be assessed in Part D. The DLT assessment period will be 28 days prior to study treatment.

A DLT is defined as any of the following events that occurred during the DLT Assessment Period and were assessed by the Investigator to be clinically significant and related to the combination therapy; events attributable to pembrolizumab alone and consistent with the known safety profile of pembrolizumab will not be considered DLTs. • Grade 5 toxicities not clearly related to disease progression or external causes • ≥ Grade 3 non-hematologic, non-laboratory treatment-related AEs, with the following exceptions: ○ Grade 3 fatigue that resolves within 72 hours with or without intervention ○ Grade 3 nausea, vomiting, diarrhea, or constipation that resolves within 72 hours with or without intervention ○ Grade 3 IRR that resolves to ≤ Grade 1 within 24 hours with or without intervention without sequelae and without hospitalization other than observation NOTE: If ≥ Grade 3 IRR occurs in ≥20% of subjects (i.e., 2 or more of the first 10 subjects), all subsequent subjects will require upfront medication and/or infusion method modification based on the SMC recommendation and the regimen will be modified. • Grade 3 or 4 non-hematologic laboratory abnormality if: ○ The abnormality persists for >72 hours, or ○ The abnormality meets the definition of potential DILI, or ○ ≥ Grade 3 elevation of transaminases (ALT and/or AST) • Grade 4 anemia or thrombocytopenia • Grade 4 hematologic toxicity (other than anemia/thrombocytopenia) persisting for >7 days • Grade 3 thrombocytopenia with clinically significant bleeding • ≥ Grade 3 febrile neutropenia • Dose delay of ≥14 days due to toxicity Part E - Combination Therapy Expansion Group

After completion of Part D, the sponsor may initiate expansion cohorts in Part E to further characterize the safety, PK, and antitumor activity of the combination of SGN-B7H4V and pembrolizumab. Approximately 30 individuals will be enrolled in each expansion cohort. • Cohort E1: SGN-B7H4V with pembrolizumab in 1L PD-L1-positive (CPS ≥10) TNBC • Cohort E2: SGN-B7H4V with pembrolizumab in 1L PD-L1-negative (CPS <10) TNBC • Cohort E3: SGN-B7H4V with pembrolizumab as adjuvant therapy in individuals with residual disease after neoadjuvant therapy and surgery

The dosing and schedule of SGN-B7H4V for Part E will be based on all data generated from previous parts of the study, including Part D.

Interim analyses will be performed for Part E, Cohort E1 and Cohort E2, after responses in approximately 12 individuals are evaluable. Enrollment will continue uninterrupted during the interim analysis period. Duration of treatment Parts A, B, and C:

Subjects may continue treatment with SGN-B7H4V until progressive disease (PD) according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, unacceptable toxicity, withdrawal of consent, death, or study termination, whichever occurs first. Section D and Section E Cohorts E1 and E2:

Subjects may continue treatment with SGN-B7H4V until PD per RECIST version 1.1, unacceptable toxicity, withdrawal of consent, death, or study discontinuation, whichever occurs first. Pembrolizumab may be administered for up to 24 months or until PD per RECIST version 1.1, unacceptable toxicity, withdrawal of consent, death, or study discontinuation, whichever occurs first. Partial E Group E3:

Subjects may receive SGN-B7H4V for up to 8 cycles (16 doses) or until unacceptable toxicity, withdrawal of consent, death, or study discontinuation, whichever occurs first. Pembrolizumab may be administered at 400 mg every 6 weeks (Q6W) for up to 4 doses or until unacceptable toxicity, withdrawal of consent, death, or study discontinuation, whichever occurs first. Retreatment

For individuals who achieve a complete response (CR) or partial response (PR) according to RECIST v1.1 in the study and then experience disease progression after stopping initial treatment with SGN-B7H4V, retreatment with SGN-B7H4V is permitted in the monotherapy group in consultation with the medical supervisor. The retreatment dose level for each individual will be determined by the medical supervisor and site investigator. No retreatment is permitted in the combination group. Patient Selection Inclusion Criteria 1. Disease Indications: a. Part A, B, and C: Individuals must have one of the following histologically or cytologically confirmed locally advanced unresectable or metastatic solid tumor types: ○ High-grade serous epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer ○ HER2-negative, HR-positive breast cancer (based on the most recent available biopsy according to American Society of Clinical Oncology [ASCO]/CAP [American College of Pathologists] criteria) ○ NBC (based on the most recent available biopsy according to ASCO/CAP criteria) ○ Endometrial cancer (Part C: Up to 10 individuals with endometrial carcinosarcoma may be enrolled in the single therapy dose expansion cohort) ○ NSCLC (SqCC, AC) ○ Cholangiocarcinoma or gallbladder cancer ○ ACC b. Section D: ○ Individuals must have histologically or cytologically confirmed locally advanced unresectable or metastatic TNBC (per ASCO/CAP criteria, based on the most recent available biopsy) c. Section E: ○ Group E1 : 1L TNBC PD-L1+ (CPS ≥10) Individuals must have histologically or cytologically confirmed locally advanced unresectable or metastatic TNBC (per ASCO/CAP criteria, based on the most recent available biopsy). Individuals must have a CPS ≥ 10 by local testing. ○ Group E2: 1L TNBC PD-L1- (CPS <10) Individuals must have histologically or cytologically confirmed locally advanced unresectable or metastatic TNBC (per ASCO/CAP criteria, based on the most recent available biopsy). Individuals must have a CPS < 10 by local testing. ○ Group E3: TNBC with Residual Disease after Neoadjuvant Therapy and Definitive Surgery Individuals must have histologically or cytologically confirmed TNBC (per ASCO/CAP criteria, based on the most recently available biopsy). Individuals must have stage I-III disease with evidence of residual disease in the breast and/or axillary lymph nodes after definitive surgical resection following neoadjuvant therapy. Individuals must have adequate excision and surgical removal of all clinically significant disease in the breast and/or lymph nodes. Individuals with evidence of local or distant recurrence are not eligible. Individuals with known germline BRCA1 or BRCA2 mutations are not eligible. 2. Prior Therapy: a. Sections A and B* (* See Section B 2Q4W Single Therapy Optimization for TNBC): Subjects must have disease that is relapsed or refractory or intolerant to SOC therapy and should not have appropriate SOC treatment options based on the investigator’s judgment. If a SOC therapy is available but not administered, the reason why that therapy is inappropriate must be documented. * Section B 2Q4W Single Therapy Optimization for TNBC: Subjects must have TNBC that is relapsed or refractory or intolerant to SOC therapy as specified below: ○ Treated with at least 1 and no more than 3 prior lines of systemic chemotherapy in the setting of locally advanced unresectable or metastatic TNBC. ○ If an individual subsequently develops locally advanced unresectable or metastatic disease within 12 months of completion of adjuvant or neoadjuvant therapy, adjuvant or neoadjuvant therapy for early-stage disease will count as 1 line of systemic chemotherapy. ○ If eligible based on biomarker status and consistent with the SOC, the individual must have received a PD-(L)1 inhibitor. ○ Treatment with a topoisomerase-1 (TOPO-1) inhibitor-based ADC, if available, has been discussed by the investigator. If an individual has received treatment with a TOPO-1 inhibitor-based ADC, that treatment will count as 1 line of systemic chemotherapy. ○ Hormonal therapy will not be considered as a prior line of systemic chemotherapy. b. Section C: Subjects must have disease that is relapsed or refractory or intolerant to SOC therapy as specified below: • High-grade serous epithelial ovarian, primary peritoneal, or fallopian tube cancer ○ Treated with platinum-based chemotherapy and considered to have platinum-resistant disease, defined as disease that has progressed radiographically within 6 months after completing at least 4 cycles of platinum-containing therapy. Subjects who have received platinum-based chemotherapy and are considered intolerant to platinum-based agents are eligible. Subjects with primary platinum-refractory disease, defined as disease that has not responded or has progressed within 3 months after the last dose of first-line platinum-containing chemotherapy, are not eligible. ○ If eligible, subjects must have received a regimen containing bevacizumab. If eligible based on biomarker status and consistent with SOC, must have received a poly ADP ribose polymerase (PARP) inhibitor. • TNBC ○ Treated with at least 1 and no more than 3 prior lines of systemic chemotherapy in the locally advanced unresectable or metastatic TNBC setting. ○ If an individual subsequently develops locally advanced unresectable or metastatic disease within 12 months of completion of adjuvant or neoadjuvant therapy, adjuvant or neoadjuvant therapy for earlier disease will count as 1 line of systemic chemotherapy. ○ If eligible based on biomarker status and consistent with SOC, treatment must have included a PD-(L)1 inhibitor. ○ Treatment with TOPO-1 inhibitor-based ADCs, if available, has been discussed by the investigator. If the individual has received treatment with a TOPO-1 inhibitor-based ADC, that treatment will count as 1 line of systemic chemotherapy. ○ Hormonal therapy will not be considered as prior line of systemic chemotherapy. • HER2 -negative, HR-positive breast cancer ○ Treated with endocrine therapy. The individual must have progressed and no longer be eligible for endocrine therapy, as assessed by the investigator. ○ Treated with a cyclin D-dependent kinase (CDK) 4/6 inhibitor, unless treatment with a CDK 4/6 inhibitor is not appropriate due to safety considerations, as assessed by the investigator. ○ Treated with at least 1 and no more than 3 prior lines of systemic chemotherapy in the locally advanced unresectable or metastatic HR+/HER2- breast setting. ○ If an individual subsequently develops locally advanced unresectable or metastatic disease within 12 months of completion of adjuvant or neoadjuvant therapy, adjuvant or neoadjuvant therapy for early-stage disease will count as 1 line of systemic chemotherapy. ○ Treatment with a TOPO-1 inhibitor-based ADC, if available, has been discussed by the investigators. If an individual has received treatment with a TOPO-1 inhibitor-based ADC, that treatment will count as 1 line of systemic chemotherapy. ○ Hormonal therapy will not be considered a prior line of systemic chemotherapy. • Endometrial cancer ○ Subjects must have received at least 1 line of systemic therapy. ○ Must have received prior PD-1 inhibitor and/or the combination of pembrolizumab and lenvatinib if appropriate based on biomarker status (including but not limited to microsatellite instability [MSI] and mismatch repair deficiency [dMMR] status) and available based on local SOC. ○ Subjects must have received at least 1 prior platinum-based regimen. • Squamous NSCLC ○ Subjects with locally advanced recurrent/metastatic disease must have received prior treatment with platinum-based therapy alone or in combination and a PD-(L)1 inhibitor if indicated based on local SOC. • Cholangiocarcinoma or gallbladder cancer ○ Subjects must have received at least 1 line of systemic therapy. ○ Subjects must have received an approved targeted therapy if appropriate based on 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 based on local SOC. ○ Liver involvement is permitted. • Adenoid cystic carcinoma ○ Subjects with locally advanced recurrent/metastatic disease must have received at least 1 line of systemic therapy. ○ Subjects whose tumors harbor genomic mutations/alterations and for whom an approved targeted therapy is available based on local SOC must have received an approved and available targeted therapy. c. Section D: • Locally advanced unresectable or metastatic TNBC without prior treatment. Subjects treated in a curative setting are eligible if it has been ≥6 months since completion of self-healing therapy. d. Section E: • Groups E1 and E2: Locally advanced unresectable or metastatic TNBC with no prior treatment. Subjects treated in a curative setting are eligible if it has been ≥6 months since completion of self-healing therapy. • Group E3: Completion of at least 6 cycles of neoadjuvant therapy containing anthracycline and/or taxane with or without immune CPI for locally advanced unresectable or metastatic TNBC. Radiation therapy (if indicated) must be administered prior to the start of study treatment. Subjects who have received prior adjuvant therapy are not eligible. 3. Tumor tissue is required for registration. • For Part A and Part B , archival tumor tissue from the most recent biopsy collected within 24 months of registration is required (if available). For all individuals in Part C (Disease Specific Groups and Biological Groups), Part D, and Part E , archival tumor tissue from the most recent biopsy collected within 12 months of registration is required (if available). If archival tissue is not available for individuals in Part A, Part B, Part C Disease Specific Groups, Part D, and Part E, a fresh pre-treatment biopsy must be submitted (appropriate lesions can be accessed by minimally invasive procedures that do not present a significant risk). *For Part A subjects enrolled for additional dose finding and Part B T NBC subjects enrolled for 2Q4W monotherapy dose optimization, archival tumor tissue from the most recent biopsy collected within 12 months of enrollment is required (if available). For all other Part A subjects, archival tumor tissue from the most recent biopsy collected within 24 months of enrollment is required (if available). • For Part C biologic groups, a fresh pre-treatment biopsy, an intra-treatment biopsy on Day 15 of Cycle 1, and an end-of-treatment (EO T ) biopsy are required. 4. Age 18 years or older. 5. Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1. 6. Measurable disease according to RECIS T version 1.1 at baseline. Not applicable to individuals receiving adjuvant treatment for residual disease in Section E. 7. The following baseline laboratory test results: • Absolute neutrophil count (ANC) ≥1500/µL • Hemoglobin (Hgb) ≥9 g/dL • Platelet count ≥100,000/μL • Serum bilirubin ≤1.5 × upper limit of normal (ULN) or ≤3 × ULN for individuals with Gilbert’s disease • Estimated glomerular filtration rate (eGFR) ≥45 mL/min/1.73 m2 using the Modification of Diet in Renal Disease (MDRD) study equation if applicable or 24-hour creatinine clearance (CrCl) ≥45 mL/min/1.73 ^m2 • ALT and AST ≤3 × ULN (≤5 × ULN if there is evidence of malignant disease involving the liver) 8. Subjects of childbearing potential were eligible under 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 [β-hCG]) result within 7 days prior to the first dose of SGN-B7H4V. Subjects with a false-positive result and documented confirmation that the subject is not pregnant were eligible to participate. b. Must agree not to attempt to conceive during the study and for at least 2 months after the final dose of SGN-B7H4V (and in Parts D and E only, for at least 4 months after the last dose of pembrolizumab). c. Must agree not to breastfeed or donate eggs, beginning at the time of informed consent and continuing until 2 months after the last dose of SGN B7H4V (and in Parts D and E only, until at least 4 months after the last dose of pembrolizumab). d. Must continue to use at least 2 acceptable methods of birth control (contraception), at least 1 of which must be highly effective, beginning at the time of informed consent and continuing until at least 2 months after the last dose of SGN B7H4V (and in Parts D and E only, until at least 4 months after the last dose of pembrolizumab). 9. Individuals who can impregnate someone under the following conditions: a. Must agree not to donate sperm from the time of informed consent and continue for the duration of the study and at least 4 months after the final dose of study treatment. b. If engaging in sexual activity with a person of childbearing potential in a manner that could result in pregnancy, must continue to 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 continue for at least 4 months after the final dose of study treatment. c. If engaging in sexual activity with a person who is pregnant or breastfeeding, must continue to use condoms from the time of informed consent and continue for at least 4 months after the final dose of study treatment. 10. Partial E group E3 only: Left ventricular ejection fraction (LVEF) ≥50% based on echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan within 28 days before the start of study treatment. Exclusion criteria 1. History of another malignant tumor within 3 years before the first dose of study drug, or any evidence of residual disease from a previously diagnosed malignant tumor. Exceptions are malignant tumors with negligible risk of metastasis or death (e.g., 5-year OS ≥90%), such as adequately treated cervical carcinoma in situ, non-melanoma skin cancer, 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 were eligible to participate provided that they were clinically stable for at least 4 weeks prior to study entry after treatment of brain metastases, did not have new or enlarging brain metastases, and were off prescription corticosteroids for symptoms related to brain metastases for at least 7 days prior to the first dose of study drug. 3. Carcinomatous meningitis. 4. Prior receipt of an agent containing MMAE or targeting B7H4. 5. Pre-existing neuropathy of ≥ Grade 2 according to the 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 was permitted. 7. Uncontrolled diabetes, defined as Hgb A1c ≥8% or Hgb A1c between 7 and <8% with associated diabetic symptoms not otherwise explained (polyuria or thirst). 8. Positive for hepatitis B based on surface antigen expression and/or positive anti-hepatitis B core (HBc) total antibody titer. Active hepatitis C infection (based on positive polymerase chain reaction [PCR] or receipt of antiviral therapy for hepatitis C within the past 6 months). Individuals with treated hepatitis C infection are permitted if a sustained virologic response has been documented for 12 weeks. 9. Known positive for human immunodeficiency virus. 10. History of a documented cerebrovascular 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. Class III or IV congestive heart failure according to New York Heart Association criteria. 12. Active or uncontrolled lung disease ≥ Grade 2 not related to an underlying malignancy. 13. Active autoimmune disease that required systemic therapy (i.e., use of disease-modifying agents, corticosteroids, or immunosuppressive drugs) within the past 2 years. Replacement therapies (e.g., thyroid hormones, insulin, or physiologic corticosteroid replacement for adrenal or pituitary insufficiency) are not considered a form of systemic therapy and are permitted. 14. Corneal disease or injury requiring treatment or active monitoring. 15. Parts A and D only: Use of strong cytochrome P450 3A (CYP3A) inhibitors or inducers within 14 days prior to the start of study treatment. 16. Receipt of vaccines containing live or attenuated viruses within 30 days prior to the first dose of study drug. 17. Chemotherapy, immunotherapy, biologics, and/or other approved or investigational anti-cancer therapy that was not completed 4 weeks prior to the start of study treatment (for all parts) or within 2 weeks prior to the start of study treatment (for parts A, B, C) if the underlying disease has progressed on treatment. 18. Localized radiation therapy or major surgery that was not completed 2 weeks prior to the start of study treatment. 19. Subjects who are breastfeeding, pregnant, or planning to become pregnant from the time of informed consent until 2 months after the last dose of SGN-B7H4V and until 4 months after the last dose of pembrolizumab (for parts D and E). 20. Known hypersensitivity to any formulation of the drug formulation of SGN B7H4V or other treatment to be administered. 21. Estimated life expectancy < 12 weeks. 22. Other serious underlying medical conditions that the investigator believes will impair the individual's ability to receive or tolerate planned treatment and follow-up. 23. Any toxicity related to previous therapy that has not recovered to baseline or > Grade 1, except alopecia and well-controlled immune-mediated endocrine toxicity (such as Grade 2 hypothyroidism) caused by previous immunotherapy. 24. Individuals who are familially or financially dependent on the sponsor, the sponsor's legal representative, the clinical research organization, or the investigator. 25. For Germany only, individuals were submitted to the institution pursuant to an order issued by a judicial or administrative authority. 26. Parts D and E only : received prior therapy with a PD-1 inhibitor, anti-PD(L)1 or anti-PD L2, or with an agent directed against another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA 4, OX40, CD137) and discontinued that therapy due to a Grade 3 or higher IMAE. 27. Parts D and E only : diagnosed as immunodeficient within 7 days before the first dose of study drug or receiving long-term systemic corticosteroid therapy (daily dosing of more than 10 mg of prednisone equivalents) or any other form of immunosuppressive therapy. 28. Parts D and E only : underwent an allogeneic tissue/organ transplant. 29. Parts D and E only : History of (non-infectious) pneumonitis/interstitial lung disease requiring steroids or current pneumonitis/interstitial lung disease. 30. Parts D and E only : Received >30 Gy of lung radiation within 6 months after the first dose of study drug.

All subjects will receive SGN-B7H4V, the investigational agent being studied in this protocol, by IV infusion at a dose and on a schedule determined by the cohort and dose level in which they are enrolled. For Parts D and E, pembrolizumab will be administered by IV infusion. Pembrolizumab will be administered first, followed by SGN-B7H4V. At least 30 minutes should elapse after the completion of pembrolizumab administration before initiating administration of SGN-B7H4V. Concomitant Therapy

All concomitant medications, blood products, and radiation therapy administered will be recorded from Day 1 (pre-dose) through the safety reporting period. Any concomitant medications given for protocol-related AEs should be recorded from the time of informed consent. Required pre- and post-dose medications

Routine premedication for infusion reactions should not be administered prior to the first dose of study treatment. However, individuals experiencing an IRR may receive follow-up treatment with premedication, such as antihistamines (e.g., diphenhydramine 50 mg IV or equivalent and famotidine 40 mg IV or equivalent), corticosteroids (e.g., hydrocortisone 100 mg IV or equivalent), or antipyretics (e.g., acetaminophen, e.g., 500 to 1000 mg, oral [PO]). As clinical experience with SGN-B7H4V infusions evolves, routine premedication may be administered prior to the first dose of study treatment as recommended or required by the SMC. No postmedication is required for SGN-B7H4V. Required Premedication and Postmedication

Granulocyte colony stimulating factor (G-CSF) is required in the following situations: • Treatment of febrile neutropenia • Individuals who experience grade 4 neutropenia or any grade of febrile neutropenia in any cycle must receive prophylactic G-CSF in all subsequent cycles. If G-CSF is initiated, the following should be considered: • G-CSF administration should be consistent with established guidelines • Prophylactic G-CSF should be started 1 to 3 days after SGN-B7H4V administration • If pegfilgrastim is used, it is recommended that it should not be administered within 14 days prior to or on the day of SGN-B7H4V administration • If daily G-CSF is used, it is recommended that it should not be administered within 24 hours prior to or on the day of SGN-B7H4V administration; treatment should continue until ANC ≥ 1500/µL.

No other concomitant therapy is required. Based on emerging safety data, the SMC may require concomitant therapy, such as pre-administration of medication. Permitted Concomitant Therapy

When applicable, the use of platelet and/or red cell supportive growth factors or transfusions is permitted at the discretion of the investigator in the institution’s SOC below. The use of colony stimulating factors for the treatment of neutropenia is permitted during therapy outside the DLT Evaluation Period, consistent with institutional practice, and may be permitted during therapy during the DLT Evaluation Period in consultation with the medical supervisor. Concomitant prednisone (or equivalent) may be used at a dose of ≤10 mg/day or at higher physiologic replacement doses, as appropriate. Intermittent high-dose corticosteroid therapy may be permitted to prevent or manage hypersensitivity reactions (including prior use of medications known to cause hypersensitivity reactions to contrast agents used for radiologic evaluations) in consultation with the medical supervisor. Intermittent high-dose corticosteroid therapy for other reasons may be permitted in consultation with the medical supervisor.

Antibiotics, including prophylactics, are permitted when appropriate.

In Sections C and E, concomitant use of strong inhibitors or inducers of CYP3A with SGN-B7H4V is permitted. Individuals receiving strong inhibitors or inducers of CYP3A concomitantly with SGN-B7H4V should be closely monitored for adverse reactions. Based on evaluation of the anti-CD 30 MMAE ADC vebrectin (ADCETRIS ^® Prescribing Information, Seagen, October 2019), concomitant use of strong CYP3A inhibitors has the potential to increase exposure to MMAE, the cytotoxic component of SGN-B7H4V and vebrectin. Concomitant use of strong CYP3A inducers may reduce exposure to MMAE. ac-MMAE and MMAE PK parameters can be estimated for subjects who receive strong inhibitors or inducers of CYP3A concomitantly with SGN-B7H4V and compared to estimates of corresponding parameters for subjects who do not receive them.

In consultation with the Medical Supervisor, study treatment may be interrupted by palliative radiation therapy that does not involve the target lesion. This intervention will not be considered as subsequent anticancer therapy. Study intervention should be maintained for at least 7 days before and at least 14 days after radiation administration.

Killed (non-live virus) vaccines are permitted, including for influenza and/or COVID-19.

For subjects receiving pembrolizumab, concomitant long-term prednisone (or equivalent) at doses ≤10 mg/day may be used for management of pre-existing conditions, with approval of the medical supervisor. Higher doses of prednisone (or equivalent) are permitted for limited duration as medically indicated for treatment of acute conditions that arise during the study. Subjects requiring systemic steroids (≥10 mg/day of prednisone or equivalent) for more than 24 hours for management of treatment-related AEs should be notified to the medical supervisor. Long-term use of inhaled or topical steroids is permitted in the absence of active autoimmune disease. Prohibited Concomitant Therapies

During dose escalation (Part A), concomitant use of strong CYP3A inhibitors or inducers or P-glycoprotein (P-gp) inhibitors is prohibited. Subjects must have discontinued use of strong CYP3A inhibitors or inducers and P-gp inhibitors for at least 14 days prior to the first dose of study drug.

During the combined safety run-in (Part D), concomitant use of strong CYP3A inhibitors or inducers was prohibited. Subjects must have discontinued use of strong CYP3A inhibitors or inducers for at least 14 days prior to the first dose of study drug.

During dose expansion, subjects receiving strong inhibitors/inducers of CYP3A or P-gp inhibitors should be closely monitored for AEs.

No other study medications, immunosuppressive medications, non-study systemic antineoplastic therapy, or growth factors and transfusion support were permitted within 7 days prior to the initial study drug administration in Cycle 1. During the DLT period (Cycle 1 of Part A and Part D), growth factors and transfusion support were discouraged unless medically indicated; subjects who received growth factors (e.g., G-CSF or granulocyte-macrophage colony-stimulating factor [GM-CSF]) or transfusion support for reasons other than DLT during this period may not be evaluated for DLT.

During the study, subjects were not allowed to receive other study medications, immunosuppressive drugs, radiation therapy, or systemic antineoplastic therapy.

For Sections D and E, individuals receiving pembrolizumab should not receive more than 10 mg/kg of prednisone or equivalent corticosteroids without the approval of their medical supervisor, unless used to manage immune -related adverse events . Target Corresponding endpoint main To evaluate the safety and tolerability of SGN-B7H4V in subjects with advanced solid tumors To evaluate the safety and tolerability of the combination of SGN-B7H4V and pembrolizumab in subjects with TNBC • Type, incidence, severity, severity and relevance of adverse events (AEs) • Type, incidence and severity of laboratory abnormalities Identification of the Maximum Tolerated Dose (MTD) of SGN-B7H4V in Individuals with Advanced Solid Tumors • Incidence of dose-limiting toxicity (DLT) Identification of recommended doses and schedules for SGN-B7H4V Identification of recommended doses and schedules for the combination of SGN-B7H4V and pembrolizumab • DLT incidence and cumulative safety by dose level secondary Evaluation of the anti-tumor activity of SGN-B7H4V Evaluation of the anti-tumor activity of the combination of SGN-B7H4V and pembrolizumab • ORR (complete response [CR] or partial response [PR]) as assessed by investigator according to RECIST, version 1.1 (not applicable to the residual disease study cohort in Part E Cohort E3) • CR rate (CRR) according to RECIST, version 1.1 (not applicable to Cohort E3) • Duration of objective response (DOR) according to RECIST, version 1.1 (not applicable to Cohort E3) • Progression-free survival (PFS) according to RECIST, version 1.1 (not applicable to Cohort E3) • Invasive disease-free survival (iDFS) (only for Cohort E3) Evaluation of the pharmacokinetics (PK) of SGN-B7H4V • Estimation of selected PK parameters for plasma SGN-B7H4V antibody binding to MMAE and other clinically relevant analytes Evaluation of the immunogenicity of SGN-B7H4V • The incidence of anti-drug antibodies (ADA) Evaluation of the PK of the combination of SGN-B7H4V and pembrolizumab • Estimation of selected PK parameters for plasma SGN-B7H4V antibody binding to MMAE and other clinically relevant analytes Evaluation of the immunogenicity of the combination of SGN-B7H4V and pembrolizumab • The incidence of anti-drug antibodies (ADA) Exploratory Evaluation of biomarkers associated with response, toxicity, pharmacodynamics, PK/pharmacodynamic relationships, or resistance to SGN-B7H4V • Correlation analysis of pharmacodynamic measurements with PK, response, toxicity and resistance assessments. • Characterization of B7-H4 expression on malignant cells • Biomarkers of SGN-B7H4V-mediated pharmacodynamic effects • Correlation analysis of pharmacodynamic and PK exposure measurements To evaluate the impact of SGN-B7H4V on health-related quality of life (HRQoL) in patients with metastatic breast cancer from an individual perspective • Descriptive results of qualitative interviews To evaluate the anti-tumor activity of SGN-B7H4V as monotherapy or in combination with pembrolizumab • Overall survival (OS)

Figure 1 shows the Phase 1 B7-H4-ADC clinical study design. AiBW is ideal adjusted body weight. TNBC is triple negative breast cancer. Figure 2A is a waterfall plot showing the change in the sum of diameters of target lesion size (SoD) from baseline. Each bar represents an individual given a specific dose for a 2Q3W schedule. Figure 2B is a spider plot showing the change in tumor size from baseline over weeks. Each line represents an individual given a specific dose for a 2Q3W schedule. Bars or lines marked with an asterisk indicate ongoing treatment. The upper dashed line indicates a 20% increase in SoD, and the lower dashed line indicates a 30% decrease in SoD. Figure 3A is a waterfall plot showing the change in the sum of diameters of target lesion size (SoD) from baseline. Each bar represents an individual given a particular dose for a 2Q4W schedule. Figure 3B is a spider graph showing the change in tumor size from baseline over several weeks. Each line represents an individual given a particular dose for a 2Q4W schedule. Bars or lines marked with an asterisk indicate ongoing treatment. The upper dashed line indicates a 20% increase in SoD, and the lower dashed line indicates a 30% decrease in SoD. Figure 4 shows a stacked bar graph quantifying the prevalence of B7-H4 expression in tumor sections obtained from individuals diagnosed with the indicated cancer. Each bar is categorized by an immunohistochemical staining intensity score of 1 to 3. For prevalence calculations, a tumor was considered positive if staining was observed on greater than 25% of tumor cells. Figure 5 shows a waterfall plot demonstrating the change from baseline in the sum of diameters of target lesion sizes (SoD) for tumors with triple-negative breast cancer. Each bar represents an individual given a particular dose for a 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". Bars marked with triangles indicate ongoing treatment. The upper dashed line indicates a 20% increase in SoD, and the lower dashed line indicates a 30% decrease in SoD. Figure 6 shows a waterfall plot showing the change from baseline in the sum of diameters of target lesion sizes (SoD) for HR+ Her2- breast cancer tumors. Each bar represents an individual given a particular dose for a 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". Bars marked with triangles indicate ongoing treatment. The upper dashed line indicates a 20% increase in SoD, and the lower dashed line indicates a 30% decrease in SoD.

TW202517301A_113137965_SEQL.xml

Claims (68)

A method for treating a solid tumor in an individual, the method comprising administering a B7-H4 antibody-drug conjugate (B7-H4-ADC) to the individual twice every three weeks (2Q3W), wherein the B7-H4-ADC comprises an anti-B7-H4 antibody conjugated to vcMMAE (valine-citrulline-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 three complementary determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or an antigen-binding fragment thereof comprises three CDRs of SEQ ID NO: 12; wherein the vcMMAE comprises the following structure: or a pharmaceutically acceptable salt thereof. A method for treating a solid tumor in an individual, the method comprising administering a B7-H4-ADC to the individual once every three weeks (Q3W), wherein the B7-H4-ADC comprises an anti-B7-H4 antibody conjugated to vcMMAE (valine-citrulline-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 three complementary determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or an antigen-binding fragment thereof comprises three CDRs of SEQ ID NO: 12; wherein the vcMMAE comprises the following structure: or a pharmaceutically acceptable salt thereof. 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 based on the subject's body weight. 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 based on the subject's body weight. 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 based on the subject's body weight. 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 based on the subject's body weight. 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, 0.58 mg/kg/week, 0.67 mg/kg/week, about 0.75 mg/kg/week, or about 0.80 mg/kg/week based on the subject's body weight. The method of any one of claims 1 to 7, wherein the weight of the individual is an actual weight. The method of any one of claims 1 to 7, wherein the individual's weight is an adjusted ideal weight. The method of any one of claims 1 and 3 to 6, wherein the B7-H4-ADC is administered on day 1 and day 8 of the three-week period. The method of any one of claims 2 to 5 and 7, wherein the B7-H4-ADC is administered on day 1 of the three-week period. The method of any one of claims 1, 3 to 6, and 8 to 10, wherein the B7-H4-ADC is administered at least four times. The method of any one of claims 2 to 5, 7 to 9 and 11, wherein the B7-H4-ADC is administered at least twice. A method for treating a solid tumor in an individual, the method comprising administering a B7-H4-ADC to the individual twice every four weeks (2Q4W), wherein the B7-H4-ADC comprises an anti-B7-H4 antibody conjugated to vcMMAE (valine-citrulline-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 three complementary determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or an antigen-binding fragment thereof comprises three CDRs of SEQ ID NO: 12; wherein the vcMMAE comprises the following structure: or a pharmaceutically acceptable salt thereof. A method for treating a solid tumor in an individual, the method comprising administering a B7-H4-ADC to the individual three times every four weeks (3Q4W), wherein the B7-H4-ADC comprises an anti-B7-H4 antibody conjugated to vcMMAE (valine-citrulline-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 three complementary determining regions (CDRs) of SEQ ID NO: 11, and the light chain variable region of the antibody or an antigen-binding fragment thereof comprises three CDRs of SEQ ID NO: 12; wherein the vcMMAE comprises the following structure: or a pharmaceutically acceptable salt thereof. 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 based on the subject's body weight. 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 based on the subject's body weight. 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 based on the subject's body weight. 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 based on the subject's body weight. 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 based on the subject's body weight. The method of any one of claims 14 to 20, wherein the individual's weight is actual weight. The method of any one of claims 14 to 20, wherein the individual's weight is an adjusted ideal weight. The method of any one of claims 14, 16 to 19 and 22, wherein the B7-H4-ADC is administered on day 1 and day 15 of the four week period. 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. The method of any one of claims 14, 16-19, and 21-23, wherein the B7-H4-ADC is administered at least four times. 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. The method of any one of claims 1 to 26, wherein the B7-H4-ADC is administered intravenously (IV). The method of any one of claims 1 to 27, wherein the solid tumor is an advanced solid tumor. 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 cancer, lung cancer, bile duct cancer, gall bladder cancer, and head and neck cancer. The method of claim 29, wherein the ovarian cancer is high-grade serous ovarian cancer (HGSOC). The method of claim 29, wherein the breast cancer is HER2-negative/HR-positive breast cancer. The method of claim 29, wherein the breast cancer is triple negative breast cancer (TNBC). The method of claim 32, wherein the TNBC is locally advanced unresectable or metastatic TNBC. The method of claim 29, wherein the lung cancer is non-small cell lung cancer (NSCLC). The method of claim 34, wherein the NSCLC is squamous cell lung cancer or adenocarcinoma. The method of claim 29, wherein the head and neck cancer is adenoid cystic carcinoma (ACC). The method of any one of claims 1 to 36, further comprising determining the expression level of B7-H4 in the entity tumor. The method of claim 37, wherein the expression level is determined by immunohistochemistry (IHC). The method of claim 38, wherein greater than 25% of the solid tumors have an IHC intensity score of 1 to 3. The method of claim 38, wherein greater than 25% of the cells of the solid tumor express B7-H4. The method of claim 38, wherein greater than 50% of the cells of the solid tumor express B7-H4. The method of any one of claims 1 to 41, wherein such treatment produces one or more therapeutic effects selected from the group consisting of size of tumors arising from the cancer, duration of response, progression-free survival, and overall survival. The method of any one of claims 1 to 42, wherein such treatment results in a reduction in tumor size of at least about 15% in the subject. The method of any one of claims 1 to 43, wherein such treatment produces a durable response. The method of claim 44, wherein the sustained response lasts for at least 67 weeks. The method of any one of claims 1 to 45, wherein such treatment results in an improvement in one or more treatment effects in the subject relative to baseline following administration of the B7-H4-ADC. The method of any one of claims 1 to 46, wherein after administration of the B7-H4-ADC, the subject exhibits a 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 18 months, at least about two years, at least about three years, at least about four years, or at least about five years. The method of any one of claims 1 to 47, wherein after administration of the B7-H4-ADC, the subject exhibits an 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 18 months, at least about two years, at least about three years, at least about four years, or at least about five years. The method of any one of claims 1 to 48, wherein after administration of the B7-H4-ADC, 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 18 months, at least about two years, at least about three years, at least about four years, or at least about five years. The method of any one of claims 1 to 49, wherein the anti-B7-H4 antibody comprises the heavy chain variable region (VH)-complementary determining region (CDR) 1, VH-CDR2, VH-CDR3 and light chain variable region (VL)-CDR1, VL-CDR2 and VL-CDR3 sequences of SEQ ID NOs: 5-10, respectively. The method of any one of claims 1 to 50, wherein the anti-B7-H4 antibody comprises a heavy chain variable region (HCVR) that is at least 95% identical to SEQ ID NO: 11, and a light chain variable region (LCVR) that is at least 95% identical to SEQ ID NO: 12. The method of any one of claims 1 to 51, wherein the B7-H4-ADC comprises an anti-B7-H4 antibody conjugated to vcMMAE (valine-citrulline-monomethylauristatin 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. The method of any one of claims 1 to 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. The method of any one of claims 1 to 53, wherein the heavy chain variable region is at least 99% identical to SEQ ID NO:11 and the light chain variable region is at least 99% identical to SEQ ID NO:12. The method of any one of claims 1 to 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. The method of any one of claims 1 to 55, wherein the B7-H4-ADC comprises the following structure: wherein Ab is the anti-B7-H4 antibody, and wherein p is the vcMMAE:antibody ratio. The method of any one of claims 1 to 55, wherein the B7-H4-ADC comprises the following structure: (a) or (b) wherein Ab is the anti-B7-H4 antibody, and wherein p is the vcMMAE:antibody ratio. The method of claim 56 or 57, wherein p is about 1 to about 8. The method of claim 58, wherein p is approximately 4. The method of any one of claims 1 to 59, wherein the anti-B7-H4 antibody is a fully human antibody. The method of any one of claims 1 to 60, wherein the anti-B7-H4 antibody is an IgG1 monoclonal antibody. The method of any one of claims 1 to 61, wherein the B7-H4-ADC is within a heterogeneous population of B7-H4-ADCs, wherein the anti-B7-H4 antibodies contained within the heterogeneous population of B7-H4-ADCs exhibit variable post-translational modifications. The method of claim 62, wherein in at least 50%, 60%, 70%, 80%, 90% or 95% of the anti-B7-H4 antibodies comprised in the heterogeneous B7-H4-ADC population: (i) the C-terminal lysine residue is removed from both heavy chains; (ii) the N-terminal glutamate of each heavy chain is cyclized to pyroglutamate; and/or (iii) the consensus glycosylation site at Asn300 of each heavy chain is predominantly occupied by ditentacled, core-fucosylated glycans without a terminal galactose residue. The method of any one of claims 1 to 63, wherein the B7-H4-ADC is administered as a monotherapy. The method of any one of claims 1 to 63, wherein the method further comprises administering to the individual about 400 mg of pembrolizumab once every 6 weeks (Q6W). The method of any one of claims 1 to 63, wherein the method further comprises administering to the individual about 200 mg of pembrolizumab once every 3 weeks (Q3W). The method of claim 65 or 66, wherein the pembrolizumab is administered starting on day 1. The method of any one of claims 65 to 67, wherein the pembrolizumab is administered intravenously (IV).