Anti-αVβ6 antibodies and antibody-drug conjugates and their use in the treatment of cancer

Abstract

Methods and compositions are provided for treating solid tumors, such as non-small cell lung cancer, head and neck cancer, breast cancer, esophageal cancer, ovarian cancer, skin cancer, pancreatic cancer, bladder cancer, cervical cancer, and gastric cancer, in a subject, such as by administering antibodies and antibody-drug conjugates that bind to alpha-v beta-6 (αvβ6). Articles of manufacture and compositions comprising the antibodies and antibody-drug conjugates that bind to αvβ6 for use in treating solid tumors (e.g., non-small cell lung cancer, head and neck cancer, breast cancer, esophageal cancer, ovarian cancer, skin cancer, pancreatic cancer, bladder cancer, cervical cancer, and gastric cancer) are also provided. [Figure 1] TIFF2025537099000051.tif76157

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63 / 422,098, filed November 3, 2022, and U.S. Provisional Application No. 63 / 457,205, filed April 5, 2023, each of which is incorporated by reference in its entirety for all purposes.

[0002] Sequence Listing Reference This application contains an electronic sequence listing in the file named AVB6-00412PC_Sequence_Listing, created on October 6, 2023, and containing 11 Kb, which is incorporated herein by reference.

[0003] The present invention relates to methods and compositions for treating solid tumors, such as non-small cell lung cancer, head and neck cancer, breast cancer, esophageal cancer, ovarian cancer, skin cancer, pancreatic cancer, bladder cancer, cervical cancer, and gastric cancer, in a subject, such as by administering antibodies and antibody-drug conjugates that bind to alpha-v beta-6 (αvβ6). [Background technology]

[0004] αvβ6, also known as alpha-v beta-6, is a cell adhesion receptor that binds to extracellular matrix proteins such as fibronectin. αvβ6 is composed of alpha v and beta 6 subunits and is upregulated in multiple cancers, including non-small cell lung cancer (NSCLC).

[0005] Subjects with metastatic or unresectable solid tumor malignancies who have disease that has relapsed or is refractory to all standard of care therapies, or who have disease for which current therapies are not believed to be providing benefit, i.e., who have exhausted all standard of care treatments, are in need of new treatment options that have the potential to delay the development of new metastatic lesions and / or control or reduce the disease burden. Summary of the Invention [Problem to be solved by the invention]

[0006] The present invention fulfills the need for improved treatment of solid tumors such as non-small cell lung cancer, head and neck cancer, breast cancer, esophageal cancer, ovarian cancer, skin cancer, pancreatic cancer, bladder cancer, cervical cancer, and gastric cancer by providing highly specific and effective anti-αvβ6 antibody-drug conjugates.

[0007] All references cited herein, including patent applications, patent publications, and scientific literature, are incorporated herein by reference in their entirety, to the same extent as if each individual reference was specifically and individually indicated to be incorporated by reference. [Means for solving the problem]

[0008] 1. A method of treating a solid tumor in a subject, comprising administering to the subject an antibody-drug conjugate or antigen-binding fragment thereof that binds to alpha-v beta-6 (αvβ6), conjugated to monomethyl auristatin, or a functional analogue or functional derivative thereof, wherein the antibody-drug conjugate is administered at a dose ranging from about 0.7 mg / kg to about 2.5 mg / kg of the subject's body weight, and wherein the anti-αvβ6 antibody or antigen-binding fragment of the antibody-drug conjugate comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region is: (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1; (ii) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 2; and (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 3 and the light chain variable region comprises: (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 4; (ii) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and (iii) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 6 Provided herein are methods comprising: In some embodiments, the anti-αvβ6 antibody or antigen-binding fragment thereof of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO:7, and a light chain variable region comprising an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO:8. In some embodiments, the anti-αvβ6 antibody or antigen-binding fragment thereof of the antibody-drug conjugate comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:7, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:8. In some embodiments, the anti-αvβ6 antibody or antigen-binding fragment thereof of the antibody-drug conjugate comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:9, and a light chain comprising the amino acid sequence of SEQ ID NO:10. In some embodiments, the monomethyl auristatin is monomethyl auristatin E (MMAE). In some embodiments, the anti-αvβ6 antibody or antigen-binding fragment thereof of the antibody-drug conjugate is a monoclonal antibody or monoclonal antigen-binding fragment thereof. In some embodiments, the antibody-drug conjugate further comprises a linker between the anti-αvβ6 antibody or antigen-binding fragment thereof and the monomethyl auristatin. In some embodiments, the linker is a cleavable peptide linker. In some embodiments, the cleavable peptide linker has the formula: -MC-vc-PAB-, wherein: a) MC is

[0009] [ka] and b) vc is the dipeptide valine-citrulline; c) PAB is

[0010] [ka] In some embodiments, the linker is attached to a sulfhydryl residue of an anti-αvβ6 antibody obtained by partial or complete reduction of the anti-αvβ6 antibody or antigen-binding fragment thereof. In some embodiments, the linker is attached to monomethyl auristatin E (MMAE), and the antibody-drug conjugate has the following structure:

[0011] [ka] where p is a number between 1 and 8, S represents a sulfhydryl residue of an anti-αvβ6 antibody, and Ab refers to an anti-αvβ6 antibody or antigen-binding fragment thereof. In some embodiments, the average value of p in a population of antibody-drug conjugates is about 4. In some embodiments, the dose is about 0.8 mg / kg, about 1.0 mg / kg, about 1.2 mg / kg, about 1.25 mg / kg, about 1.5 mg / kg, about 1.8 mg / kg, about 2.0 mg, or about 2.4 mg / kg of subject body weight. In some embodiments, the dose is 0.8 mg / kg, 1.0 mg / kg, 1.2 mg / kg, 1.25 mg / kg, 1.5 mg / kg, 1.8 mg / kg, 2.0 mg, or 2.4 mg / kg of subject body weight. In some embodiments, the dose is 1.8 mg / kg of subject body weight. In some embodiments, the dose is 1.25 mg / kg of subject body weight. In some embodiments, the dose is 1.5 mg / kg of subject body weight. In some embodiments, the subject body weight is the subject's ideal body weight (IBW). In some embodiments, the subject body weight is the subject's adjusted ideal body weight (AIBW). In some embodiments, the antibody-drug conjugate is administered about once every week, about once every two weeks, about once every three weeks, or about twice every three weeks. In some embodiments, the antibody-drug conjugate is administered about once every week. In some embodiments, the antibody-drug conjugate is administered about once every two weeks. In some embodiments, the antibody-drug conjugate is administered at a dose of 1.8 mg / kg of subject body weight about once every two weeks. In some embodiments, the antibody-drug conjugate is administered at a dose of 1.5 mg / kg of subject body weight about once every two weeks. In some embodiments, the antibody-drug conjugate is administered about once every three weeks. In some embodiments, the antibody-drug conjugate is administered about once every week for two consecutive weeks, followed by a rest period of about one week during which the antibody-drug conjugate is not administered, so that each cycle time, including the rest period, is about 21 days. In some embodiments, the antibody-drug conjugate is administered on days 1 and 8, but not on day 15, of each 21-day cycle.In some embodiments, the antibody-drug conjugate is administered approximately once per week for two consecutive weeks, followed by a rest period of approximately one week during which the antibody-drug conjugate is not administered, such that each cycle time, including the rest period, is approximately 21 days, and the antibody-drug conjugate is administered at a dose of 1.25 mg / kg of subject body weight. In some embodiments, the antibody-drug conjugate is administered approximately once per week for two consecutive weeks, followed by a rest period of approximately one week during which the antibody-drug conjugate is not administered, such that each cycle time, including the rest period, is approximately 21 days, and the antibody-drug conjugate is administered at a dose of 1.5 mg / kg of subject body weight. In some embodiments, the subject has previously been treated for a solid tumor with one or more therapeutic agents but has failed to respond to treatment, relapsed after treatment, or experienced disease progression during treatment, and the one or more therapeutic agents are not an antibody-drug conjugate. In some embodiments, the solid tumor is locally advanced or metastatic. In some embodiments, the solid tumor is selected from the group consisting of lung cancer, head and neck cancer, breast cancer, esophageal cancer, gastroesophageal junction cancer, ovarian cancer, peritoneal cancer, or fallopian tube cancer, skin cancer, pancreatic cancer, bladder cancer, cervical cancer, and gastric cancer. In some embodiments, the lung cancer is non-small cell lung cancer. In some embodiments, the non-small cell lung cancer is squamous cell carcinoma. In some embodiments, the non-small cell lung cancer is non-squamous cell carcinoma. In some embodiments, the solid tumor is lung cancer, and the lung cancer does not have a known epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) mutation. In some embodiments, the solid tumor is lung cancer, and the lung cancer has a known epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) mutation. In some embodiments, the solid tumor is lung cancer, and the subject has received prior platinum-based therapy and prior therapy with a PD-1 / PD-L1 inhibitor. In some embodiments, the solid tumor is lung cancer, and the subject has not received prior therapy with a taxane. In some embodiments, the head and neck cancer is head and neck squamous cell carcinoma. In some embodiments, the solid tumor is head and neck cancer and the subject has received prior platinum-based therapy and prior therapy with a PD-1 / PD-L1 inhibitor.In some embodiments, the breast cancer is HER2-negative breast cancer. In some embodiments, the solid tumor is breast cancer, and the subject has received one or more prior lines of therapy for breast cancer. In some embodiments, the one or more prior lines of therapy included a taxane administered as a single agent or in combination with a different agent. In some embodiments, the esophageal cancer is esophageal squamous cell carcinoma. In some embodiments, the solid tumor is esophageal cancer, and the subject has received prior platinum-based chemotherapy. In some embodiments, the esophageal cancer is esophageal adenocarcinoma. In some embodiments, the gastroesophageal junction cancer is gastroesophageal junction adenocarcinoma. In some embodiments, the subject has received prior platinum-based chemotherapy. In some embodiments, the ovarian cancer is high-grade serous epithelial ovarian cancer. In some embodiments, the skin cancer is cutaneous squamous cell carcinoma. In some embodiments, the solid tumor is skin cancer, and the subject has received prior therapy with a PD-1 / PD-L1 inhibitor. In some embodiments, the pancreatic cancer is exocrine pancreatic adenocarcinoma. In some embodiments, the solid tumor is advanced cancer. In some embodiments, the advanced cancer is stage 3 or stage 4 cancer. In some embodiments, the advanced cancer is metastatic cancer. In some embodiments, the route of administration of the antibody-drug conjugate is intravenous. 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 αvβ6. In some embodiments, the subject experiences an improvement in one or more therapeutic effects after administration of the antibody-drug conjugate compared to baseline. In some embodiments, the one or more therapeutic effects are selected from the group consisting of size of a tumor derived from the cancer, objective response rate, duration of response, time to response, progression-free survival, and overall survival.In some embodiments, the size of a tumor derived from the cancer is reduced by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, or at least about 80% compared to the size of a tumor derived from the cancer before administration of the antibody-drug conjugate. In some embodiments, the objective response rate is 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%. In some embodiments, the subject exhibits progression-free survival of at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 18 months, at least about 2 years, at least about 3 years, at least about 4 years, or at least about 5 years after administration of the antibody-drug conjugate. In some embodiments, 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 2 years, at least about 3 years, at least about 4 years, or at least about 5 years after administration of the antibody-drug conjugate.In some embodiments, the duration of response to the antibody-drug conjugate 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 2 years, at least about 3 years, at least about 4 years, or at least about 5 years after administration of the antibody-drug conjugate. In some embodiments, the subject has one or more adverse events and is further administered an additional therapeutic agent to eliminate or reduce the severity of the one or more adverse events. In some embodiments, the subject is at risk of developing one or more adverse events and is further administered an additional therapeutic agent to prevent or reduce the severity of the one or more adverse events. In some embodiments, the antibody-drug conjugate is administered as monotherapy. In some embodiments, the method further comprises administering one or more additional therapeutic agents to the subject. In some embodiments, the one or more additional therapeutic agents is a checkpoint inhibitor. In some embodiments, the checkpoint inhibitor is a PD-1 inhibitor or a PD-L1 inhibitor. In some embodiments, the PD-1 inhibitor is an anti-PD-1 antibody. In some embodiments, the anti-PD-1 antibody is pembrolizumab or a biosimilar thereof. In some embodiments, pembrolizumab or a biosimilar thereof is administered at a dose of about 200 mg. In some embodiments, pembrolizumab or a biosimilar thereof is administered about once every three weeks. In some embodiments, pembrolizumab or a biosimilar thereof is administered at a dose of about 400 mg. In some embodiments, pembrolizumab or a biosimilar thereof is administered about once every six weeks. In some embodiments, the route of administration of pembrolizumab or a biosimilar thereof is intravenous. In some embodiments, prior to treatment, the tumor comprises one or more cells that express PD-L1. In some embodiments, the subject has a tumor that expresses PD-L1 with a TPS of ≧1%.In some embodiments, the subject has a tumor that expresses PD-L1 with a TPS of ≧20%. In some embodiments, the subject has a tumor that expresses PD-L1 with a TPS of ≧50%. In some embodiments, the subject has a tumor that expresses PD-L1 with a CPS of ≧1. In some embodiments, the subject has a tumor that expresses PD-L1 with a CPS of ≧20. In some embodiments, the one or more additional therapeutic agents is a platinum-based agent. In some embodiments, the platinum-based agent is carboplatin or cisplatin. In some embodiments, the first dose of the antibody-drug conjugate is administered prior to the administration of the first dose of the one or more additional therapeutic agents. In some embodiments, the first dose of the antibody drug conjugate is administered at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 2 months, at least 3 months, or at least 4 days after the administration of the first dose of the one or more additional therapeutic agents. In some embodiments, the antibody-drug conjugate is administered at least one month, at least five months, or at least six months prior to administration. In some embodiments, the subject is a human. In some embodiments, the antibody-drug conjugate is in a pharmaceutical composition comprising the antibody-drug conjugate and a pharmaceutically acceptable carrier.

[0012] (a) an antibody-drug conjugate that binds to αvβ6, comprising an anti-αvβ6 antibody or antigen-binding fragment thereof conjugated to monomethyl auristatin, or a functional analog or functional derivative thereof, in a dosage ranging from about 0.7 mg / kg to about 2.5 mg / kg; and (b) Instructions for using the antibody drug conjugate according to any of the embodiments provided herein. Also provided herein is a kit comprising:

[0013] Also provided herein is the use of an antibody-drug conjugate that binds to αvβ6 for the manufacture of a medicament for use in any of the embodiments provided herein, wherein the antibody-drug conjugate comprises an anti-αvβ6 antibody or antigen-binding fragment thereof conjugated to monomethyl auristatin, or a functional analogue or functional derivative thereof.

[0014] Also provided herein is an antibody-drug conjugate that binds to αvβ6 for use in any of the embodiments provided herein, comprising an anti-αvβ6 antibody or antigen-binding fragment thereof conjugated to monomethyl auristatin, or a functional analog or functional derivative thereof. [Brief explanation of the drawings]

[0015] [Figure 1] Graph showing best percentage change from baseline in target lesion SoD (sum of diameters) per RECIST v1.1 in the NSCLC subset of the dose escalation study. Q3W = 1 dose every 3 weeks. 2Q3W = 2 doses every 3 weeks. 2Q4W = 2 doses every 4 weeks. Q1W = 1 dose every week. [Figure 2] Graph showing best percentage change from baseline in target lesion SoD per RECIST v1.1 in the esophageal cancer (EC) subset of the dose escalation study. Q3W = 1 dose every 3 weeks. 2Q3W = 2 doses every 3 weeks. 2Q4W = 2 doses every 4 weeks. Q1W = 1 dose every week. [Figure 3] Graph showing best percentage change from baseline in target lesion SoD per RECIST v1.1 in the HNSCC subset of the dose escalation study. 2Q3W = 2 doses every 3 weeks. 2Q4W = 2 doses every 4 weeks. Q1W = 1 dose every week. [Figure 4]

[0023] Figure 1 shows the best percentage change from baseline in target lesion SoD per RECIST v1.1 in the HNSCC 2Q3W subset of the dose expansion study. 2Q3W = 2 doses every 3 weeks. [Figure 5A] Kaplan-Meier plot showing percent survival over time, a survival endpoint, for mice implanted subcutaneously with syngeneic Renca cells engineered to express human integrin beta-6, resulting in a four-fold tumor expansion. [Figure 5B]

[0023] Figure 1 is a series of graphs showing tumor growth over time in individual mice treated with a murine surrogate of SGN-B6A (mSGN-B6A), a murine anti-PD-1 antibody (anti-mPD1), or both. All test articles were dosed once weekly for three doses. Black triangles indicate the dosing schedule for mSGN-B6A. Blue / gray triangles indicate the dosing schedule for anti-mPD1. DETAILED DESCRIPTION OF THE INVENTION

[0016] Detailed Description I. Definition In order that this disclosure may be more readily understood, certain terms are first defined. As used in this application, unless otherwise expressly provided herein, each of the following terms shall have the meaning set forth below. Additional definitions are set forth throughout this application.

[0017] The term "and / or" as used herein should be taken as a specific disclosure of each of the two specified attributes or components, with or without the other. Thus, the term "and / or" used herein in phrases such as "A and / or B" is intended to include "A and B," "A or B," "A" (alone), and "B" (alone). Similarly, the term "and / or" used in phrases such as "A, B, and / or C" is intended to encompass the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0018] It is understood that aspects and embodiments of the invention described herein include "comprising," "consisting of," and "consisting essentially of" aspects and embodiments.

[0019] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art in the technical field to which this disclosure relates.For example, Concise Dictionary of Biomedicine and Molecular Biology, Juo, Pei-Show, 2nd Edition, 2002, CRC Press; The Dictionary of Cell and Molecular Biology, 3rd Edition, 1999, Academic Press; and Oxford Dictionary of Biochemistry And Molecular Biology, revised edition, 2000, Oxford University Press provide those skilled in the art with a general dictionary for many of the terms used in this disclosure.

[0020] Units, prefixes, and symbols are shown in their Systeme International de Unites (SI) accepted form. Numerical ranges include the numerical values ​​that define the range. The headings provided herein are not limitations of the various aspects of this disclosure, which may be had by reference to this specification in its entirety. Accordingly, the terms defined immediately below are more fully defined by reference to this specification in its entirety.

[0021] The terms "αvβ6," "avb6," "alpha-v beta-6," or "β6" are used interchangeably herein and, unless otherwise specified, include any variants, isoforms, and species homologs of human αvβ6 that are generally expressed by cells or expressed on cells transfected with the αvβ6 gene.

[0022] The term "immunoglobulin" refers to a class of structurally related glycoproteins consisting of two pairs of polypeptide chains, one pair of light (L) low molecular weight chains and one pair of heavy (H) chains, all four interconnected by disulfide bonds. The structure of immunoglobulins has been well characterized. See, e.g., Fundamental Immunology, Chapter 7 (Paul, W., ed., 2nd ed., Raven Press, NY (1989)). Briefly, each heavy chain typically comprises a heavy chain variable region (referred to herein as V H or abbreviated VH) and a heavy chain constant region (C H The heavy chain constant region is typically composed of C H 1. C H 2, and C H Heavy chains are generally interconnected via disulfide bonds in the so-called "hinge region." Each light chain typically contains a light chain variable region (referred to herein as V L or VL) and a light chain constant region (C L The light chain constant region is typically composed of C LCL is composed of one domain, CL. CL can be of the κ (kappa) or λ (lambda) isotype. The terms "constant domain" and "constant region" are used interchangeably herein. Immunoglobulins can be derived from any of the commonly known isotypes, including, but not limited to, IgA, secretory IgA, IgG, and IgM. IgG subclasses are also well known to those skilled in the art and include, but are not limited to, human IgG1, IgG2, IgG3, and IgG4. "Isotype" refers to the antibody class or subclass (e.g., IgM or IgG1) encoded by the heavy chain constant region gene.

[0023] The term "variable region" or "variable domain" refers to the domain of an antibody heavy or light chain that is involved in binding the antibody to an antigen. The variable regions of the heavy and light chains of a native antibody (V H and V L ) can be further subdivided into regions of hypervariability, also termed complementarity-determining regions (CDRs) (or hypervariable regions that may be hypervariable in sequence and / or in the form of structurally defined loops), interspersed with more conserved regions termed framework regions (FRs). The terms "complementarity-determining region" and "CDR," synonymous with "hypervariable region" or "HVR," are known in the art to refer to non-contiguous sequences of amino acids within an antibody variable region that confer antigen specificity and / or binding affinity. Generally, there are three CDRs in each heavy chain variable region (CDR-H1, CDR-H2, CDR-H3), and three CDRs in each light chain variable region (CDR-L1, CDR-L2, CDR-L3). "Framework region" and "FR" are known in the art to refer to the non-CDR portions of heavy and light chain variable regions. Generally, each full-length heavy chain variable region has four FRs (FR-H1, FR-H2, FR-H3, and FR-H4), and each full-length light chain variable region has four FRs (FR-L1, FR-L2, FR-L3, and FR-L4). H and V LWithin, the three CDRs and four FRs are typically arranged from the amino terminus to the carboxy terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4 (see also Chothia and Lesk J. Mot. Biol., 195, 901-917 (1987)).

[0024] The term "antibody" (Ab) in the context of the present invention refers to an immunoglobulin molecule, a fragment of an immunoglobulin molecule, or a derivative of either thereof, that has the ability to specifically bind to an antigen under typical physiological conditions with a half-life of a significant period, such as at least about 30 minutes, at least about 45 minutes, at least about 1 hour (h), at least about 2 hours, at least about 4 hours, at least about 8 hours, at least about 12 hours (h), about 24 hours or more, about 48 hours or more, about 3, 4, 5, 6, 7 days or more, etc., or any other relevant functionally defined period (such as a period sufficient to induce, promote, enhance, and / or modulate a physiological response associated with antibody binding to the antigen and / or a period sufficient for the antibody to recruit effector activity). The variable regions of the heavy and light chains of an immunoglobulin molecule contain binding domains that interact with antigen. The constant region of an antibody (Ab) can mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (such as effector cells) and components of the complement system, such as C1q, the first component in the classical pathway of complement activation. Antibodies can also be bispecific antibodies, diabodies, multispecific antibodies, or similar molecules.

[0025] As used herein, the term "monoclonal antibody" refers to a preparation of antibody molecules recombinantly produced with a single primary amino acid sequence and generated from murine B-cell fusion. A monoclonal antibody composition displays a single binding specificity and affinity for a particular epitope. Thus, the term "human monoclonal antibody" refers to an antibody displaying a single binding specificity having variable and constant regions derived from human germline immunoglobulin sequences. Human monoclonal antibodies can be produced by hybridomas comprising B cells obtained from a transgenic or transchromosomal non-human animal, such as a transgenic mouse, whose genome contains human heavy chain and light chain transgenes, fused to an immortalized cell.

[0026] An "isolated antibody" refers to an antibody that is substantially free of other antibodies with different antigen specificities (e.g., an isolated antibody that specifically binds to αvβ6 is substantially free of antibodies that specifically bind to antigens other than αvβ6). However, an isolated antibody that specifically binds to αvβ6 may have cross-reactivity to other antigens, such as αvβ6 molecules from different species. Furthermore, an isolated antibody may be substantially free of other cellular material and / or chemicals. In one embodiment, an isolated antibody comprises an antibody conjugate attached to another agent (e.g., a small molecule drug). In some embodiments, an isolated anti-αvβ6 antibody comprises a conjugate of an anti-αvβ6 antibody and a small molecule drug (e.g., MMAE or MMAF).

[0027] A "human antibody" (HuMAb) refers to an antibody having variable regions in which both the FRs and CDRs are derived from human germline immunoglobulin sequences. Furthermore, if the antibody contains a constant region, the constant region also is derived from a human germline immunoglobulin sequence. The human antibodies of the present disclosure may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo). However, as used herein, the term "human antibody" is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences. The terms "human antibody" and "fully human antibody" are used interchangeably.

[0028] As used herein, the term "humanized antibody" refers to a genetically engineered non-human antibody containing a human antibody constant domain and a non-human variable domain that has been modified to contain a high level of sequence homology with the human variable domain. This can be achieved by grafting the six non-human antibody complementarity-determining regions (CDRs) that together form an antigen-binding site into homologous human acceptor framework regions (FRs) (see WO92 / 22653 and EP0629240). To fully reconstitute the binding affinity and specificity of the parent antibody, substitution (backmutation) of framework residues from the parent antibody (i.e., non-human antibody) into the human framework regions may be required. Structural homology modeling can help identify amino acid residues in the framework regions that are important for the binding properties of the antibody. Thus, a humanized antibody can contain non-human CDR sequences, primarily human framework regions optionally containing one or more amino acid backmutations to non-human amino acid sequences, and a fully human constant region. Optionally, additional amino acid modifications, not necessarily back mutations, can be applied to obtain humanized antibodies with favorable characteristics such as affinity and biochemical properties.

[0029] As used herein, the term "chimeric antibody" refers to an antibody whose variable region is derived from a non-human species (e.g., from a rodent) and whose constant region is derived from a different species, such as human. Chimeric antibodies can be produced by antibody engineering. "Antibody engineering" is a general term used to refer to various types of antibody modification, a process well known to those skilled in the art. In particular, chimeric antibodies can be produced using standard DNA techniques as described in Sambrook et al., 1989, Molecular Cloning: A Laboratory Manual, New York: Cold Spring Harbor Laboratory Press, Chapter 15. Thus, chimeric antibodies can be recombinant antibodies engineered genetically or enzymatically. Creating chimeric antibodies is within the knowledge of those skilled in the art; therefore, the production of chimeric antibodies according to the present invention can be performed by methods other than those described herein. Chimeric monoclonal antibodies for therapeutic applications are developed to reduce antibody immunogenicity. They typically contain a non-human (e.g., murine) variable region specific for an antigen of interest, and human constant antibody heavy and light chain domains. The term "variable region" or "variable domain" as used in the context of a chimeric antibody refers to the region comprising the CDRs and framework regions of both the heavy and light chains of an immunoglobulin.

[0030] "Anti-antigen antibody" refers to an antibody that binds to an antigen. For example, an anti-αvβ6 antibody is an antibody that binds to the antigen αvβ6.

[0031] An "antigen-binding portion" or "antigen-binding fragment" of an antibody refers to one or more fragments of an antibody that retain the ability to specifically bind to the antigen bound by the whole antibody. Examples of antibody fragments (e.g., antigen-binding fragments) include, but are not limited to, Fv, Fab, Fab', Fab'-SH, F(ab')2; diabodies; linear antibodies; single-chain antibody molecules (e.g., scFv); and multispecific antibodies formed from antibody fragments. Papain digestion of an antibody produces two identical antigen-binding fragments called "Fab" fragments, each with a single antigen-binding site, and a remaining "Fc" fragment, the name of which reflects its ability to readily crystallize. Pepsin treatment yields an F(ab')2 fragment that has two antigen-binding sites and is still capable of cross-linking antigen.

[0032] "Percent sequence identity (%)" to a reference polypeptide sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical to those in the reference polypeptide sequence, after aligning the sequences and introducing gaps as necessary to achieve the maximum percent sequence identity, without considering any conservative substitutions as part of the sequence identity. Alignment for determining percent amino acid sequence identity can be achieved in a variety of ways within the skill of the art, for example, using publicly available computer software such as BLAST, BLAST-2, SnapGene Align, or ClustalW BioEdit software. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms required to achieve maximum alignment across the entire length of the sequences being compared. For example, the percent sequence identity of a given amino acid sequence A to, with, or relative to a given amino acid sequence B (which can alternatively be expressed as a given amino acid sequence A having or containing a certain percent sequence identity to, with, or relative to a given amino acid sequence B) is calculated as follows: 100 times the fraction X / Y where X is the number of amino acid residues scored as identical matches by the program's sequences in its alignment of A and B, and where Y is the total number of amino acid residues in B. It is understood that if the length of amino acid sequence A is not equal to the length of amino acid sequence B, then the % sequence identity of A to B will not equal the % sequence identity of B to A.

[0033] As used herein, the terms "binding," "bind," or "specifically bind" in the context of antibody binding to a predetermined antigen typically refer to a specific binding activity of about 10, as determined, for example, by biolayer interferometry (BLI) technology on an Octet HTX instrument using the antibody as the ligand and the antigen as the analyte. -6 M or less, e.g. 10 -7 M or less, for example, about 10 -8 M or less, for example, about 10 -9 M or less, about 10 -10 M or less, or about 10 -11 K below M D and the antibody binds with an affinity equivalent to its K for binding to a nonspecific antigen other than the given antigen or a closely related antigen (e.g., BSA, casein). D K less than 1 / 10, for example less than 1 / 100, for example less than 1 / 1,000, for example less than 1 / 10,000, for example less than 1 / 100,000 D binds to a given antigen with an affinity equivalent to the K D The lower the amount of antibody D Therefore, the K D If the K of binding to the antigen is very low, D is the K for nonspecific antigen binding D The amount may be at least 10,000 times lower (ie, the antibody is highly specific).

[0034] As used herein, "K D The term "(M)" refers to the dissociation equilibrium constant for a particular antibody-antigen interaction. As used herein, affinity and K Dis inversely proportional, i.e., the higher the affinity, the lower the K D A lower affinity is intended to refer to a higher K D is intended to refer to

[0035] The term "ADC" refers to an antibody-drug conjugate, which in the context of the present invention refers to an anti-αvβ6 antibody coupled to a drug moiety (e.g., MMAE or MMAF) as described in this application.

[0036] The abbreviations "vc" and "val-cit" refer to the dipeptide valine-citrulline.

[0037] The abbreviation VKG refers to the tripeptide linker valine-lysine-glycine.

[0038] The abbreviation "PAB" stands for self-immolating spacer:

[0039] [ka] Refers to...

[0040] The abbreviation "MC" stands for stretcher maleimidocaproyl:

[0041] [ka] Refers to...

[0042] The abbreviation "MP" stands for maleimidopropionyl stretcher:

[0043] [ka] Refers to...

[0044] As used herein, a "PEG unit" refers to an organic moiety composed of repeating ethylene-oxy subunits (PEG or PEG subunits), which may be polydisperse, monodisperse, or discrete (i.e., having a discrete number of ethylene-oxy subunits). Polydisperse PEGs are a heterogeneous mixture of sizes and molecular weights, while monodisperse PEGs are typically purified from a heterogeneous mixture and therefore provide a single chain length and molecular weight. Preferred PEG units include discrete PEGs, which are compounds synthesized in a stepwise manner and without a polymerization process. Discrete PEGs provide a single molecule with a defined and specified chain length.

[0045] The PEG units provided herein comprise one or more polyethylene glycol chains, each composed of one or more ethyleneoxy subunits covalently attached to one another. The polyethylene glycol chains can be linked together, for example, in a linear, branched, or star-shaped configuration. Typically, at least one of the polyethylene glycol chains prior to incorporation into the camptothecin conjugate is derivatized at one end with an alkyl moiety substituted with an electrophilic group for covalent attachment to the carbamate nitrogen of the methylene carbamate unit (i.e., representing an example of R). Typically, the terminal ethyleneoxy subunit in each polyethylene glycol chain not involved in covalent attachment to the remainder of the linker unit is modified with a PEG capping unit, typically an optionally substituted alkyl such as -CH3, CH2CH3, or CH2CH2CO2H. A preferred PEG unit has a single polyethylene glycol chain having 2 to 24 -CH2CHO- subunits covalently attached in series and terminated at one end with a PEG capping unit.

[0046] "Cancer" refers to a broad group of diverse diseases characterized by the uncontrolled growth of abnormal cells in the body. "Cancer" or "cancerous tissue" can include tumors. Unregulated cell division and growth lead to the formation of malignant tumors that can invade nearby tissues and metastasize to distant parts of the body through the lymphatic system or bloodstream. After metastasis, the distant tumor can be said to "originate" from the pre-metastatic tumor.

[0047] The term "antibody-dependent cellular cytotoxicity" (ADCC) is a mechanism for inducing cell death that relies on the interaction of antibody-coated target cells with immune cells (also called effector cells) possessing lytic activity. Such effector cells include natural killer cells, monocytes / macrophages, and neutrophils. Effector cells attach to the Fc effector domain of Ig bound to target cells via their antigen-binding sites. Death of antibody-coated target cells occurs as a result of effector cell activity.

[0048] The term "antibody-dependent cellular phagocytosis" or ADCP refers to the process by which antibody-coated cells are internalized in whole or in part by phagocytic immune cells (e.g., macrophages, neutrophils, and dendritic cells) that bind to the Fc effector domain of Ig.

[0049] The term "complement-dependent cytotoxicity" or CDC refers to a mechanism for inducing cell death in which the Fc effector domain of an antibody bound to a target activates a series of enzymatic reactions, ultimately leading to the formation of holes in the target cell membrane. Typically, antigen-antibody complexes, such as those on antibody-coated target cells, bind to and activate the 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 target cell surface, which promotes ADCC by binding to complement receptors (e.g., CR3) on leukocytes.

[0050] A "cytostatic effect" refers to the inhibition of cell proliferation. A "cytostatic agent" refers to an agent that has a cytostatic effect on cells, thereby inhibiting the growth and / or expansion of specific cell subsets. The cytostatic agent may be conjugated to the antibody or administered in combination with the antibody.

[0051] "Treatment" or "therapy" of a subject refers to any type of intervention or process performed on a subject, or the administration of an active agent to a subject, for the purpose of reversing, alleviating, ameliorating, inhibiting, slowing, or preventing the onset, progression, development, severity, or recurrence of symptoms, complications, conditions, or biochemical manifestations associated with a disease. In some embodiments, the disease is cancer.

[0052] A "subject" includes any human or non-human animal. The term "non-human animal" includes, but is not limited to, vertebrates such as non-human primates, sheep, dogs, and rodents such as mice, rats, and guinea pigs. In some embodiments, the subject is a human. The terms "subject," "patient," and "individual" are used interchangeably herein.

[0053] An "effective amount" or "therapeutically effective amount" or "therapeutically effective dosage" of a drug or therapeutic agent is any amount of drug that, when used alone or in combination with another therapeutic agent, protects a subject from developing a disease or promotes disease regression as evidenced by a decrease in the severity of disease symptoms, an increase in the frequency and duration of disease symptom-free periods, or prevention of functional impairment or disability due to disease affliction. The ability of a therapeutic agent to promote disease regression can be evaluated using a variety of methods known to skilled practitioners, such as by assaying the activity of the agent in human subjects during clinical trials, in animal model systems predictive of efficacy in humans, or in in vitro assays.

[0054] As an example of treating a tumor, a therapeutically effective amount of an anti-cancer agent inhibits cell growth or tumor growth by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, or at least about 80%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% in treated subjects (e.g., one or more treated subjects) compared to untreated subjects (e.g., one or more untreated subjects). In some embodiments, a therapeutically effective amount of an anti-cancer agent inhibits cell growth or tumor growth by 100% in treated subjects (e.g., one or more treated subjects) compared to untreated subjects (e.g., one or more untreated subjects).

[0055] In other embodiments of the present disclosure, tumor regression may be observed and may last for a period of at least about 20 days, at least about 30 days, at least about 40 days, at least about 50 days, or at least about 60 days.

[0056] A therapeutically effective amount of a drug (e.g., an anti-αvβ6 antibody-drug conjugate) includes a "prophylactically effective amount," which is any amount of drug that, when administered alone or in combination with an anti-cancer drug to a subject at risk of developing cancer (e.g., a subject with a precancerous condition) or a subject at risk of suffering from cancer relapse, inhibits the onset or relapse of cancer. In some embodiments, a prophylactically effective amount completely prevents the onset or relapse of cancer. "Inhibiting" the onset or relapse of cancer means either reducing the likelihood of cancer onset or relapse, or completely preventing the onset or relapse of cancer.

[0057] As used herein, a "subtherapeutic dose" means a dose of a therapeutic compound (e.g., an anti-αvβ6 antibody-drug conjugate) that is lower than the usual or typical dose of the therapeutic compound when administered alone for the treatment of a hyperproliferative disease (e.g., cancer).

[0058] "Immune-related response pattern" refers to the clinical response pattern often observed in cancer patients treated with immunotherapeutic agents that induce cancer-specific immune responses or modify natural immune processes to produce anti-tumor effects.This response pattern is characterized by an initial increase in tumor burden or the appearance of new lesions followed by a beneficial therapeutic effect, which in the evaluation of traditional chemotherapy drugs is classified as disease progression and is synonymous with drug failure.Therefore, proper evaluation of immunotherapeutic agents may require long-term monitoring of the effects of these agents on target diseases.

[0059] By way of example, an "anti-cancer drug" promotes cancer regression in a subject. In some embodiments, a therapeutically effective amount of a drug promotes cancer regression to the point of eliminating the cancer. "Promoting cancer regression" means that administering an effective amount of a drug, alone or in combination with an anti-cancer drug, results in a decrease in tumor growth or size, tumor necrosis, a decrease in the severity of at least one disease symptom, an increase in the frequency and duration of disease symptom-free periods, or prevention of functional impairment or disability due to disease affliction. Additionally, the terms "effective" and "efficacy" with respect to treatment include both pharmacological effectiveness and physiological safety. Pharmacological effectiveness refers to the ability of a drug to promote cancer regression in a patient. Physiological safety refers to the level of toxicity or other adverse physiological effects (side effects) at the cellular, organ, and / or organism level resulting from the administration of a drug.

[0060] "Durable response" refers to a sustained effect on reducing tumor growth after treatment has stopped. For example, the tumor size may remain the same or smaller than the size at the beginning of the administration phase. In some embodiments, the durable response has a duration that is at least the same as the duration of treatment, or at least 1.5, 2.0, 2.5, or 3 times longer than the duration of treatment.

[0061] As used herein, "complete response" or "CR" refers to the disappearance of all target lesions; "partial response" or "PR" refers to at least a 30% reduction in the sum of the longest diameters (SLD) of target lesions, referenced to the baseline SLD; and "stable disease" or "SD" refers to neither a sufficient reduction in target lesions to qualify for PR nor a sufficient increase to qualify for PD, referenced to the smallest SLD since treatment began.

[0062] As used herein, "progression-free survival" or "PFS" refers to the length of time during and after treatment during which the disease being treated (e.g., cancer) does not worsen. Progression-free survival can include the amount of time a patient experiences a complete or partial response, as well as the amount of time a patient experiences stable disease.

[0063] As used herein, "overall response rate" or "ORR" refers to the sum of the complete response (CR) rate and the partial response (PR) rate.

[0064] As used herein, "overall survival" or "OS" refers to the percentage of individuals in a group who may be alive after a particular duration.

[0065] The phrase "pharmaceutically acceptable" indicates that the substance or composition must be chemically and / or toxicologically compatible with the other ingredients of the formulation and / or the mammal being treated therewith.

[0066] As used herein, the phrase "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable organic or inorganic salt of a compound of the present invention. Exemplary salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate "mesylate", ethanesulfonate, benzenesulfonate, p-toluenesulfonate, pamoate (i.e., 4,4'-methylene-bis-(2-hydroxy-3-naphthoic acid)) salts, alkali metal (e.g., sodium and potassium) salts, alkaline earth metal (e.g., magnesium) salts, and ammonium salts. Pharmaceutically acceptable salts may involve the inclusion of another molecule, such as acetate ion, succinate ion, or other counter ion. Counter ion can be any organic or inorganic moiety that stabilizes the charge of parent compound. Furthermore, pharmaceutically acceptable salts may have more than one charged atom in their structure. If multiple charged atoms are part of a pharmaceutically acceptable salt, it may have multiple counter ions. Therefore, a pharmaceutically acceptable salt may have one or more charged atoms and / or one or more counter ions.

[0067] "Administering" or "administration" refers to the physical introduction of a therapeutic agent into a subject using any of a variety of methods and delivery systems known to those skilled in the art. Exemplary routes of administration for anti-αvβ6 antibody-drug conjugates include intravenous, intramuscular, subcutaneous, intraperitoneal, intraspinal, or other parenteral routes of administration, such as injection or infusion (e.g., intravenous infusion). As used herein, the phrase "parenteral administration" refers to modes of administration other than enteral and topical administration, usually by injection, and includes, but is not limited to, intravenous, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal injection and infusion, as well as in vivo electroporation. Therapeutic agents can be administered via non-parenteral routes or orally. Other non-parenteral routes include topical, epidermal, or mucosal routes of administration, e.g., intranasal, intravaginal, rectal, sublingual, or topical. Administration can also be carried out, e.g., once, multiple times, and / or over one or more extended periods of time.

[0068] The terms "baseline" or "baseline value," as used interchangeably herein, may refer to the measurement or characterization of symptoms before administration of a therapy (e.g., an anti-αvβ6 antibody-drug conjugate described herein) or at the start of administration of the therapy. The baseline value may be compared to a reference value to determine the reduction or improvement of symptoms of an αvβ6-related disease (e.g., cancer) contemplated herein. The terms "reference" or "reference value," as used interchangeably herein, may refer to the measurement or characterization of symptoms after administration of a therapy (e.g., an anti-αvβ6 antibody-drug conjugate described herein). The reference value may be measured one or more times during a dosage regimen or treatment cycle, or at the completion of a dosage regimen or treatment cycle. A "reference value" may be an absolute value; a relative value; a value with upper and / or lower limits; a range of values; an average value; a median value; an average value; or a value compared to a baseline value.

[0069] Similarly, a "baseline value" can be an absolute value; a relative value; a value with upper and / or lower limits; a range of values; an average value; a median value; an average value; or a value compared to a baseline value. Reference and / or baseline values ​​can be obtained from one individual, from two different individuals, or from a group of individuals (e.g., a group of 2, 3, 4, 5 or more individuals).

[0070] The term " monotherapy " used herein means that anti-αvβ6 antibody-drug conjugate is the only anticancer drug that is administered to the subject during the treatment cycle.However, other therapeutic agents can be administered to the subject.For example, anti-inflammatory agents or other active substances that are administered to the subject with cancer to treat the symptoms associated with cancer, not the underlying cancer itself, can be administered during the monotherapy period, including inflammation, pain, weight loss and general fatigue.

[0071] As used herein, an "adverse event" (AE) is any unfavorable and generally unintended or undesired sign (including abnormal laboratory findings), symptom, or disease associated with the use of a medical treatment. A medical treatment may have one or more associated AEs, and each AE may have the same or different levels of severity. Reference to a method that can "modify an adverse event" refers to a treatment regime that reduces the incidence and / or severity of one or more AEs associated with the use of a different treatment regime.

[0072] As used herein, a "serious adverse event" or "SAE" is an adverse event that meets one of the following criteria: Fatal or life-threatening (when used in the definition of serious adverse events, "life-threatening" refers to an event in which the patient was at risk of death at the time of the event; it does not refer to an event that could hypothetically have caused death if it had been more severe). · Causes lasting or serious physical impairment or incapacity. ·Congenital anomalies / birth defects. Medically significant, i.e., defined as an event that may endanger the patient or require medical or surgical intervention to prevent one of the outcomes listed above. Medical and scientific judgment must be exercised in determining whether an AE is "medically significant." The following: 1) routine treatment or monitoring of an underlying disease without any worsening of the condition; 2) elective or pre-planned treatment of a pre-existing condition that is unrelated to the indication under study and that has not worsened since the informed consent was signed; and 3) requiring inpatient hospitalization or an extension of an existing hospitalization, except for social reasons and respite care, in the absence of any worsening of the patient's general condition.

[0073] The use of the alternative (e.g., "or") should be understood to mean one, both, or any combination thereof of the alternatives. As used herein, the indefinite article "a" or "an" should be understood to refer to "one or more" of any described or listed components.

[0074] The term "about" or "essentially consisting of" refers to a value or composition that is within an acceptable error range for a particular value or composition as determined by one of ordinary skill in the art, which depends in part on how the value or composition is measured or determined, i.e., the limitations of the measurement system. For example, "about" or "essentially consisting of" can mean within one standard deviation or more than one standard deviation, according to practice in the art. Alternatively, "about" or "essentially consisting of" can mean a range of up to 20%. Furthermore, particularly with respect to biological systems or processes, the term can mean up to one order of magnitude or up to five times the value. When a particular value or composition is provided in this application and claims, unless otherwise specified, the meaning of "about" or "essentially consisting of" should be assumed to be within an acceptable error range for that particular value or composition.

[0075] Reference herein to "about" a value or parameter includes (and describes) embodiments directed to that value or parameter itself. For example, a description that refers to "about X" includes and describes "X."

[0076] The term "combined positive score" or "CPS" as used herein refers to an immunohistochemical method for measuring PD-L1 expression in cancer, such as tumor samples derived from cancer. CPS is the number of PD-L1-stained cells (tumor cells, lymphocytes, macrophages) divided by the total number of viable tumor cells and multiplied by 100. For some therapeutic treatments, a tumor sample is considered to have PD-L1 expression if its CPS is ≥ 1. For example, a CPS of ≥ 1 is required for subjects eligible for certain PD-1 or PD-L1 inhibitor therapy, such as subjects with gastric cancer, cervical cancer, and head and neck squamous cell carcinoma. In some cases, a CPS of ≥ 10 is required for subjects eligible for certain PD-1 or PD-L1 inhibitor therapy, such as subjects with urothelial carcinoma (bladder cancer), esophageal squamous cell carcinoma (ESCC), or triple-negative breast cancer who are being treated with pembrolizumab.

[0077] As used herein, the term "tumor proportion score" or "TPS" refers to an immunohistochemical method for measuring PD-L1 expression in cancer, such as tumor samples derived from cancer. TPS is the percentage of viable tumor cells that exhibit partial or complete membrane staining at any intensity. For some therapeutic treatments, a tumor sample is considered to have low PD-L1 expression if its TPS is ≥ 1%, and high PD-L1 expression if its TPS is ≥ 50%. For example, a TPS of ≥ 1% is required for subjects eligible for certain PD-1 or PD-L1 inhibitor therapies (e.g., pembrolizumab), such as subjects with non-small cell lung cancer. In some cases, a TPS of ≥ 50% is required for subjects eligible for certain PD-1 or PD-L1 inhibitor therapies (e.g., cemiplimab).

[0078] As used herein, the term "ideal body weight" or "IBW" refers to a size descriptor that is independent of total body weight. IBW is an estimate of weight corrected for gender and height, and optionally frame size. IBW can be calculated, for example, using the formula IBW=0.9H-88 (for men) and IBW=0.9H-92 (for women), where H=height in cm. Alternatively, IBW can be calculated, for example, using the following formula: IBW (men)=50 kg+2.3 kg×(height, inches-60); IBW (women)=45.5 kg+2.3 kg×(height, inches-60).

[0079] As used herein, the term "adjusted ideal body weight" or "AIBW" refers to a size descriptor that takes into account gender, total weight, and height. AIBW can be calculated, for example, using the formula AIBW=IBW+0.4(weight in kg−IBW).

[0080] As described herein, any concentration range, percentage range, ratio range, or integer range should be understood to include any integer value within the stated range, and fractions thereof, where appropriate (such as integer tenths and hundredths), unless otherwise indicated.

[0081] Various aspects of the disclosure are described in further detail in the following subsections.

[0082] II. Overview The present invention provides an antibody that specifically binds to αvβ6. The present invention is based in part on the discovery that antibody-drug conjugates, including vcMMAE antibody-drug conjugates, targeted to αvβ6 are particularly effective in killing αvβ6+ expressing cells. αvβ6 has been shown to be expressed in a variety of cancers, including non-small cell lung cancer (NSCLC) (squamous and adenocarcinoma), head and neck cancer (including head and neck squamous cell carcinoma), esophageal cancer, breast cancer (including invasive breast cancer), ovarian cancer, bladder cancer (including urothelial carcinoma), skin cancer (squamous cell carcinoma, i.e., SCC), kidney cancer (including renal clear cell, renal papillary cell, and renal chromophobe cell), cervical cancer, gastric cancer, prostate cancer (including prostate adenocarcinoma), endometrial cancer (including uterine carcinosarcoma and uterine corpus endometrium), rectal adenocarcinoma, thyroid cancer, colon adenocarcinoma, gastric adenocarcinoma, and pancreatic cancer (including pancreatic adenocarcinoma). The present invention provides anti-αvβ6 antibody-drug conjugates that bind to αvβ6 for use in the treatment of non-small cell lung cancer, head and neck cancer (e.g., head and neck squamous cell carcinoma), breast cancer (e.g., advanced HER2-negative breast cancer), esophageal cancer (e.g., esophageal squamous cell carcinoma), ovarian cancer (e.g., high-grade serous epithelial ovarian cancer), skin cancer (e.g., cutaneous squamous cell carcinoma), pancreatic cancer (e.g., exocrine pancreatic adenocarcinoma), bladder cancer, cervical cancer, and gastric cancer. In some embodiments, the cancer is non-small cell lung cancer. In some embodiments, the non-small cell lung cancer is squamous cell carcinoma. In some embodiments, the non-small cell lung cancer is non-squamous cell carcinoma. In some embodiments, the cancer is head and neck cancer (e.g., head and neck squamous cell carcinoma). In some embodiments, the cancer is breast cancer (e.g., advanced HER2-negative breast cancer). In some embodiments, the cancer is esophageal cancer (e.g., esophageal squamous cell carcinoma). In some embodiments, the cancer is ovarian cancer (such as high-grade serous epithelial ovarian cancer). In some embodiments, the cancer is skin cancer (such as cutaneous squamous cell carcinoma). In some embodiments, the cancer is pancreatic cancer (such as exocrine pancreatic adenocarcinoma). In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is cervical cancer. In some embodiments, the cancer is gastric cancer.

[0083] III.Target molecule Unless otherwise indicated, αvβ6 refers to human αvβ6. An exemplary β6 human sequence is assigned GenBank accession number AAA36122. An exemplary αv human sequence is assigned NCBI NP_002201.1.

[0084] IV. Antibodies of the Invention Generally, the anti-αvβ6 antibodies of the present disclosure bind to αvβ6, e.g., human αvβ6, and exert cytostatic and cytotoxic effects on malignant cells, such as non-small cell lung cancer, head and neck cancer (e.g., head and neck squamous cell carcinoma), breast cancer (e.g., advanced HER2-negative breast cancer), esophageal cancer (e.g., esophageal squamous cell carcinoma), ovarian cancer (e.g., high-grade serous epithelial ovarian cancer), skin cancer (e.g., cutaneous squamous cell carcinoma), pancreatic cancer (e.g., exocrine pancreatic adenocarcinoma), bladder cancer, cervical cancer, and gastric cancer cells. The anti-αvβ6 antibodies of the present disclosure are preferably monoclonal and may be multispecific, human, humanized, or chimeric antibodies, single-chain antibodies, Fab fragments, F(ab') fragments, fragments produced by a Fab expression library, and αvβ6-binding fragments of any of the above. In some embodiments, the anti-αvβ6 antibodies of the present disclosure specifically bind to αvβ6. Immunoglobulin molecules of the present disclosure can be of any type (e.g., IgG, IgE, IgM, IgD, IgA, and IgY), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2), or subclass of immunoglobulin molecule.

[0085] In certain embodiments of the present disclosure, the anti-αvβ6 antibody is an antigen-binding fragment described herein, including Fab, Fab' and F(ab')2, Fd, single-chain Fv (scFv), single-chain antibodies, disulfide-linked Fv (sdFv), and V L or V HAntigen-binding fragments, including single-chain antibodies, may contain the variable region alone or in combination with all or a portion of the following: hinge region, CH1, CH2, CH3, and CL domains. Antigen-binding fragments containing any combination of the variable region and the hinge region, CH1, CH2, CH3, and CL domains are also included in the present disclosure. In some embodiments, the anti-αvβ6 antibody or antigen-binding fragment thereof is human, murine (e.g., mouse and rat), donkey, sheep, rabbit, goat, guinea pig, camelid, horse, or chicken.

[0086] The anti-αvβ6 antibody of the present disclosure can be monospecific, bispecific, trispecific, or even more multispecific. Multispecific antibodies can be specific for different epitopes of αvβ6, or can be specific for both αvβ6 and a heterologous protein. See, for example, PCT Publications WO93 / 17715; WO92 / 08802; WO91 / 00360; WO92 / 05793; Tutt et al., 1991, J. Immunol. 147:60 69; U.S. Patent Nos. 4,474,893; 4,714,681; 4,925,648; 5,573,920; 5,601,819; Kostelny et al., 1992, J. Immunol. 148:1547 1553.

[0087] The anti-αvβ6 antibodies of the present disclosure may be described or designated in terms of the particular CDRs they contain. The precise amino acid sequence boundaries of a given CDR or FR can be determined using the methods of Kabat et al. (1991), "Sequences of Proteins of Immunological Interest," 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD ("Kabat" numbering scheme); Al-Lazikani et al. (1997) JMB 273, 927-948 ("Chothia" numbering scheme); MacCallum et al., J. Mol. Biol. 262:732-745 (1996), "Antibody-antigen interactions: Contact analysis and binding site topography," J. Mol. Biol. 262, 732-745 ("Contact" numbering scheme); Lefranc MP et al., "IMGT unique numbering for immunoglobulin and T cell receptor variable domains and Ig superfamily V-like domains," Dev Comp Immunol, 2003 January;27(1):55-77 ("IMGT" numbering scheme); Honegger A and Pluckthun A, "Yet another numbering scheme for immunoglobulin variable domains: an automatic modeling and analysis tool," J Mol Biol, 2001 June 8;309(3):657-70, ("Aho" numbering scheme); and Martin et al., "Modeling antibody hypervariable loops: a combined algorithm," PNAS, 1989, 86(23):9268-9272, ("AbM" numbering scheme). The boundaries of a given CDR may vary depending on the scheme used to identify it.In some embodiments, the "CDRs" or "complementarity determining regions" of a given antibody or region thereof (e.g., its variable region), or individual designated CDRs (e.g., CDR-H1, CDR-H2, CDR-H3), should be understood to encompass CDRs (or specific CDRs) defined by any of the foregoing schemes. For example, a particular CDR (e.g., CDR-H3) may be associated with a given V. H or V L When a region amino acid sequence is described as containing the amino acid sequence of a corresponding CDR, it is understood that such CDR has the sequence of a corresponding CDR (e.g., CDR-H3) within the variable region as defined by any of the above schemes. Schemes for identifying a particular CDR or CDRs may be specified, such as CDRs defined by the Kabat, Chothia, AbM, or IMGT methods.

[0088] The CDR sequences provided herein follow the Kabat numbering scheme as described in Kabat et al. (1991), "Sequences of Proteins of Immunological Interest," 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD ("Kabat" numbering scheme).

[0089] In certain embodiments, the anti-αvβ6 antibody of the present disclosure comprises one or more CDRs of the antibody described in WO2021 / 113697. In certain embodiments, the antibody of the present disclosure comprises one or more CDRs of the humanized antibody anti-αvβ6 h2A2 HCLG. See WO2021 / 113697. The present disclosure encompasses an antibody or derivative thereof comprising a heavy or light chain variable domain, wherein the variable domain comprises (a) a set of three CDRs derived from monoclonal antibody h2A2 HCLG, and (b) a set of four framework regions that differ from the set of framework regions in monoclonal antibody h2A2 HCLG, and the antibody or derivative thereof binds to αvβ6. In some embodiments, the antibody or derivative thereof specifically binds to αvβ6. In certain embodiments, the anti-αvβ6 antibody is h2A2 HCLG.

[0090] In one embodiment, also provided herein are anti-αvβ6 antibodies that compete with h2A2 HCLG binding to αvβ6. Also provided herein are anti-αvβ6 antibodies that bind to the same epitope as h2A2 HCLG.

[0091] In one embodiment, provided herein is an anti-αvβ6 antibody comprising one, two, three, four, five, or six of the CDR sequences of h2A2 HCLG.

[0092] In one aspect, provided herein is an anti-αvβ6 antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1, (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 2, and (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 3; and / or the light chain variable region comprises (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 4, (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 5, and (iii) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 6.

[0093] The anti-αvβ6 antibodies described herein can comprise any suitable framework variable domain sequence, provided that the antibody retains the ability to bind to αvβ6 (e.g., human αvβ6). As used herein, heavy chain framework regions are designated "HC-FR1-FR4," and light chain framework regions are designated "LC-FR1-FR4."

[0094] In some embodiments of the anti-αvβ6 antibodies described herein, the heavy chain variable domain is The light chain variable domain comprises the amino acid sequence of QFQLVQSGAEVKKPGASVKVSCKASGYSFTDYNVNWVRQAPGQGLEWIGVINPKYGTTRYNQKFKGRATLTVDKSTSTAYMELSSLRSEDTAVYYCTRGLNAWDYWGQGTLVTVSS (SEQ ID NO: 7), and the light chain variable domain comprises the amino acid sequence of DIQMTQSPSSLSASVGDRVTITCGASENIYGALNWYQQKPGKAPKLLIYGATNLEDGVPSRFSGSGSGRDYTFTISSLQPEDIATYYCQNVLTTPYTFGQGTKLEIK (SEQ ID NO: 8).

[0095] In some embodiments of the anti-αvβ6 antibodies described herein, the heavy chain is QFQLVQSGAEVKKPGASVKVSCKASGYSFTDYNVNWVRQAPGQGLEWIGVINPKYGTTRYNQKFKGRATLTVDKSTSTAYMELSSLRSEDTAVYYCTRGLNAWDYWGQGTLVTVSSA STKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELL and the light chain comprises the amino acid sequence of: GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 9). It comprises the amino acid sequence of DIQMTQSPSSLSASVGDRVTITCGASENIYGALNWYQQKPGKAPKLLIYGATNLEDGVPSRFSGSGSGRDYTFTISSLQPEDIATYYCQNVLTTPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 10).

[0096] In some embodiments of the anti-αvβ6 antibodies described herein, the heavy chain CDR sequences are as follows: a) CDR-H1: DYNVN (SEQ ID NO: 1); b) CDR-H2: VINPKYGTTRYNQKFKG (SEQ ID NO: 2); and c) CDR-H3: GLNAWDY (SEQ ID NO: 3) Includes.

[0097] In some embodiments of the anti-αvβ6 antibodies described herein, the light chain CDR sequences are as follows: a) CDR-L1: GASENIYGALN (SEQ ID NO: 4); b) CDR-L2: GATNLED (SEQ ID NO: 5); and c) CDR-L3: QNVLTTPYT (SEQ ID NO: 6) Includes.

[0098] In one embodiment, provided herein is an anti-αvβ6 antibody comprising a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 7, or comprising a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 8. In one embodiment, provided herein is an anti-αvβ6 antibody comprising a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 7 and comprising a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 8.

[0099] In some embodiments, provided herein are anti-αvβ6 antibodies comprising a heavy chain variable domain comprising an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 7. In certain embodiments, the heavy chain variable domain comprising an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 7 contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence and retains the ability to bind to αvβ6 (e.g., human αvβ6). In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in SEQ ID NO: 7. In certain embodiments, the substitutions, insertions, or deletions (e.g., 1, 2, 3, 4, or 5 amino acids) occur in regions outside the CDRs (i.e., within the FRs). In some embodiments, the anti-αvβ6 antibody comprises a heavy chain variable domain sequence of SEQ ID NO: 7, including post-translational modifications of that sequence. In certain embodiments, the heavy chain variable domain comprises one, two, or three CDRs selected from (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 2, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 3.

[0100] In some embodiments, provided herein are anti-αvβ6 antibodies comprising a light chain variable domain comprising an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 8. In certain embodiments, the light chain variable domain comprising an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 8 contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence and retains the ability to bind to αvβ6 (e.g., human αvβ6). In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in SEQ ID NO: 8. In certain embodiments, the substitutions, insertions, or deletions (e.g., 1, 2, 3, 4, or 5 amino acids) occur in regions outside the CDRs (i.e., within the FRs). In some embodiments, the anti-αvβ6 antibody comprises a light chain variable domain sequence of SEQ ID NO: 8, including post-translational modifications of that sequence. In certain embodiments, the light chain variable domain comprises one, two, or three CDRs selected from (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 4, (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 5, and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 6.

[0101] In some embodiments, the anti-αvβ6 antibody comprises a heavy chain variable domain as in any of the embodiments provided above, and a light chain variable domain as in any of the embodiments provided above. In one embodiment, the antibody comprises a heavy chain variable domain sequence of SEQ ID NO:7 and a light chain variable domain sequence of SEQ ID NO:8, including post-translational modifications of those sequences.

[0102] In some embodiments, the anti-αvβ6 antibody of the anti-αvβ6 antibody-drug conjugate comprises i) a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 1, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 2, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 3; and ii) a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 4, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 6.

[0103] In some embodiments, the anti-αvβ6 antibody of the anti-αvβ6 antibody-drug conjugate comprises i) an amino acid sequence having at least 85% sequence identity with a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:7, and ii) an amino acid sequence having at least 85% sequence identity with a light chain variable region comprising the amino acid sequence of SEQ ID NO:8.

[0104] In some embodiments, the anti-αvβ6 antibody of the anti-αvβ6 antibody-drug conjugate is a monoclonal antibody.

[0105] In some embodiments, the anti-αvβ6 antibody of the anti-αvβ6 antibody-drug conjugate is h2A2 HCLG described in WO2021 / 113697.

[0106] The anti-αvβ6 antibodies of the present invention may also be described or designated in terms of their binding affinity to αvβ6 (e.g., human αvβ6). A preferred binding affinity is 5×10 -2 M, 10 -2 M, 5 x 10 -3 M, 10 -3 M, 5 x 10 -4 M, 10 -4 M, 5 x 10 -5 M, 10 -5 M, 5 x 10 -6 M, 10 -6 M, 5 x 10 -7 M, 10 -7 M, 5 x 10 -8 M, 10 -8 M, 5 x 10 -9M、 10 -9 M, 5 x 10 -10M、 10 -10 M, 5 x 10-11 M, 10 -11 M, 5 x 10 -12 M, 10 -12 M, 5 x 10 -13 M, 10 -13 M, 5 x 10 -14 M, 10 -14 M, 5 x 10 -15 M, or 10 -15 These include those with a dissociation constant, or Kd, less than M.

[0107] There are five classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, with heavy chains designated α, δ, ε, γ, and μ, respectively. The γ and α classes are further divided into subclasses; for example, humans express the following subclasses: IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. IgG1 antibodies can exist in multiple polymorphic variants called allotypes (reviewed in Jefferis and Lefranc 2009. mAbs, Vol. 1, No. 4, pp. 1-7), any of which are suitable for use in some of the embodiments herein. Common allotypic variants in the human population are those designated by the letters a, f, n, z, or combinations thereof. In any of the embodiments herein, the antibody may comprise a heavy chain Fc region comprising a human IgG Fc region. In a further embodiment, the human IgG Fc region comprises human IgG1.

[0108] The heavy and light chain variable regions of a humanized antibody can be linked to at least a portion of a human constant region. The choice of constant region depends in part on whether antibody-dependent cell-mediated cytotoxicity, antibody-dependent cellular phagocytosis, and / or complement-dependent cytotoxicity are desired. For example, human isotopes IgG1 and IgG3 have strong complement-dependent cytotoxicity, human isotope IgG2 has weak complement-dependent cytotoxicity, and human IgG4 lacks complement-dependent cytotoxicity. Human IgG1 and IgG3 also induce stronger cell-mediated effector functions than human IgG2 and IgG4. The light chain constant region can be lambda or kappa. Antibodies can be expressed as tetramers containing two light chains and two heavy chains, as separate heavy and light chains, as Fab, Fab', F(ab')2, and Fv, or as single-chain antibodies in which the heavy and light chain variable domains are linked via a spacer.

[0109] Human constant regions exhibit allotypic and isoallotypic variation between different individuals, i.e., the constant region may differ at one or more polymorphic positions in different individuals. Isoallotypes differ from allotypes in that sera that recognize an isoallotype bind to non-polymorphic regions of one or more other isotypes.

[0110] One or several amino acids at the amino or carboxy termini of the light and / or heavy chains, such as the C-terminal lysine of the heavy chain, may be absent or derivatized in some or all of the molecules. Substitutions in the constant region may be made to reduce or increase effector functions such as complement-mediated cytotoxicity or ADCC (see, e.g., Winter et al., U.S. Pat. No. 5,624,821; Tso et al., U.S. Pat. No. 5,834,597; and Lazar et al., Proc. Natl. Acad. Sci. USA 103:4005, 2006), or to increase half-life in humans (see, e.g., Hinton et al., J. Biol. Chem. 279:6213, 2004).

[0111] Exemplary substitutions include amino acid substitutions of native amino acids with cysteine ​​residues introduced at amino acid positions 234, 235, 237, 239, 267, 298, 299, 326, 330, or 332, preferably the S239C mutation in the human IgG1 isotype (US20100158909). The presence of an additional cysteine ​​residue allows interchain disulfide bond formation. Such interchain disulfide bond formation can cause steric hindrance, thereby reducing the affinity of the Fc region-FcyR binding interaction. Cysteine ​​residues introduced within or near the Fc region of the IgG constant region can also serve as sites for conjugation to therapeutic agents (i.e., coupling to a cytotoxic drug using a thiol-specific reagent, such as a maleimide derivative of the drug). The presence of a therapeutic agent can cause steric hindrance, thereby further reducing the affinity of the Fc region-FcyR binding interaction. Other substitutions at any of positions 234, 235, 236, and / or 237 reduce affinity for Fcγ receptors, particularly the FcγRI receptor (see, e.g., US Pat. No. 6,624,821, US Pat. No. 5,624,821).

[0112] The in vivo half-life of an antibody can also affect its effector function. Increasing or decreasing the half-life of an antibody can alter its therapeutic activity. FcRn is a receptor structurally similar to MHC class I antigens that noncovalently associates with β2-microglobulin. FcRn regulates the catabolism of IgG and their transcytosis across tissues (Ghetie and Ward, 2000, Annu. Rev. Immunol. 18:739-766; Ghetie and Ward, 2002, Immunol. Res. 25:97-113). IgG-FcRn interaction occurs at pH 6.0 (the pH of intracellular vesicles) but not at pH 7.4 (the pH of blood); this interaction allows IgG to be recycled back into the circulation (Ghetie and Ward, 2000, Ann. Rev. Immunol. 18:739-766; Ghetie and Ward, 2002, Immunol. Res. 25:97-113). The region on human IgG1 involved in FcRn binding has been mapped (Shields et al., 2001, J. Biol. Chem. 276:6591-604). Alanine substitutions at positions Pro238, Thr256, Thr307, Gln311, Asp312, Glu380, Glu382, or Asn434 of human IgG1 enhance FcRn binding (Shields et al., 2001, J. Biol. Chem. 276:6591-604). IgG1 molecules with these substitutions have a longer serum half-life. As a result, these modified IgG1 molecules may be able to perform their effector functions for a longer period of time compared to unmodified IgG1, and therefore may be able to exert their therapeutic efficacy. Other exemplary substitutions for increasing binding to FcRn include Gln at position 250 and / or Leu at position 428. EU numbering is used for all positions within the constant region.

[0113] The oligosaccharide covalently attached to the conserved Asn297 is involved in the ability of the Fc region of IgG to bind to FcyR (Lund et al., 1996, J. Immunol. 157:4963-69; Wright and Morrison, 1996, Trends Biotechnol. 15:26-31). Engineering this glycoform on IgG can significantly improve IgG-mediated ADCC. The addition of branched N-acetylglucosamine modifications to this glycoform (Umana et al., 1999, Nat. Biotechnol. 17:176-180; Davies et al., 2001, Biotech. Bioeng. 74:288-94) or the removal of fucose from this glycoform (Shields et al., 2002, J. Biol. Chem. 277:26733-40; Shinkawa et al., 2003, J. Biol. Chem. 278:6591-604; Niwa et al., 2004, Cancer Res. 64:2127-33) are two examples of IgG Fc engineering that improve binding between IgG Fc and FcyR, thereby enhancing Ig-mediated ADCC activity.

[0114] Systematic substitution of solvent-exposed amino acids in the human IgG1 Fc region has generated IgG variants with altered FcyR binding affinity (Shields et al., 2001, J. Biol. Chem. 276:6591-604). Compared to the parent IgG1, a subset of these variants with substitutions at Thr256 / Ser298, Ser298 / Glu333, Ser298 / Lys334, or Ser298 / Glu333 / Lys334 to Ala exhibit both increased binding affinity to FcγR and increased ADCC activity (Shields et al., 2001, J. Biol. Chem. 276:6591-604; Okazaki et al., 2004, J. Mol. Biol. 336:1239-49).

[0115] The complement fixation activity (both C1q binding and CDC activity) of antibodies can be improved by substitutions at Lys326 and Glu333 (Idusogie et al., 2001, J. Immunol. 166:2571-2575). The same substitutions on the human IgG2 backbone can convert antibody isotypes that are poor at binding C1q and severely deficient in complement activation activity into those that can both bind C1q and mediate CDC (Idusogie et al., 2001, J. Immunol. 166:2571-75). Several other methods have also been applied to improve the complement fixation activity of antibodies. For example, grafting an 18-amino acid carboxyl-terminal tail piece of IgM onto the carboxyl terminus of IgG greatly enhances their CDC activity. This has been observed even for IgG4, which normally has no detectable CDC activity (Smith et al., 1995, J. Immunol. 154:2226-36). Furthermore, substituting Cys for Ser444, located near the carboxy terminus of the IgG1 heavy chain, induced tail-to-tail dimerization of IgG1, with a 200-fold increase in CDC activity compared to monomeric IgG1 (Shopes et al., 1992, J. Immunol. 148:2918-22). Additionally, bispecific diabody constructs with specificity for C1q also confer CDC activity (Kontermann et al., 1997, Nat. Biotech. 15:629-31).

[0116] Complement activity can be reduced by mutating at least one of amino acid residues 318, 320, and 322 of the heavy chain to a residue with a different side chain, such as Ala. Other alkyl-substituted non-ionic residues, such as Gly, He, Leu, or Val, or aromatic non-polar residues, such as Phe, Tyr, Trp, and Pro, in place of any one of the three residues, also reduce or abolish C1q binding. Ser, Thr, Cys, and Met can be used at residues 320 and 322, rather than 318, to reduce or abolish C1q binding activity.

[0117] Replacement of residue 318 (Glu) with a polar residue can alter, but not abolish, C1q binding activity. Replacement of residue 297 (Asn) with Ala results in the elimination of lytic activity but only slightly reduces affinity for C1q (approximately three-fold weaker). This change destroys the glycosylation site and the presence of carbohydrates required for complement activation. Any other substitution at this site also destroys the glycosylation site. The following mutations, and any combination thereof, also reduce C1q binding: D270A, K322A, P329A, and P31 IS (see WO06 / 036291). The L234A / L235A mutation (or LALA mutation) also reduces C1q binding as well as FcyR binding.

[0118] Reference to a human constant region includes a constant region having any naturally occurring allotype, or any permutation of residues occupying polymorphic positions in a naturally occurring allotype, and there may be up to 1, 2, 5, or 10 mutations relative to a native human constant region, such as those set forth above, to reduce Fc gamma receptor binding or increase binding to Fc RN.

[0119] Antibodies also include derivatives that have been modified, i.e., by the covalent attachment of any type of molecule to the antibody, such that the covalent attachment does not prevent the antibody from binding to αvβ6 or from exerting a cytostatic or cytotoxic effect on HD cells. For example, but not by way of limitation, antibody derivatives include antibodies that have been modified by, e.g., glycosylation, acetylation, PEGylation, phosphorylation, amidation, derivatization with known protecting / blocking groups, proteolytic cleavage, linkage to cellular ligands or other proteins, etc. Any of a number of chemical modifications can be made by known techniques, including, but not limited to, specific chemical cleavage, acetylation, formylation, metabolic synthesis of tunicamycin, etc. Additionally, derivatives may contain one or more non-classical amino acids.

[0120] V. Expression of Recombinant Antibodies Humanized antibodies are typically produced by recombinant expression. Recombinant polynucleotide constructs typically contain expression control sequences, including naturally associated or heterologous promoter regions, operably linked to the coding sequences of the antibody chains. Preferably, the expression control sequences are eukaryotic promoter systems in vectors capable of transforming or transfecting eukaryotic host cells. Once the vector is incorporated into an appropriate host, the host is maintained under conditions suitable for high-level expression of the nucleotide sequence and the collection and purification of cross-reacting antibodies.

[0121] Mammalian cells are preferred hosts for expressing nucleotide segments encoding immunoglobulins or fragments thereof. See Winnacker, From Genes to Clones (VCH Publishers, NY, 1987). Several suitable host cell lines capable of secreting intact heterologous proteins have been developed in the art, including CHO cell lines (e.g., DG44), various COS cell lines, HeLa cells, HEK293 cells, L cells, and non-antibody-producing myelomas, including Sp2 / 0 and NS0. Preferably, the cells are non-human. Expression vectors for these cells may include expression control sequences, such as an origin of replication, a promoter, and an enhancer (Queen et al., Immunol. Rev. 89:49 (1986)), as well as necessary processing information sites, such as ribosome binding sites, RNA splice sites, polyadenylation sites, and transcription terminator sequences. Preferred expression control sequences are promoters derived from endogenous genes, cytomegalovirus, SV40, adenovirus, bovine papillomavirus, etc. See Co et al., J. Immunol. 148:1149 (1992).

[0122] Once expressed, antibodies can be purified according to standard procedures in the art, including HPLC purification, column chromatography, gel electrophoresis, etc. (for an overview, see Scopes, Protein Purification (Springer-Verlag, NY, 1982)).

[0123] VI. Nucleic acids The present invention further provides nucleic acids encoding any of the humanized heavy and light chains described above. Typically, the nucleic acids also encode signal peptides fused to the mature heavy and light chains. The coding sequence on the nucleic acid can be operably linked to regulatory sequences ensuring expression of the coding sequence, such as promoters, enhancers, ribosome binding sites, and transcription termination signals. The nucleic acids encoding the heavy and light chains can be in isolated form or cloned into one or more vectors. The nucleic acids can be synthesized, for example, by solid-phase synthesis or PCR of overlapping oligonucleotides. The nucleic acids encoding the heavy and light chains can be joined as a single continuous nucleic acid, for example, within an expression vector, or can be separate, for example, each cloned into its own expression vector.

[0124] In some aspects, also provided herein are nucleic acids encoding the anti-αvβ6 antibodies or antigen-binding fragments thereof described herein.Further provided herein are vectors comprising nucleic acids encoding the anti-αvβ6 antibodies or antigen-binding fragments thereof described herein.Further provided herein are host cells expressing nucleic acids encoding the anti-αvβ6 antibodies or antigen-binding fragments thereof described herein.Further provided herein are host cells comprising vectors comprising nucleic acids encoding the anti-αvβ6 antibodies or antigen-binding fragments thereof described herein.

[0125] The anti-αvβ6 antibodies described herein can be prepared by well-known recombinant techniques using well-known expression vector systems and host cells. In one embodiment, the antibodies are prepared in CHO cells using the GS expression vector system disclosed in De la Cruz Edmunds et al., 2006, Molecular Biotechnology 34;179-190, EP216846, U.S. Patent No. 5,981,216, WO87 / 04462, EP323997, U.S. Patent No. 5,591,639, U.S. Patent No. 5,658,759, EP338841, U.S. Patent No. 5,879,936, and U.S. Patent No. 5,891,693.

[0126] The monoclonal anti-αvβ6 antibodies described herein can be produced by the hybridoma method first described by Kohler et al., Nature, 256, 495 (1975), for example, or by recombinant DNA methods. Monoclonal antibodies can also be isolated from phage antibody libraries using the techniques described in Clackson et al., Nature, 352, 624-628 (1991) and Marks et al., J Mol. Biol., 222(3):581-597 (1991). Monoclonal antibodies can be obtained from any suitable source. Thus, for example, monoclonal antibodies can be obtained from hybridomas prepared from murine splenic B cells obtained from mice immunized with an antigen of interest, e.g., cells expressing the antigen on their surface or in the form of a nucleic acid encoding the antigen of interest. Monoclonal antibodies can also be obtained from hybridomas derived from antibody-expressing cells of immunized humans or non-human mammals such as rats, dogs, primates, etc.

[0127] VII. Antibody-Drug Conjugates Anti-αvβ6 antibodies can be conjugated with cytotoxic or cytostatic moieties (including pharmaceutically acceptable salts thereof) to form antibody-drug conjugates (ADCs). Particularly suitable moieties for conjugation to antibodies are cytotoxic agents (e.g., chemotherapeutic agents), prodrug-converting enzymes, radioisotopes or compounds, or toxins (collectively referred to as therapeutic agents). For example, anti-αvβ6 antibodies can be conjugated with cytotoxic agents such as chemotherapeutic agents, or toxins (e.g., abrin, ricin A, Pseudomonas exotoxin, or diphtheria toxin, for example, cytostatic or cytocidal agents).

[0128] The anti-αvβ6 antibody can be conjugated to a prodrug-converting enzyme. The prodrug-converting enzyme can be recombinantly fused to the antibody or chemically conjugated to it using known methods. Exemplary prodrug-converting enzymes are carboxypeptidase G2, beta-glucuronidase, penicillin V-amidase, penicillin G-amidase, beta-lactamase, beta-glucosidase, nitroreductase, and carboxypeptidase A.

[0129] Techniques for conjugating therapeutic agents to proteins, particularly antibodies, are well known. (See, e.g., Arnon et al., "Monoclonal Antibodies For Immunotargeting Of Drugs In Cancer Therapy," in Monoclonal Antibodies And Cancer Therapy (Reisfeld et al., eds., Alan R. Liss, Inc., 1985); Hellstrom et al., "Antibodies For Drug Delivery," in Controlled Drug Delivery (Robinson et al., eds., Marcel Dekker, Inc., 2nd ed., 1987); Thorpe, "Antibody Carriers Of Cytotoxic Agents In Cancer Therapy: A Review," in Monoclonal Antibodies '84: Biological And Clinical Applications (Pinchera et al., eds., 1985); "Analysis, Results, and Future Prospect of the Therapeutic Use of Radiolabeled Antibodies In Cancer" in Monoclonal Antibodies For Cancer Detection And Therapy (Baldwin et al., eds., Academic Press, 1985). (See, e.g., PCT Publication WO 89 / 12624.)

[0130] The therapeutic agent can be conjugated in a manner that reduces its activity unless it is cleaved from the antibody (e.g., by hydrolysis, antibody degradation, or by a cleaving agent). Such a therapeutic agent is attached to the antibody using a cleavable linker that is susceptible to cleavage in the intracellular environment of αvβ6-expressing cancer cells but is substantially insensitive to the extracellular environment, so that the conjugate is cleaved from the antibody when it is internalized by αvβ6-expressing cancer cells (e.g., in endosomes, or in lysosomal or caveolar environments, e.g., by pH- or protease-sensitivity).

[0131] Typically, ADCs contain a linker region between the therapeutic agent and the anti-αvβ6 antibody. As described above, the linker is typically cleavable under intracellular conditions, so that cleavage of the linker releases the therapeutic agent from the antibody in the intracellular environment (e.g., within a lysosome, endosome, or caveolae). The linker can be, for example, a peptidyl linker that is cleaved by an intracellular peptidase or protease enzyme, including a lysosomal or endosomal protease. Typically, the peptidyl linker is at least two amino acids long or at least three amino acids long. Cleavage agents can include cathepsin B and D and plasmin (see, e.g., Dubowchik and Walker, 1999, Pharm. Therapeutics 83:67-123). Most typical are peptidyl linkers that are cleavable by enzymes present in αvβ6-expressing cells. For example, a peptidyl linker cleavable by cathepsin-B, a thiol-dependent protease highly expressed in cancerous tissues, can be used (e.g., a linker comprising a Phe-Leu or Gly-Phe-Leu-Gly peptide). Other such linkers are described, for example, in U.S. Pat. No. 6,214,345. In a specific embodiment, the peptidyl linker cleavable by an intracellular protease comprises a Val-Cit linker or a Phe-Lys dipeptide (see, for example, U.S. Pat. No. 6,214,345, which describes the synthesis of doxorubicin with a Val-Cit linker). One advantage of using intracellular proteolytic release of a therapeutic agent is that the agent is typically attenuated when conjugated, and the serum stability of the conjugate is typically high.

[0132] The cleavable linker may be pH-sensitive, i.e., sensitive to hydrolysis at a certain pH value. Typically, the pH-sensitive linker is hydrolyzable under acidic conditions. For example, an acid-labile linker (e.g., hydrazone, semicarbazone, thiosemicarbazone, cis-aconitic acid amide, orthoester, acetal, ketal, etc.) that is hydrolyzable in lysosomes may be used. (See, for example, U.S. Patent Nos. 5,122,368; 5,824,805; 5,622,929; Dubowchik and Walker, 1999, Pharm. Therapeutics 83:67-123; Neville et al., 1989, Biol. Chem. 264:14653-14661.) Such linkers are relatively stable under neutral pH conditions, such as those in blood, but are unstable below pH 5.5 or 5.0, which is the approximate pH of lysosomes. In certain embodiments, the hydrolyzable linker is a thioether linker (such as a thioether attached to the therapeutic agent via an acylhydrazone bond (see, eg, US Pat. No. 5,622,929)).

[0133] Other linkers are cleavable under reducing conditions (e.g., disulfide linkers), including those that can be formed using SATA (N-succinimidyl-S-acetylthioacetate), SPDP (N-succinimidyl-3-(2-pyridyldithio)propionate), SPDB (N-succinimidyl-3-(2-pyridyldithio)butyrate), and SMPT (N-succinimidyl-oxycarbonyl-alpha-methyl-alpha-(2-pyridyl-dithio)toluene), SPDB, and SMPT. (See, e.g., Thorpe et al., 1987, Cancer Res. 47:5924-5931; Wawrzynczak et al., In Immunoconjugates: Antibody Conjugates in Radioimagery and Therapy of Cancer (C.W. Vogel, ed., Oxford U.S. Press, 1987). See also U.S. Pat. No. 4,880,935.)

[0134] The linker can also be a malonate linker (Johnson et al., 1995, Anticancer Res. 15:1387-93), a maleimidobenzoyl linker (Lau et al., 1995, Bioorg-Med-Chem. 3(10):1299-1304), or a 3'-N-amide analog (Lau et al., 1995, Bioorg-Med-Chem. 3(10):1305-12). The linker can also be a malonate linker (Johnson et al., 1995, Anticancer Res. 15:1387-93), a maleimidobenzoyl linker (Lau et al., 1995, Bioorg-Med-Chem. 3(10):1299-1304), or a 3'-N-amide analog (Lau et al., 1995, Bioorg-Med-Chem. 3(10):1305-12).

[0135] The linker can also be a non-cleavable linker, such as a maleimide-alkylene- or maleimide-aryl-linker that is directly attached to the therapeutic agent (e.g., drug). The active drug-linker is released by degradation of the antibody.

[0136] The linker may facilitate cellular internalization. The linker may facilitate cellular internalization when conjugated to a therapeutic agent (i.e., in the context of the linker-therapeutic agent portion of an ADC or ADC derivative described herein). Alternatively, the linker may facilitate cellular internalization when conjugated to both a therapeutic agent and an anti-αvβ6 antibody (i.e., in the context of an ADC described herein).

[0137] The anti-αvβ6 antibody can be conjugated to a linker via a heteroatom of the antibody. These heteroatoms can be present on the antibody in its natural state or can be introduced into the antibody. In some embodiments, the anti-αvβ6 antibody is conjugated to a linker via the nitrogen atom of a lysine residue. In other embodiments, the anti-αvβ6 antibody is conjugated to a linker via the sulfur atom of a cysteine ​​residue. The cysteine ​​residue can be naturally occurring or engineered into the antibody. Methods for conjugating linkers and drug-linkers to antibodies via lysine and cysteine ​​residues are known in the art.

[0138] Exemplary antibody-drug conjugates include auristatin-based antibody-drug conjugates (i.e., the drug component is an auristatin drug). Auristatins have been shown to bind to tubulin, disrupt microtubule dynamics, and nuclear and cell division, and have anti-cancer activity. Typically, auristatin-based antibody-drug conjugates include a linker between the auristatin drug and the anti-αvβ6 antibody. The linker can be, for example, a cleavable linker (e.g., a peptidyl linker, a carbohydrate linker) or a non-cleavable linker (e.g., a linker that is released by antibody degradation). Auristatins include (but are not limited to) auristatin T, MMAF, and MMAE. The synthesis and structures of exemplary auristatins are described in U.S. Publication Nos. 7,659,241, 7,498,298, 2009-0111756, 2009-0018086, and 7,968,687, each of which is incorporated herein by reference in its entirety and for all purposes.

[0139] Exemplary auristatin-based antibody drug conjugates are the vcMMAE (or 1006), vcMMAF, and mcMMAF antibody drug conjugates shown below, where p represents drug loading, Ab is an anti-αvβ6 antibody described herein, and val-cit or "vc" represents the valine-citrulline dipeptide:

[0140] [ka] or a pharmaceutically acceptable salt thereof. Drug loading is represented by p, the number of drug-linker molecules per antibody. When referring to an αββ-targeting antibody-drug conjugate, the subscript p represents drug loading, which, depending on the context, can represent the number of drug-linker molecules attached to each antibody molecule, and thus is an integer value, or can represent the average drug loading, and thus can be an integer or non-integer value, but is typically a non-integer value. Average drug loading represents the average number of drug-linker molecules per antibody in a population. Often, but not necessarily, when we refer to an antibody, e.g., a monoclonal antibody, we are referring to a population of antibody molecules. In a composition comprising a population of antibody-drug conjugate molecules, average drug loading is an important quality characteristic because it determines the amount of drug that can be delivered to target cells. The percentage of unconjugated antibody molecules in the composition is included in the average drug loading value.

[0141] In preferred aspects of the present invention, the average drug loading (drug-to-antibody ratio (DAR)), when referring to a composition comprising a population of antibody-drug conjugate compounds, is about 1 to about 16, preferably about 2 to about 14, and more preferably about 2 to about 10. In one embodiment, the DAR is about 2 to about 5. In a further embodiment, the DAR is about 4. In a further embodiment, the DAR is 4. In another embodiment, the DAR is about 6 to about 10. In a further embodiment, the DAR is about 8. In a further embodiment, the DAR is 8. The average number of drugs per antibody in a preparation can be characterized by conventional means, such as mass spectrometry, HIC, ELISA assay, and HPLC. In some aspects, the anti-αvβ6 antibody is attached to the drug-linker through a cysteine ​​residue in the antibody. In some aspects, the cysteine ​​residue is engineered into the antibody. In other aspects, the cysteine ​​residue is an interchain disulfide cysteine ​​residue.

[0142] In some embodiments, incorporation of a polyethylene glycol polymer as a side chain to a cleavable β-glucuronide MMAE drug-linker provides antibody drug conjugates with reduced plasma clearance and increased anti-tumor activity in xenograft models compared to non-PEGylated controls. Thus, a particularly advantageous drug-linker for attachment to an antibody of the invention is as follows, in Formula V:

[0143] [ka] or a pharmaceutically acceptable salt thereof.

[0144] The preferred stereochemistry for such a drug-linker is shown below in Formula Va:

[0145] [ka] or a pharmaceutically acceptable salt thereof, wherein, with respect to Formulas V and Va, Z represents an organic moiety having a reactive site that can react with a functional group on an antibody to form a covalent attachment thereto; n ranges from 8 to 36, and most preferably ranges from 8 to 14 (most preferably 12); R 21 is a capping unit for the polyethylene glycol moiety, preferably -CH3 or -CH2CH2CO2H.

[0146] Preferred Z moieties are maleimide-containing moieties. Particularly preferred Z moieties are the drug-linkers below:

[0147] [ka] or a pharmaceutically acceptable salt thereof.

[0148] The preferred stereochemistry for such drug-linkers is shown below:

[0149] [ka] or a pharmaceutically acceptable salt thereof, wherein, for Formulas VI, VIa, VII, and VIIa, n ranges from 8 to 36, and most preferably ranges from 8 to 14 (most preferably 12); R PR is hydrogen or a protecting group, e.g., an acid-labile protecting group, e.g., BOC; R 21 is a capping unit for the polyethylene glycol moiety, preferably -CH3 or -CH2CH2CO2H.

[0150] As noted above, R PR can be hydrogen or a protecting group. As used herein, a protecting group refers to a group that selectively blocks, temporarily or permanently, a reactive site in a multifunctional compound. A protecting group is suitable if it can prevent or avoid unwanted side reactions or premature loss of the protecting group under the reaction conditions required to effect the desired chemical transformation elsewhere in the molecule, and, if necessary, during purification of the newly formed molecule, and can be removed under conditions that do not adversely affect the structural or stereochemical integrity of the newly formed molecule. Suitable amine protecting groups include acid-labile nitrogen protecting groups, including those provided by Isidro-Llobel et al., "Amino acid-protecting groups," Chem. Rev. (2009) 109:2455-2504. Typically, acid-labile nitrogen protecting groups convert primary or secondary amino groups to their corresponding carbamates and include t-butyl, allyl, and benzyl carbamates.

[0151] As noted above, R 21 is a capping unit for the polyethylene glycol moiety. As will be appreciated by those skilled in the art, the polyethylene glycol unit can be end-capped with a wide variety of organic moieties, typically those that are relatively unreactive. Alkyl and substituted alkyl groups are preferred.

[0152] For MMAE-PEGylated ADCs such as those exemplified herein, a particularly preferred average drug loading is about 8. In exemplary embodiments, the drug-linker is conjugated to the cysteine ​​residue of the reduced interchain disulfide. In some aspects, the actual drug loading for individual antibody molecules in a population of antibody-drug conjugate compounds is 1 to 10 (or 6 to 10, or 6 to 8), with a primary drug loading of 8. For example, higher drug loadings can be achieved when, in addition to the interchain disulfide, a drug-linker is conjugated to an introduced cysteine ​​residue (such as a cysteine ​​residue introduced at position 239 according to the EU index).

[0153] An exemplary ADC is as follows:

[0154] [ka]

[0155] [ka]

[0156] [ka] or a pharmaceutically acceptable salt thereof, wherein n ranges from 8 to 36, and most preferably ranges from 8 to 14 (most preferably 12); PR is hydrogen or a protecting group, e.g., an acid-labile protecting group, e.g., BOC; R 21 is a capping unit for the polyethylene glycol moiety, preferably -CH3 or -CH2CH2CO2H; Ab represents an anti-αVβ6 antibody; and p represents an integer ranging from 1 to 16, preferably 1 to 14, 6 to 12, 6 to 10, or 8 to 10, when referring to an individual antibody molecule, or an average drug loading of about 4 or about 6 to about 14, preferably about 8, when referring to a population of antibody molecules.

[0157] As noted above, the PEG (polyethylene glycol) portion of the drug linker can range from 8 to 36 units; however, PEGs of 12 ethylene oxide units have been found to be particularly preferred. It has been found that longer PEG chains can result in slower clearance, while shorter PEG chains can result in reduced activity. Accordingly, the subscript n in all of the above embodiments is preferably 8 to 14, 8 to 12, 10 to 12, or 10 to 14, and most preferably 12.

[0158] Polydisperse PEG, monodisperse PEG, and discrete PEG can be used to prepare the PEGylated antibody-drug conjugates of the present invention. Polydisperse PEG is a heterogeneous mixture of sizes and molecular weights, while monodisperse PEG is typically purified from a heterogeneous mixture and therefore provides a single chain length and molecular weight. A preferred PEG unit is discrete PEG, which is a compound synthesized in a stepwise manner without a polymerization process. Discrete PEG provides a single molecule with a defined and specified chain length. As with the subscript "p," when referring to a population of antibody-drug conjugates, the value for the subscript "n" can be an average number and can be an integer or non-integer number.

[0159] In a preferred embodiment, covalent attachment of the antibody to the drug-linker is accomplished through a sulfhydryl functional group on the antibody, which interacts with a maleimide functional group on the drug-linker to form a thio-substituted succinimide. The sulfhydryl functional group may be present on the Ligand unit in the native state of the Ligand, for example, a naturally occurring residue (interchain disulfide residue), or may be introduced into the Ligand via chemical modification or by bioengineering, or a combination of the two. It will be understood that the antibody-substituted succinimide may exist in a hydrolyzed form. For example, in a preferred embodiment, the ADC, when bound to an antibody,

[0160] [ka] or when attached to an antibody, comprises a succinimide moiety represented by the structure

[0161] [ka] The wavy line indicates the connection to the remainder of the drug-linker.

[0162] In some embodiments, the anti-αvβ6 antibody of the invention has the structure:

[0163] [ka] or a pharmaceutically acceptable salt thereof, wherein n ranges from 8 to 36, most preferably from 8 to 14 (most preferably 12); and R PR is hydrogen or a protecting group, e.g., an acid-labile protecting group, e.g., BOC; R 21 is a capping unit for the polyethylene glycol moiety, preferably -CH3 or -CH2CH2CO2H; Ab represents an anti-αVβ6 antibody; and p represents an integer ranging from 1 to 16, preferably 1 to 14, 6 to 12, 6 to 10, or 8 to 10, when referring to an individual antibody molecule, or an average drug loading of about 4 or about 6 to about 14, preferably about 8, when referring to a population of antibody molecules.

[0164] Exemplary antibody-drug conjugates also include camptothecin-based antibody-drug conjugates (i.e., the drug component is a camptothecin drug). Camptothecin is a topoisomerase inhibitor that has been shown to have anti-cancer activity. Typically, camptothecin-based antibody-drug conjugates include a linker between the camptothecin drug and the anti-αvβ6 antibody. The linker can be, for example, a cleavable linker (e.g., a peptidyl linker, a carbohydrate linker) or a non-cleavable linker (e.g., a linker that is released by degradation of the antibody). The synthesis and structure of exemplary camptothecin drug-linkers are described in PCT / US19 / 025968 (filed April 5, 2019), which is incorporated herein by reference in its entirety and for all purposes.

[0165] Exemplary anti-αvβ6 antibody drug conjugates include camptothecin antibody drug conjugates as follows, where p represents the drug loading and Ab represents the anti-αvβ6 antibody:

[0166] In some embodiments, the camptothecin ADC has the formula (IC):

[0167] [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, Ab is anti-αvβ6 antibody; y is 1, 2, 3, or 4, or is 1 or 4; z is an integer from 2 to 12, or 2, 4, 8, or 12; p is 1 to 16.

[0168] In some aspects of these embodiments, p is 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some aspects, p is 2, 4, or 8.

[0169] In some embodiments, the camptothecin ADC has the formula:

[0170] [ka] or a pharmaceutically acceptable salt thereof, In the formula, p is 2, 4, or 8, and preferably p is 8.

[0171] In some embodiments, the camptothecin ADC has the formula:

[0172] [ka] or a pharmaceutically acceptable salt thereof, In the formula, p is 2, 4, or 8, and preferably p is 8.

[0173] In some embodiments, the camptothecin drug-linker has the formula:

[0174] [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, y is 1, 2, 3, or 4, or is 1 or 4; z is an integer from 2 to 12, or is 2, 4, 8, or 12.

[0175] In some embodiments, the camptothecin drug-linker has the formula:

[0176] [ka] It has.

[0177] In some embodiments, the camptothecin drug-linker has the formula:

[0178] [ka] It has.

[0179] In some embodiments, the camptothecin drug-linker has the formula:

[0180] [ka] It has.

[0181] Other exemplary antibody-drug conjugates include maytansinoid antibody-drug conjugates (i.e., the drug component is a maytansinoid drug), and benzodiazepine antibody-drug conjugates (i.e., the drug component is a benzodiazepine (e.g., pyrrolo[1,4]benzodiazepine dimers (PBD dimers), indolinobenzodiazepine dimers, and oxazolidinobenzodiazepine dimers)).

[0182] In some embodiments, PBD dimers for use in the present invention are represented by Formula I. A preferred stereochemistry for PBD dimers is Formula Ia:

[0183] [ka] or as shown in a pharmaceutical salt, solvate, or solvate of said salt, wherein subscript n is 1 or 3.

[0184] Solvates of formula (I) and (Ia) are typically formed by addition of water or an alcohol solvent to the imine functional groups of one or both PBD monomers to form carbinolamines and / or carbinolamine ethers. For example, at the N10-C11 positions, solvates of formula I' and Ia' below are available:

[0185] [ka] There may be an imine (N=C), a carbinolamine (NH-CH(OH)), or a carbinolamine ether (NH-CH(Ome)) represented by During the ceremony, (a)R 10is H and R 11 is OH or OR A where R A is saturated C 1~4 alkyl (preferably methyl), or (b)R 10 and R 11 form a nitrogen-carbon double bond between the nitrogen and carbon atoms to which they are attached, or (c)R 10 One of them is H and the other is R 11 is OH or OR A where R A is saturated C 1~4 alkyl (preferably methyl), and R 10 and R 11 The other forms a nitrogen-carbon double bond between the nitrogen and carbon atoms to which they are attached.

[0186] The PBD dimer of Formula I or Ia (or a pharmaceutical salt, solvate, or solvate of its salt) is typically linked to an antibody via a linker unit LU. The linker unit acts to release the PBD dimer of Formula I or Ia (or a pharmaceutical salt, solvate, or solvate of its salt) at the target site (e.g., inside a cancer cell). PBD drug-linker compounds for use in the present invention are represented by Formula II below (preferred stereochemistry is shown in IIa), where LU is the linker unit. The linker unit can be, for example, a cleavable peptide linker unit (e.g., a linker comprising a valine-alanine peptide) or a cleavable disulfide linker unit:

[0187] [ka] or a pharmaceutical salt, solvate, or solvate of said salt, wherein the subscript n is 1 or 3.

[0188] Preferred PBD drug-linker compounds for use in the present invention have Formula III below:

[0189] [ka] or a pharmaceutical salt, solvate, or solvate of said salt, wherein the subscript n is 1 or 3, and the subscript m is an integer from 2 to 5.

[0190] The PBD drug-linker is conjugated to an anti-αvβ6 antibody to produce an αvβ6-targeted antibody-drug conjugate. For example, the antibody can be conjugated to a drug-linker of Formula II or Formula III. Exemplary αvβ6-targeted antibody-drug conjugates are shown below in Formulas IV, IVa, and IVb:

[0191] [ka] or a pharmaceutical salt, solvate, or solvate of said salt, wherein subscript n is 1 or 3, subscript m is an integer from 2 to 5, and subscript p is 1 to 4.

[0192] Useful classes of cytotoxic agents for conjugating to anti-αvβ6 antibodies include, for example, anti-tubulin agents, DNA minor groove binders, DNA replication inhibitors, chemotherapy sensitizers, etc. Other exemplary classes of cytotoxic agents include anthracyclines, auristatins, camptothecins, duocarmycins, etoposide, maytansinoids, and vinca alkaloids. Some exemplary cytotoxic agents include auristatins (e.g., auristatin T, auristatin E, AFP, monomethyl auristatin F (MMAF), lipophilic monomethyl auristatin F, monomethyl auristatin E (MMAE)), DNA minor groove binders (e.g., enediynes and lexitropsins), duocarmycins, taxanes (e.g., paclitaxel and docetaxel), vinca alkaloids, nicotinamide phosphoribosyltransferase inhibitors (NAMPTi), tubulysin M, doxorubicin, morpholino-doxorubicin, and cyanomorpholino-doxorubicin.

[0193] The cytotoxic agent can be, for example, a chemotherapeutic drug such as doxorubicin, paclitaxel, melphalan, a vinca alkaloid, methotrexate, mitomycin C, or etoposide. The agent can also be a CC-1065 analog, a calicheamicin, a maytansine, an analog of dolastatin 10, rhizoxin, or palytoxin.

[0194] The cytotoxic agent can also be an auristatin. The auristatin can be an auristatin E derivative, such as an ester formed between auristatin E and a keto acid. For example, auristatin E can react with paraacetylbenzoic acid or benzoylvaleric acid to produce AEB and AEVB, respectively. Other typical auristatins include auristatin T, AFP, MMAF, and MMAE. The synthesis and structure of various auristatins are described, for example, in US2005-0238649 and US2006-0074008.

[0195] The cytotoxic agent can be a DNA minor groove binder. (See, e.g., U.S. Patent No. 6,130,237.) For example, the minor groove binder can be a CBI compound or an enediyne (e.g., a calicheamicin).

[0196] The cytotoxic or cytostatic agent can be an antitubulin agent. Examples of antitubulin agents include taxanes (e.g., Taxol® (paclitaxel), Taxotere® (docetaxel)), T67 (Tularik), vinca alkaloids (e.g., vincristine, vinblastine, vindesine, and vinorelbine), and auristatins (e.g., auristatin E, AFP, MMAF, MMAE, AEB, AEVB). Exemplary auristatins are shown in Formulas III to XIII below. Other suitable antitubulin agents include, for example, baccatin derivatives, taxane analogs (e.g., epothilones A and B), nocodazole, colchicine and colcemid, estramustine, cryptophysin, cemadotin, maytansinoids, combretastatins, discodermolide, and eleuthrobin.

[0197] The cytotoxic agent can be a maytansinoid (e.g., DM1, DM2, DM3, DM4), another group of antitubulin agents. For example, the maytansinoid can be maytansine or a maytansine-containing drug linker, such as DM-1 or DM-4 (ImmunoGen, Inc.; see also Chari et al., 1992, Cancer Res.).

[0198] VIII. Therapeutic applications The anti-αvβ6 antibodies of the present invention can be used alone or as anti-αvβ6 antibody-drug conjugates thereof to treat cancer. Some such cancers exhibit detectable levels of αvβ6, measured either at the protein level (e.g., by immunoassay, such as using one of the exemplified antibodies) or at the mRNA level. Some such cancers exhibit elevated levels of αvβ6 compared to non-cancerous tissue of the same type, preferably from the same patient. An exemplary level of αvβ6 on cancer cells suitable for treatment is 5,000 to 500,000 αvβ6 molecules per cell, although higher or lower levels can also be treated. Optionally, the level of αvβ6 in the cancer is measured before treatment is administered.

[0199] Examples of cancers associated with αvβ6 expression and suitable for treatment include non-small cell lung cancer (NSCLC) (squamous and adenocarcinoma), head and neck cancer (including head and neck squamous cell carcinoma), esophageal cancer, breast cancer (including invasive breast cancer), ovarian cancer, bladder cancer (including urothelial carcinoma), skin cancer (squamous cell carcinoma, i.e., SCC), kidney cancer (including renal clear cell, renal papillary cell, and renal chromophobe cell), cervical cancer, gastric cancer, prostate cancer (including prostate adenocarcinoma), endometrial cancer (including uterine carcinosarcoma and uterine corpus endometrium), rectal adenocarcinoma, thyroid cancer, colon adenocarcinoma, gastric adenocarcinoma, and pancreatic cancer (including pancreatic adenocarcinoma). In some embodiments, the antibody or antibody-drug conjugate of the present invention is used in a method for treating NSCLC. In some embodiments, the NSCLC is squamous cell carcinoma. In some embodiments, the NSCLC is non-squamous cell carcinoma. In some embodiments, the NSCLC is adenocarcinoma. In some embodiments, the NSCLC does not have a known mutation / alteration that confers eligibility for an approved targeted therapy (e.g., epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), etc.). In some embodiments, the NSCLC has one or more known mutations / alterations that confers eligibility for an approved targeted therapy (e.g., epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), etc.). In some embodiments, the NSCLC has a known EGFR mutation. In some embodiments, the NSCLC has a known ALK mutation. In some embodiments, the antibody or antibody-drug conjugate of the invention is used in a method of treating head and neck cancer. In some embodiments, the head and neck cancer is squamous cell carcinoma. In some embodiments, the antibody or antibody-drug conjugate of the invention is used in a method of treating skin cancer. In some embodiments, the skin cancer is cutaneous squamous cell carcinoma. In some embodiments, the antibody or antibody-drug conjugate of the invention is used in a method of treating esophageal cancer. In some embodiments, the esophageal cancer is esophageal squamous cell carcinoma. In some embodiments, the antibody or antibody-drug conjugate of the present invention is used in a method for treating breast cancer. In some embodiments, the breast cancer is HER2-negative breast cancer. In some embodiments, the breast cancer is invasive breast cancer.In some embodiments, antibodies or antibody-drug conjugates of the invention are used in methods of treating ovarian cancer. In some embodiments, the ovarian cancer is high-grade serous epithelial ovarian cancer. In some embodiments, antibodies or antibody-drug conjugates of the invention are used in methods of treating primary peritoneal cancer. In some embodiments, antibodies or antibody-drug conjugates of the invention are used in methods of treating fallopian tube cancer. In some embodiments, antibodies or antibody-drug conjugates of the invention are used in methods of treating bladder cancer. In some embodiments, the bladder cancer is urothelial carcinoma. In some embodiments, antibodies or antibody-drug conjugates of the invention are used in methods of treating cervical cancer. In some embodiments, antibodies or antibody-drug conjugates of the invention are used in methods of treating gastric cancer. In some embodiments, antibodies or antibody-drug conjugates of the invention are used in methods of treating prostate cancer. In some embodiments, the prostate cancer is prostate adenocarcinoma. In some embodiments, antibodies or antibody-drug conjugates of the invention are used in methods of treating renal cancer. In some embodiments, the renal cancer is renal clear cell carcinoma. In some embodiments, the renal cancer is renal papillary cell carcinoma. In some embodiments, the renal cancer is renal chromophobe cell carcinoma. In some embodiments, an antibody or antibody-drug conjugate of the invention is used in a method of treating endometrial cancer. In some embodiments, the endometrial cancer is a uterine carcinosarcoma. In some embodiments, the endometrial cancer is uterine corpus endometrial carcinoma. In some embodiments, an antibody or antibody-drug conjugate of the invention is used in a method of treating rectal adenocarcinoma. In some embodiments, an antibody or antibody-drug conjugate of the invention is used in a method of treating thyroid cancer. In some embodiments, an antibody or antibody-drug conjugate of the invention is used in a method of treating colon adenocarcinoma. In some embodiments, an antibody or antibody-drug conjugate of the invention is used in a method of treating stomach cancer. In some embodiments, the stomach cancer is gastric adenocarcinoma.In some embodiments, the antibodies or antibody-drug conjugates of the present invention are used in methods for treating pancreatic cancer. In some embodiments, the pancreatic cancer is exocrine pancreatic adenocarcinoma. The treatment may be applied to patients with any of these types of locally advanced tumors. The treatment may be applied to patients with any of these types of primary or metastatic tumors. The treatment may also be applied to patients with any of these types of tumors that are refractory to conventional treatment or have relapsed after responding to such treatment. In some embodiments, the subject has received one or more prior lines of therapy to treat any of these types of tumors. In some embodiments, the subject has previously been treated with a platinum-based therapy for any of these types of tumors. In some embodiments, the subject has previously been treated with a PD-1 / PD-L1 inhibitor for any of these types of tumors. In some embodiments, the subject has previously been treated with a taxane for any of these types of tumors. In some embodiments, the subject has not previously been treated with a taxane for any of these types of tumors. In some embodiments, the subject has previously been treated with a phosphoinositide 3-kinase (PI3K) inhibitor for any of these tumor types. In some embodiments, the subject has previously been treated with a poly-ADP ribose polymerase (PARP) inhibitor for any of these tumor types. In some embodiments, the subject has previously been treated with bevacizumab for any of these tumor types. In some embodiments, the subject has previously been treated with a CDK4 / 6 inhibitor for any of these tumor types. In some embodiments, the subject has previously been treated with hormone-directed therapy for any of these tumor types. Treatment may be applied to patients with any of these tumor types that are unresectable. In some embodiments, the subject has no history of another malignancy within three years prior to the first administration of the antibody or antibody-drug conjugate of the invention.In some embodiments, the subject does not have any evidence of residual disease from a previously diagnosed malignant tumor at the time of the first administration of the antibody or antibody-drug conjugate of the present invention. In some embodiments, the subject does not have known central nervous system metastasis. In some embodiments, the subject does not have carcinomatous meningitis. In some embodiments, the subject has not previously received treatment with an MMAE-containing agent or an agent that targets integrin beta-6.

[0200] The anti-αvβ6 antibody of the present invention, such as a humanized antibody, alone or as a conjugate thereof, is administered in an effective regimen, which refers to the dosage, route of administration, and frequency of administration, that delays the onset of cancer, reduces its severity, inhibits its further progression, and / or improves at least one or more signs or symptoms thereof. If the patient already has cancer, the regimen can be referred to as a therapeutically effective regimen. If the patient is at an elevated risk of cancer compared to the general population but has not yet experienced symptoms, the regime can be referred to as a prophylactically effective regimen. In some cases, therapeutic or prophylactic efficacy can be observed in individual patients compared to historical controls or past experience in the same patient. In other cases, therapeutic or prophylactic efficacy can be demonstrated in preclinical or clinical trials in a population of treated patients compared to a control population of untreated patients.

[0201] Exemplary dosages for anti-αvβ6 monoclonal antibodies or antibody-drug conjugates described herein are 0.1 mg / kg to 50 mg / kg of subject body weight, more typically 1 mg / kg to 30 mg / kg, 1 mg / kg to 20 mg / kg, 1 mg / kg to 15 mg / kg, 1 mg / kg to 12 mg / kg, or 1 mg / kg to 10 mg / kg, or 2 mg / kg to 30 mg / kg, 2 mg / kg to 20 mg / kg, 2 mg / kg to 15 mg / kg, 2 mg / kg to 12 mg / kg, or 2 mg / kg to 10 mg / kg, or 3 mg / kg to 30 mg / kg, 3 mg / kg to 20 mg / kg, 3 mg / kg to 15 mg / kg, 3 mg / kg to 12 mg / kg, or 3 mg / kg to 10 mg / kg. In some embodiments, the subject's body weight is the subject's ideal body weight (IBW). In some embodiments, the subject's body weight is the subject's adjusted ideal body weight (AIBW). Exemplary dosages for a monoclonal antibody or antibody-drug conjugate thereof are 1 mg / kg to 7.5 mg / kg, or 2 mg / kg to 7.5 mg / kg, or 3 mg / kg to 7.5 mg / kg, or 0.1 to 20, or 0.5 to 5 mg / kg body weight (e.g., 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mg / kg), or a fixed dose of 10 to 1500 mg or 200 to 1500 mg. In some embodiments, the dose is 0.8 mg / kg. In some embodiments, the dose is 1.0 mg / kg. In some embodiments, the dose is 1.2 mg / kg. In some embodiments, the dose is 1.25 mg / kg. In some embodiments, the dose is 1.5 mg / kg. In some embodiments, the dose is 1.8 mg / kg. In some embodiments, the dose is 2.4 mg / kg. In some methods, the patient is administered a dose of at least 0.8 mg / kg, at least 1.0 mg / kg, at least 1.2 mg / kg, at least 1.25 mg / kg, at least 1.5 mg / kg, at least 1.8 mg / kg, or at least 2.4 mg / kg administered once weekly or more frequently.In some methods, patients are administered a dose of at least 0.8 mg / kg, at least 1.0 mg / kg, at least 1.2 mg / kg, at least 1.25 mg / kg, at least 1.5 mg / kg, at least 1.8 mg / kg, or at least 2.4 mg / kg administered once weekly. In some methods, patients are administered a dose of at least 1.5 mg / kg or at least 1.8 mg / kg administered once every two weeks or more frequently. In some methods, patients are administered a dose of at least 1.2 mg / kg or at least 1.25 mg / kg administered twice every three weeks. In some methods, patients are administered a dose of 1.25 mg / kg administered twice every three weeks. In some methods, patients are administered a dose of 1.5 mg / kg administered twice every three weeks. In some methods, patients are administered a dose of 1.8 mg / kg administered once every two weeks. In some methods, patients are administered a dose of 1.5 mg / kg administered once every two weeks. In some methods, patients are administered a dose of at least 1.5 mg / kg, at least 2 mg / kg, or at least 3 mg / kg administered once every three weeks or more frequently. The dosage will depend, among other factors, on the frequency of administration, the patient's condition and response to prior treatment, if any, whether the treatment is prophylactic or therapeutic, and whether the disease is acute or chronic.

[0202] Administration can be parenteral, intravenous, oral, subcutaneous, intraarterial, intracranial, intrathecal, intraperitoneal, topical, intranasal, or intramuscular. Administration can also be directly localized within a tumor. Administration into the systemic circulation via intravenous or subcutaneous administration is preferred. Intravenous administration can be by infusion over a period of, for example, 30 to 90 minutes, or by a single bolus injection. In some embodiments, the antibody or antibody-drug conjugate of the invention is administered by intravenous infusion.

[0203] The frequency of administration depends on, among other factors, the half-life of the antibody or conjugate in circulation, the condition of the patient, and the route of administration. The frequency of administration of the anti-αvβ6 antibodies or antibody-drug conjugates described herein can be daily, weekly, once every two weeks, twice every three weeks, once every three weeks, monthly, quarterly, or irregular, depending on changes in the patient's condition or the progression of the cancer being treated. In some embodiments, the frequency of administration is about once weekly. In some embodiments, the weekly administration is on about days 1, 8, and 15 of a 21-day cycle. In some embodiments, the frequency of administration is about once every two weeks. In some embodiments, the frequency of administration is about twice every three weeks. In some embodiments, the frequency of administration is on about days 1 and 8 of a 21-day cycle. In some embodiments, the frequency of administration is about once every three weeks. In some embodiments, the frequency of administration is once weekly. In some embodiments, the weekly administration is on days 1, 8, and 15 of a 21-day cycle. In some embodiments, the frequency of administration is once every two weeks. In some embodiments, the frequency of administration is on days 1 and 8 of a 21-day cycle. In some embodiments, the frequency of administration is twice every three weeks. In some embodiments, the frequency of administration is once every three weeks. For subcutaneous administration, exemplary dosing frequencies are daily to monthly, although more or less frequent dosing is possible. Exemplary frequencies for intravenous administration are twice weekly to once quarterly over a continuous course of treatment, although more or less frequent dosing is possible. Other exemplary frequencies for intravenous administration are once weekly to three times every four weeks over a continuous course of treatment, although more or less frequent dosing is possible. Other exemplary frequencies for intravenous administration are once every two weeks or once every three weeks over a continuous course of treatment, although more or less frequent dosing is possible. In some embodiments, the dose is administered based on the subject's body weight. In some embodiments, the subject's body weight is the subject's ideal body weight (IBW). In some embodiments, the subject's weight is the subject's adjusted ideal body weight (AIBW). In some embodiments, the dose is 0.7 mg / kg and is administered about once per week.In some embodiments, the dose is 0.7 mg / kg and is administered about once every two weeks. In some embodiments, the dose is 0.7 mg / kg and is administered about twice every three weeks. In some embodiments, the dose is 0.7 mg / kg and is administered about once every three weeks. In some embodiments, the dose is 0.8 mg / kg and is administered about once every week. In some embodiments, the dose is 0.8 mg / kg and is administered about once every two weeks. In some embodiments, the dose is 0.8 mg / kg and is administered about twice every three weeks. In some embodiments, the dose is 0.8 mg / kg and is administered about once every three weeks. In some embodiments, the dose is 0.9 mg / kg and is administered about once every week. In some embodiments, the dose is 0.9 mg / kg and is administered about once every two weeks. In some embodiments, the dose is 0.9 mg / kg and is administered about twice every three weeks. In some embodiments, the dose is 0.9 mg / kg and is administered about once every three weeks. In some embodiments, the dose is 1.0 mg / kg and is administered about once every week. In some embodiments, the dose is 1.0 mg / kg and is administered about once every two weeks. In some embodiments, the dose is 1.0 mg / kg and is administered about twice every three weeks. In some embodiments, the dose is 1.0 mg / kg and is administered about once every three weeks. In some embodiments, the dose is 1.1 mg / kg and is administered about once every week. In some embodiments, the dose is 1.1 mg / kg and is administered about once every two weeks. In some embodiments, the dose is 1.1 mg / kg and is administered about twice every three weeks. In some embodiments, the dose is 1.1 mg / kg and is administered about once every three weeks. In some embodiments, the dose is 1.2 mg / kg and is administered about once every week. In some embodiments, the dose is 1.2 mg / kg and is administered about once every two weeks. In some embodiments, the dose is 1.2 mg / kg and is administered about twice every three weeks. In some embodiments, the dose is 1.2 mg / kg and is administered about once every three weeks, hi some embodiments, the dose is 1.25 mg / kg and is administered about once every week.In some embodiments, the dose is 1.25 mg / kg and is administered about once every two weeks. In some embodiments, the dose is 1.25 mg / kg and is administered about twice every three weeks. In some embodiments, the dose is 1.25 mg / kg and is administered about once every three weeks. In some embodiments, the dose is 1.3 mg / kg and is administered about once every week. In some embodiments, the dose is 1.3 mg / kg and is administered about once every two weeks. In some embodiments, the dose is 1.3 mg / kg and is administered about twice every three weeks. In some embodiments, the dose is 1.3 mg / kg and is administered about once every three weeks. In some embodiments, the dose is 1.4 mg / kg and is administered about once every week. In some embodiments, the dose is 1.4 mg / kg and is administered about once every two weeks. In some embodiments, the dose is 1.4 mg / kg and is administered about twice every three weeks. In some embodiments, the dose is 1.4 mg / kg and is administered about once every three weeks. In some embodiments, the dose is 1.5 mg / kg and is administered about once every week. In some embodiments, the dose is 1.5 mg / kg and is administered about once every two weeks. In some embodiments, the dose is 1.5 mg / kg and is administered about twice every three weeks. In some embodiments, the dose is 1.5 mg / kg and is administered about once every three weeks. In some embodiments, the dose is 1.6 mg / kg and is administered about once every week. In some embodiments, the dose is 1.6 mg / kg and is administered about once every two weeks. In some embodiments, the dose is 1.6 mg / kg and is administered about twice every three weeks. In some embodiments, the dose is 1.6 mg / kg and is administered about once every three weeks. In some embodiments, the dose is 1.7 mg / kg and is administered about once every week. In some embodiments, the dose is 1.7 mg / kg and is administered about once every two weeks. In some embodiments, the dose is 1.7 mg / kg and is administered about twice every three weeks. In some embodiments, the dose is 1.7 mg / kg and is administered about once every three weeks, hi some embodiments, the dose is 1.8 mg / kg and is administered about once every week.In some embodiments, the dose is 1.8 mg / kg and is administered about once every two weeks. In some embodiments, the dose is 1.8 mg / kg and is administered about twice every three weeks. In some embodiments, the dose is 1.8 mg / kg and is administered about once every three weeks. In some embodiments, the dose is 1.9 mg / kg and is administered about once every week. In some embodiments, the dose is 1.9 mg / kg and is administered about once every two weeks. In some embodiments, the dose is 1.9 mg / kg and is administered about twice every three weeks. In some embodiments, the dose is 1.9 mg / kg and is administered about once every three weeks. In some embodiments, the dose is 2.0 mg / kg and is administered about once every week. In some embodiments, the dose is 2.0 mg / kg and is administered about once every two weeks. In some embodiments, the dose is 2.0 mg / kg and is administered about twice every three weeks. In some embodiments, the dose is 2.0 mg / kg and is administered about once every three weeks. In some embodiments, the dose is 2.1 mg / kg and is administered about once every week. In some embodiments, the dose is 2.1 mg / kg and is administered about once every two weeks. In some embodiments, the dose is 2.1 mg / kg and is administered about twice every three weeks. In some embodiments, the dose is 2.1 mg / kg and is administered about once every three weeks. In some embodiments, the dose is 2.2 mg / kg and is administered about once every week. In some embodiments, the dose is 2.2 mg / kg and is administered about once every two weeks. In some embodiments, the dose is 2.2 mg / kg and is administered about twice every three weeks. In some embodiments, the dose is 2.2 mg / kg and is administered about once every three weeks. In some embodiments, the dose is 2.3 mg / kg and is administered about once every week. In some embodiments, the dose is 2.3 mg / kg and is administered about once every two weeks. In some embodiments, the dose is 2.3 mg / kg and is administered about twice every three weeks. In some embodiments, the dose is 2.3 mg / kg and is administered about once every three weeks. In some embodiments, the dose is 2.4 mg / kg and is administered about once every week. In some embodiments, the dose is 2.4 mg / kg and is administered about once every two weeks.In some embodiments, the dose is 2.4 mg / kg and is administered twice about every three weeks. In some embodiments, the dose is 2.4 mg / kg and is administered once about every three weeks. In some embodiments, the dose is 2.5 mg / kg and is administered once about every week. In some embodiments, the dose is 2.5 mg / kg and is administered once about every two weeks. In some embodiments, the dose is 2.5 mg / kg and is administered twice about every three weeks. In some embodiments, the dose is 2.5 mg / kg and is administered once about every three weeks.

[0204] The number of doses administered depends on the nature of the cancer (e.g., whether it presents acute or chronic symptoms) and the response of the disorder to treatment. For acute disorders or acute exacerbations of chronic disorders, 1 to 10 doses are often sufficient. Sometimes, for acute disorders or acute exacerbations of chronic disorders, a single bolus dose, optionally in divided form, is sufficient. Treatment can be repeated upon recurrence of the acute disorder or exacerbation. For chronic disorders, the antibody can be administered at regular intervals, for example, weekly, biweekly, monthly, quarterly, or every 6 months, for at least 1, 5, or 10 years, or for the life of the patient.

[0205] Pharmaceutical compositions for parenteral administration are preferably sterile and substantially isotonic and manufactured under GMP conditions. Pharmaceutical compositions may be provided in unit dosage form (i.e., a dosage for a single administration). Pharmaceutical compositions may be formulated using one or more physiologically acceptable carriers, diluents, excipients, or adjuvants. The formulation will depend on the selected route of administration. For injection, the antibody may be formulated in an aqueous solution, preferably in a physiologically compatible buffer such as Hank's solution, Ringer's solution, or physiological saline or acetate buffer (to reduce discomfort at the injection site). The solution may contain formulating agents such as suspending agents, stabilizers, and / or dispersing agents. Alternatively, the antibody may be in lyophilized form for reconstitution with a suitable vehicle, e.g., sterile, pyrogen-free water, prior to use. The concentration of the antibody in the liquid formulation may be 1 to 100 mg / ml, e.g., 10 mg / ml.

[0206] Treatment with the anti-αvβ6 antibodies or antibody-drug conjugates described herein can be combined with one or more additional treatments, such as chemotherapy, radiation, stem cell therapy, surgery, or other treatments effective for the disorder being treated. Useful classes of other agents that can be administered with the antibodies and antibody-drug conjugates against αvβ6 described herein include, for example, antibodies against other receptors expressed on cancerous cells, antitubulin agents (e.g., auristatins), DNA minor groove binders, DNA replication inhibitors, alkylating agents (e.g., cisplatin, mono(platinum), bis(platinum), and trinuclear platinum complexes, and platinum complexes such as carboplatin), anthracyclines, antibiotics, antifolates, antimetabolites, chemotherapy sensitizers, duocarmycins, etoposide, fluorinated pyrimidines, ionophores, lexitropsin, nitrosoureas, platinol, preforming compounds, purine antimetabolites, puromycin, radiosensitizers, steroids, taxanes, topoisomerase inhibitors, vinca alkaloids, and the like. In some embodiments, the one or more additional therapies is administration of a checkpoint inhibitor. The additional therapeutic agent is a PD-1 inhibitor or a PD-L1 inhibitor. In some embodiments, the PD-1 inhibitor is an anti-PD-1 antibody. In some embodiments, the anti-PD-1 antibody is AMP-224, CT-011, cemiplimab, camrelizumab, sintilimab, tislelizumab, TSR-042, PDR001, toripalimab, BGB-A317, nivolumab (also known as ONO-4538, BMS-936558, or MDX1106), pembrolizumab (also known as MK-3475, SCH 900475, or lambrolizumab), sasanlimab (also known as PF-06801591), dostarlimab, or a biosimilar of any of these antibodies. In some embodiments, the PD-L1 inhibitor is an anti-PD-L1 antibody.In some embodiments, the anti-PD-L1 antibody is MEDI4736 (also known as durvalumab or IMFINZI®), BMS-936559 (also known as MDX-1105-01), atezolizumab (also known as MPDL3280A and Tecentriq®), avelumab (also known as BAVENCIO®), or a biosimilar of any of these antibodies. In one embodiment, the anti-PD-1 antibody is nivolumab. Nivolumab is a human IgG4 anti-PD-1 monoclonal antibody and is sold under the trade name Opdivo™. In another embodiment, the anti-PD-1 antibody is pembrolizumab. Pembrolizumab is a humanized monoclonal IgG4 antibody and is sold under the trade name Keytruda™. In yet another embodiment, the anti-PD-1 antibody is the humanized antibody CT-011. In yet another embodiment, the anti-PD-1 antibody is the fusion protein AMP-224. In another embodiment, the anti-PD-1 antibody is BGB-A317. BGB-A317 is a monoclonal antibody engineered to specifically eliminate its ability to bind to Fc gamma receptor I, possessing a unique binding signature for PD-1 with high affinity and excellent target specificity. In one embodiment, the PD-1 antibody is cemiplimab. In another embodiment, the anti-PD-1 antibody is camrelizumab. In a further embodiment, the anti-PD-1 antibody is sintilimab. In some embodiments, the anti-PD-1 antibody is tislelizumab. In certain embodiments, the anti-PD-1 antibody is TSR-042. In yet another embodiment, the anti-PD-1 antibody is PDR001. In yet another embodiment, the anti-PD-1 antibody is toripalimab. In yet another embodiment, the anti-PD-1 antibody is sasanlimab. In yet another embodiment, the anti-PD-1 antibody is dostarlimab. In some embodiments, the anti-PD-L1 antibody is MEDI4736 (also known as durvalumab or IMFINZI®), BMS-936559 (also known as MDX-1105-01), atezolizumab (also known as MPDL3280A and Tecentriq®), or avelumab (also known as BAVENCIO®).In one embodiment, the anti-PD-L1 antibody is MEDI4736 (durvalumab). In another embodiment, the anti-PD-L1 antibody is BMS-936559. In yet another embodiment, the PD-L1 inhibitor is atezolizumab. In a further embodiment, the PD-L1 inhibitor is avelumab.

[0207] In some embodiments, one or more additional therapies are administered simultaneously with the anti-αvβ6 antibody or antibody-drug conjugate described herein. In some embodiments, one or more additional therapies and the anti-αvβ6 antibody or antibody-drug conjugate described herein are administered sequentially. In some embodiments, simultaneously means that the anti-αvβ6 antibody or antibody-drug conjugate described herein and one or more additional therapies are administered to a subject less than one hour apart, such as less than about 30 minutes apart, less than about 15 minutes apart, less than about 10 minutes apart, or less than about 5 minutes apart. In some embodiments, sequential administration means that the anti-αvβ6 antibody or antibody-drug conjugate described herein and the one or more additional therapies are administered at least 1 hour apart, at least 2 hours apart, at least 3 hours apart, at least 4 hours apart, at least 5 hours apart, at least 6 hours apart, at least 7 hours apart, at least 8 hours apart, at least 9 hours apart, at least 10 hours apart, at least 11 hours apart, at least 12 hours apart, at least 13 hours apart, at least 14 hours apart, at least 15 hours apart, at least 16 hours apart, at least 17 hours apart, at least 18 hours apart, at least 19 hours apart, at least 20 hours apart, at least 21 hours apart, at least 22 hours apart, at least 23 hours apart, at least 24 hours apart, at least 25 hours apart, at least 26 hours apart, at least 27 hours apart, at least 28 hours apart, at least 29 hours apart, at least 30 hours apart, at least 31 hours apart, at least 32 hours apart, at least 33 hours apart, at least 34 hours apart, at least 35 hours apart, at least 36 hours apart, at least 37 hours apart, at least 38 hours apart, at least 39 hours apart, at least 40 hours apart, at least 41 hours apart, at least 42 hours apart, at least 43 hours apart, at least 44 hours apart, at least 45 hours apart, at least 46 hours apart, at least 47 hours apart, at least 48 hours apart, at least 49 hours apart, at least 50 hours apart, at least 51 hours apart, at least 52 hours apart, at least 53 hours apart, at least 54 hours apart, at least 55 hours apart, at least 56 hours apart, at least 57 hours apart, at least 58 hours apart, at least 59 hours apart, at least 60 hours apart, at least means administered at least 18 hours apart, at least 19 hours apart, at least 20 hours apart, at least 21 hours apart, at least 22 hours apart, at least 23 hours apart, at least 24 hours apart, at least 2 days apart, at least 3 days apart, at least 4 days apart, at least 5 days apart, at least 6 days apart, at least 7 days apart, at least 2 weeks apart, at least 3 weeks apart, at least 4 weeks apart, at least 6 weeks apart, at least 2 months apart, at least 3 months apart, at least 4 months apart, at least 5 months apart, or at least 6 months apart.

[0208] In some embodiments, the one or more additional treatments are administration of a chemotherapeutic agent. In some embodiments, the one or more additional treatments are administration of a platinum-based agent. In some embodiments, the platinum-based agent is carboplatin or cisplatin. In some embodiments, the platinum-based agent is carboplatin. In some embodiments, the platinum-based agent is cisplatin.

[0209] In some embodiments, the one or more additional therapies are administration of a platinum-based agent and a checkpoint inhibitor. In some embodiments, the platinum-based agent is carboplatin or cisplatin. In some embodiments, the platinum-based agent is carboplatin. In some embodiments, the platinum-based agent is cisplatin. In some embodiments, the checkpoint inhibitor is pembrolizumab or a biosimilar thereof. In some embodiments, the checkpoint inhibitor is pembrolizumab.

[0210] In some embodiments, the one or more additional therapies is administration of pembrolizumab or a biosimilar thereof. In some embodiments, the pembrolizumab or a biosimilar thereof is administered at a dose of about 200 mg. In some embodiments, the pembrolizumab or a biosimilar thereof is administered at a dose of 200 mg. In some embodiments, the pembrolizumab or a biosimilar thereof is administered at a dose of about 400 mg. In some embodiments, the pembrolizumab or a biosimilar thereof is administered at a dose of 400 mg. In some embodiments, the pembrolizumab or a biosimilar thereof is administered about once every three weeks. In some embodiments, the pembrolizumab or a biosimilar thereof is administered about once every three weeks. In some embodiments, the pembrolizumab or a biosimilar thereof is administered about once every six weeks. In some embodiments, the pembrolizumab or a biosimilar thereof is administered about once every six weeks. In some embodiments, pembrolizumab or a biosimilar thereof is administered at a dose of about 200 mg once every three weeks. In some embodiments, pembrolizumab or a biosimilar thereof is administered at a dose of 200 mg once every three weeks. In some embodiments, pembrolizumab or a biosimilar thereof is administered at a dose of about 400 mg once every six weeks. In some embodiments, pembrolizumab or a biosimilar thereof is administered at a dose of 400 mg once every six weeks. In some embodiments, the route of administration of pembrolizumab or a biosimilar thereof is intravenous. In some embodiments, the first dose of the anti-αvβ6 antibody or antibody-drug conjugate is administered to the subject before the first dose of pembrolizumab or a biosimilar thereof is administered. In some embodiments, the first dose of the anti-αvβ6 antibody or antibody drug conjugate is administered to the subject at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months before the administration of the first dose of pembrolizumab or a biosimilar thereof.In some embodiments, the first dose of the anti-αvβ6 antibody or antibody-drug conjugate is administered to the subject at least one day before the first dose of pembrolizumab or its biosimilar. In some embodiments, the first dose of the anti-αvβ6 antibody or antibody-drug conjugate is administered to the subject at least two days before the first dose of pembrolizumab or its biosimilar. In some embodiments, the first dose of the anti-αvβ6 antibody or antibody-drug conjugate is administered to the subject at least three days before the first dose of pembrolizumab or its biosimilar. In some embodiments, the first dose of the anti-αvβ6 antibody or antibody-drug conjugate is administered to the subject at least four days before the first dose of pembrolizumab or its biosimilar. In some embodiments, the first dose of the anti-αvβ6 antibody or antibody-drug conjugate is administered to the subject at least five days before the first dose of pembrolizumab or its biosimilar. In some embodiments, the first dose of the anti-αvβ6 antibody or antibody-drug conjugate is administered to the subject at least 6 days before the first dose of pembrolizumab or its biosimilar. In some embodiments, the first dose of the anti-αvβ6 antibody or antibody-drug conjugate is administered to the subject at least 7 days before the first dose of pembrolizumab or its biosimilar. In some embodiments, the first dose of the anti-αvβ6 antibody or antibody-drug conjugate is administered to the subject at least 1 week before the first dose of pembrolizumab or its biosimilar. In some embodiments, the first dose of the anti-αvβ6 antibody or antibody-drug conjugate is administered to the subject at least 2 weeks before the first dose of pembrolizumab or its biosimilar. In some embodiments, the first dose of the anti-αvβ6 antibody or antibody-drug conjugate is administered to the subject at least 3 weeks before the first dose of pembrolizumab or its biosimilar. In some embodiments, the first dose of the anti-αvβ6 antibody or antibody drug conjugate is administered to the subject at least 4 weeks prior to the administration of the first dose of pembrolizumab or a biosimilar thereof.In some embodiments, the first dose of the anti-αvβ6 antibody or antibody-drug conjugate is administered to the subject at least two months before the first dose of pembrolizumab or its biosimilar. In some embodiments, the first dose of the anti-αvβ6 antibody or antibody-drug conjugate is administered to the subject at least three months before the first dose of pembrolizumab or its biosimilar. In some embodiments, the first dose of the anti-αvβ6 antibody or antibody-drug conjugate is administered to the subject at least four months before the first dose of pembrolizumab or its biosimilar. In some embodiments, the first dose of the anti-αvβ6 antibody or antibody-drug conjugate is administered to the subject at least five months before the first dose of pembrolizumab or its biosimilar. In some embodiments, the first dose of the anti-αvβ6 antibody or antibody-drug conjugate is administered to the subject at least six months before the first dose of pembrolizumab or its biosimilar.

[0211] Treatment with an anti-αvβ6 antibody or antibody-drug conjugate, optionally in combination with any of the other agents or regimes described above, can be used to treat solid tumors (e.g., non-small cell lung cancer (NSCLC) (squamous and adenocarcinoma), head and neck cancer (including head and neck squamous cell carcinoma), esophageal cancer (including esophageal squamous cell carcinoma), breast cancer (including invasive breast cancer), HER2- breast cancer, ovarian cancer (high-grade serous ovarian cancer (HGSOC)), bladder cancer (including urothelial carcinoma), skin cancer (including squamous cell carcinoma, i.e., SCC), renal cancer (renal clear cell, renal papillary cell, and renal chromophobe cancer), and the like). The median progression-free survival or overall survival of patients with cancer (including uterine carcinosarcoma, uterine endometrium, rectal adenocarcinoma, thyroid cancer, colon adenocarcinoma, gastric adenocarcinoma, and pancreatic cancer (including pancreatic adenocarcinoma)), particularly in relapsed or refractory cases, may be increased by at least 30% or 40%, but preferably 50%, 60% to 70%, or even 100%, or longer, compared to the same treatment (e.g., chemotherapy) but without the anti-αvβ6 antibody alone or as a conjugate. Additionally or alternatively, a treatment (e.g., standard chemotherapy) including an anti-αvβ6 antibody alone or as a conjugate may increase the complete response rate, partial response rate, or objective response rate (complete + partial) in tumor-bearing patients by at least 30% or 40%, but preferably 50%, 60% to 70%, or even 100%, compared to the same treatment (e.g., chemotherapy) but without the anti-αvβ6 antibody alone or as a conjugate.

[0212] In one aspect, the method of treating a solid tumor with an anti-αvβ6 antibody or antibody-drug conjugate described herein results in an improvement in one or more therapeutic effects in a subject after administration of the antibody or antibody-drug conjugate described herein compared to baseline. In some embodiments, the one or more therapeutic effects are the size of a tumor derived from the cancer, the objective response rate, the duration of response, the time to response, progression-free survival, overall survival, or any combination thereof. In one embodiment, the one or more therapeutic effects are the size of a tumor derived from the cancer. In one embodiment, the one or more therapeutic effects are a reduction in tumor size. In one embodiment, the one or more therapeutic effects are stable disease. In one embodiment, the one or more therapeutic effects are a partial response. In one embodiment, the one or more therapeutic effects are a complete response. In one embodiment, the one or more therapeutic effects are an objective response rate. In one embodiment, the one or more therapeutic effects are the duration of response. In one embodiment, the one or more therapeutic effects are the time to response. In one embodiment, the one or more therapeutic effects are progression-free survival. In one embodiment, the one or more therapeutic benefits is overall survival. In one embodiment, the one or more therapeutic benefits is cancer regression.

[0213] In one embodiment of the methods or uses or products for use provided herein, the response to treatment with the anti-αvβ6 antibodies or antibody-drug conjugates described herein may include the following criteria (RECIST criteria 1.1):

[0214] [Table 1]

[0215] In one embodiment of the methods or uses or products for use provided herein, the efficacy of treatment with an anti-αvβ6 antibody or antibody-drug conjugate described herein is assessed by measuring the objective response rate. In some embodiments, the objective response rate is the percentage of patients experiencing a reduction in tumor size by a predetermined amount and for a minimum duration. In some embodiments, the objective response rate is based on RECIST v1.1. In one embodiment, the objective response rate is 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%. In one embodiment, the objective response rate is at least about 20% to 80%. In one embodiment, the objective response rate is at least about 30% to 80%. In one embodiment, the objective response rate is at least about 40% to 80%. In one embodiment, the objective response rate is at least about 50% to 80%. In one embodiment, the objective response rate is at least about 60% to 80%. In one embodiment, the objective response rate is at least about 70% to 80%. In one embodiment, the objective response rate is at least about 80%. In one embodiment, the objective response rate is at least about 85%. In one embodiment, the objective response rate is at least about 90%. In one embodiment, the objective response rate is at least about 95%. In one embodiment, the objective response rate is at least about 98%. In one embodiment, the objective response rate is at least about 99%. In one embodiment, the objective response rate is 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%. In one embodiment, the objective response rate is at least 20% to 80%. In one embodiment, the objective response rate is at least 30% to 80%. In one embodiment, the objective response rate is at least 40% to 80%. In one embodiment, the objective response rate is at least 50% to 80%. In one embodiment, the objective response rate is at least 60% to 80%.In one embodiment, the objective response rate is at least 70% to 80%. In one embodiment, the objective response rate is at least 80%. In one embodiment, the objective response rate is at least 85%. In one embodiment, the objective response rate is at least 90%. In one embodiment, the objective response rate is at least 95%. In one embodiment, the objective response rate is at least 98%. In one embodiment, the objective response rate is at least 99%. In one embodiment, the objective response rate is 100%.

[0216] In one embodiment of the methods or uses or products for use provided herein, response to treatment with an anti-αvβ6 antibody or antibody-drug conjugate described herein is assessed by measuring the size of a tumor derived from the cancer. In one embodiment, the size of a tumor derived from the cancer is reduced by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, or at least about 80% compared to the size of the tumor derived from the cancer before administration of an antibody or antibody-drug conjugate described herein. In one embodiment, the size of a tumor derived from the cancer is reduced by at least about 10% to 80%. In one embodiment, the size of a tumor derived from the cancer is reduced by at least about 20% to 80%. In one embodiment, the size of a tumor derived from the cancer is reduced by at least about 30% to 80%. In one embodiment, the size of a tumor derived from the cancer is reduced by at least about 40% to 80%. In one embodiment, the size of a tumor derived from the cancer is reduced by at least about 50% to 80%. In one embodiment, the size of a tumor derived from the cancer is reduced by at least about 60% to 80%. In one embodiment, the size of a tumor derived from the cancer is reduced by at least about 70% to 80%. In one embodiment, the size of a tumor derived from the cancer is reduced by at least about 80%. In one embodiment, the size of a tumor derived from the cancer is reduced by at least about 85%. In one embodiment, the size of a tumor derived from the cancer is reduced by at least about 90%. In one embodiment, the size of a tumor derived from the cancer is reduced by at least about 95%. In one embodiment, the size of a tumor derived from the cancer is reduced by at least about 98%. In one embodiment, the size of a tumor derived from the cancer is reduced by at least about 99%.In one embodiment, the size of a tumor derived from the cancer is reduced by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 70%, or at least 80% compared to the size of the tumor derived from the cancer prior to administration of an antibody or antibody-drug conjugate described herein. In one embodiment, the size of a tumor derived from the cancer is reduced by at least 10% to 80%. In one embodiment, the size of a tumor derived from the cancer is reduced by at least 20% to 80%. In one embodiment, the size of a tumor derived from the cancer is reduced by at least 30% to 80%. In one embodiment, the size of a tumor derived from the cancer is reduced by at least 40% to 80%. In one embodiment, the size of a tumor derived from the cancer is reduced by at least 50% to 80%. In one embodiment, the size of a tumor derived from the cancer is reduced by at least 60% to 80%. In one embodiment, the size of the cancer-derived tumor is reduced by at least 70% to 80%. In one embodiment, the size of the cancer-derived tumor is reduced by at least 80%. In one embodiment, the size of the cancer-derived tumor is reduced by at least 85%. In one embodiment, the size of the cancer-derived tumor is reduced by at least 90%. In one embodiment, the size of the cancer-derived tumor is reduced by at least 95%. In one embodiment, the size of the cancer-derived tumor is reduced by at least 98%. In one embodiment, the size of the cancer-derived tumor is reduced by at least 99%. In one embodiment, the size of the cancer-derived tumor is reduced by 100%. In one embodiment, the size of the cancer-derived tumor is measured by magnetic resonance imaging (MRI). In one embodiment, the size of the cancer-derived tumor is measured by computed tomography (CT). In one embodiment, the size of the cancer-derived tumor is measured by positron emission tomography (PET). In one embodiment, the size of the cancer-derived tumor is measured by ultrasound.

[0217] In one embodiment of the methods or uses or products for use provided herein, the response to treatment with an anti-αvβ6 antibody or antibody-drug conjugate described herein promotes regression of a tumor derived from a cancer. In one embodiment, the tumor derived from the cancer shrinks 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% compared to the size of the tumor derived from the cancer before administration of the antibody or antibody-drug conjugate described herein. In one embodiment, the tumor derived from the cancer shrinks by at least about 10% to about 80%. In one embodiment, the tumor derived from the cancer shrinks by at least about 20% to about 80%. In one embodiment, the tumor derived from the cancer shrinks by at least about 30% to about 80%. In one embodiment, the cancer-derived tumor regresses by at least about 40% to about 80%. In one embodiment, the cancer-derived tumor regresses by at least about 50% to about 80%. In one embodiment, the cancer-derived tumor regresses by at least about 60% to about 80%. In one embodiment, the cancer-derived tumor regresses by at least about 70% to about 80%. In one embodiment, the cancer-derived tumor regresses by at least about 80%. In one embodiment, the cancer-derived tumor regresses by at least about 85%. In one embodiment, the cancer-derived tumor regresses by at least about 90%. In one embodiment, the cancer-derived tumor regresses by at least about 95%. In one embodiment, the cancer-derived tumor regresses by at least about 98%. In one embodiment, the cancer-derived tumor regresses by at least about 99%. In one embodiment, the tumor derived from the cancer shrinks 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% compared to the size of the tumor derived from the cancer before administration of an antibody or antibody-drug conjugate described herein.In one embodiment, the cancer-derived tumor regresses by at least 10% to 80%. In one embodiment, the cancer-derived tumor regresses by at least 20% to 80%. In one embodiment, the cancer-derived tumor regresses by at least 30% to 80%. In one embodiment, the cancer-derived tumor regresses by at least 40% to 80%. In one embodiment, the cancer-derived tumor regresses by at least 50% to 80%. In one embodiment, the cancer-derived tumor regresses by at least 60% to 80%. In one embodiment, the cancer-derived tumor regresses by at least 70% to 80%. In one embodiment, the cancer-derived tumor regresses by at least 80%. In one embodiment, the cancer-derived tumor regresses by at least 85%. In one embodiment, the cancer-derived tumor regresses by at least 90%. In one embodiment, the cancer-derived tumor regresses by at least 95%. In one embodiment, the cancer-derived tumor regresses by at least 98%. In one embodiment, the tumor resulting from the cancer undergoes at least 99% regression. In one embodiment, the tumor resulting from the cancer undergoes 100% regression. In one embodiment, tumor regression is determined by measuring tumor size by magnetic resonance imaging (MRI). In one embodiment, tumor regression is determined by measuring tumor size by computed tomography (CT). In one embodiment, tumor regression is determined by measuring tumor size by positron emission tomography (PET). In one embodiment, tumor regression is determined by measuring tumor size by ultrasound.

[0218] In one embodiment of the methods or uses or products for use described herein, response to treatment with an anti-αvβ6 antibody or antibody-drug conjugate described herein is assessed by measuring progression-free survival time after administration of the antibody or antibody-drug conjugate described herein. In some embodiments, the subject exhibits progression-free survival for 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 2 years, at least about 3 years, at least about 4 years, or at least about 5 years after administration of the antibody or antibody-drug conjugate described herein. In some embodiments, the subject exhibits progression-free survival for at least about 6 months after administration of the antibody or antibody-drug conjugate described herein. In some embodiments, a subject exhibits progression-free survival for at least about one year after administration of an antibody or antibody-drug conjugate described herein. In some embodiments, a subject exhibits progression-free survival for at least about two years after administration of an antibody or antibody-drug conjugate described herein. In some embodiments, a subject exhibits progression-free survival for at least about three years after administration of an antibody or antibody-drug conjugate described herein. In some embodiments, a subject exhibits progression-free survival for at least about four years after administration of an antibody or antibody-drug conjugate described herein. In some embodiments, a subject exhibits progression-free survival for at least about five years after administration of an antibody or antibody-drug conjugate described herein.In some embodiments, a subject exhibits progression-free survival for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 18 months, at least 2 years, at least 3 years, at least 4 years, or at least 5 years after administration of an antibody or antibody-drug conjugate described herein. In some embodiments, a subject exhibits progression-free survival for at least 6 months after administration of an antibody or antibody-drug conjugate described herein. In some embodiments, a subject exhibits progression-free survival for at least 1 year after administration of an antibody or antibody-drug conjugate described herein. In some embodiments, a subject exhibits progression-free survival for at least 2 years after administration of an antibody or antibody-drug conjugate described herein. In some embodiments, a subject exhibits progression-free survival for at least 3 years after administration of an antibody or antibody-drug conjugate described herein. In some embodiments, the subject exhibits progression-free survival for at least four years after administration of an antibody or antibody-drug conjugate described herein, hi some embodiments, the subject exhibits progression-free survival for at least five years after administration of an antibody or antibody-drug conjugate described herein.

[0219] In one embodiment of the methods or uses or products for use described herein, response to treatment with an anti-αvβ6 antibody or antibody-drug conjugate described herein is assessed by measuring overall survival time after administration of the antibody or antibody-drug conjugate described herein. In some embodiments, the subject exhibits overall survival of at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 18 months, at least about 2 years, at least about 3 years, at least about 4 years, or at least about 5 years after administration of the antibody or antibody-drug conjugate described herein. In some embodiments, the subject exhibits overall survival of at least about 6 months after administration of the antibody or antibody-drug conjugate described herein. In some embodiments, a subject exhibits at least about one year of overall survival after administration of an antibody or antibody-drug conjugate described herein. In some embodiments, a subject exhibits at least about two years of overall survival after administration of an antibody or antibody-drug conjugate described herein. In some embodiments, a subject exhibits at least about three years of overall survival after administration of an antibody or antibody-drug conjugate described herein. In some embodiments, a subject exhibits at least about four years of overall survival after administration of an antibody or antibody-drug conjugate described herein. In some embodiments, a subject exhibits at least about five years of overall survival after administration of an antibody or antibody-drug conjugate described herein. In some embodiments, a subject exhibits overall survival of at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 18 months, at least 2 years, at least 3 years, at least 4 years, or at least 5 years after administration of an antibody or antibody-drug conjugate described herein.In some embodiments, a subject exhibits overall survival for at least six months after administration of an antibody or antibody-drug conjugate described herein. In some embodiments, a subject exhibits overall survival for at least one year after administration of an antibody or antibody-drug conjugate described herein. In some embodiments, a subject exhibits overall survival for at least two years after administration of an antibody or antibody-drug conjugate described herein. In some embodiments, a subject exhibits overall survival for at least three years after administration of an antibody or antibody-drug conjugate described herein. In some embodiments, a subject exhibits overall survival for at least four years after administration of an antibody or antibody-drug conjugate described herein. In some embodiments, a subject exhibits overall survival for at least five years after administration of an antibody or antibody-drug conjugate described herein.

[0220] In one embodiment of the methods or uses or products for use described herein, response to treatment with an anti-αvβ6 antibody or antibody-drug conjugate described herein is assessed by measuring the duration of response to the antibody or antibody-drug conjugate described herein after administration of the antibody or antibody-drug conjugate described herein. In some embodiments, the duration of response to the antibody or antibody-drug conjugate described herein 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 2 years, at least about 3 years, at least about 4 years, or at least about 5 years after administration of the antibody or antibody-drug conjugate described herein. In some embodiments, the duration of response to an antibody or antibody-drug conjugate described herein is at least about six months after administration of an antibody or antibody-drug conjugate described herein. In some embodiments, the duration of response to an antibody or antibody-drug conjugate described herein is at least about one year after administration of an antibody or antibody-drug conjugate described herein. In some embodiments, the duration of response to an antibody or antibody-drug conjugate described herein is at least about two years after administration of an antibody or antibody-drug conjugate described herein. In some embodiments, the duration of response to an antibody or antibody-drug conjugate described herein is at least about three years after administration of an antibody or antibody-drug conjugate described herein. In some embodiments, the duration of response to an antibody or antibody-drug conjugate described herein is at least about four years after administration of an antibody or antibody-drug conjugate described herein. In some embodiments, the duration of response to an antibody or antibody-drug conjugate described herein is at least about 5 years after administration of an antibody or antibody-drug conjugate described herein.In some embodiments, the duration of response to an antibody or antibody-drug conjugate described herein is at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 18 months, at least 2 years, at least 3 years, at least 4 years, or at least 5 years after administration of an antibody or antibody-drug conjugate described herein. In some embodiments, the duration of response to an antibody or antibody-drug conjugate described herein is at least 6 months after administration of an antibody or antibody-drug conjugate described herein. In some embodiments, the duration of response to an antibody or antibody-drug conjugate described herein is at least 1 year after administration of an antibody or antibody-drug conjugate described herein. In some embodiments, the duration of response to an antibody or antibody-drug conjugate described herein is at least 2 years after administration of an antibody or antibody-drug conjugate described herein. In some embodiments, the duration of response to an antibody or antibody-drug conjugate described herein is at least three years after administration of an antibody or antibody-drug conjugate described herein. In some embodiments, the duration of response to an antibody or antibody-drug conjugate described herein is at least four years after administration of an antibody or antibody-drug conjugate described herein. In some embodiments, the duration of response to an antibody or antibody-drug conjugate described herein is at least five years after administration of an antibody or antibody-drug conjugate described herein.

[0221] Typically, in clinical trials (e.g., phase I, phase II, phase II / III, or phase III trials), the above-mentioned increase in progression-free survival and / or overall survival and / or response rate and / or median duration of response of patients treated with standard therapy plus anti-αvβ6 antibody alone or as a conjugate, compared with a control group of patients receiving standard therapy alone (or plus placebo), is statistically significant, for example, at the p=0.05 or 0.01 or even 0.001 level. Complete and partial response rates are determined by objective criteria commonly used in cancer clinical trials, such as those listed or recognized by the National Cancer Institute and / or the US Food and Drug Administration.

[0222] 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 from the subject express PD-L1. In some embodiments, at least 0.1%, at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, 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% of cancer cells from a subject express PD-L1. In some of the embodiments herein, the subject's tumor expresses PD-L1 with a Tumor Proportion Score (TPS) of ≥ 1%. In some of the embodiments herein, the subject's tumor expresses PD-L1 with a TPS of ≥ 5%. In some of the embodiments herein, the subject's tumor expresses PD-L1 with a TPS of ≥ 10%. In some of the embodiments herein, the subject's tumor expresses PD-L1 with a TPS of ≥ 15%. In some of the embodiments herein, the subject's tumor expresses PD-L1 at a TPS of ≧20%. In some of the embodiments herein, the subject's tumor expresses PD-L1 at a TPS of ≧25%. In some of the embodiments herein, the subject's tumor expresses PD-L1 at a TPS of ≧30%. In some of the embodiments herein, the subject's tumor expresses PD-L1 at a TPS of ≧35%. In some of the embodiments herein, the subject's tumor expresses PD-L1 at a TPS of ≧40%. In some of the embodiments herein, the subject's tumor expresses PD-L1 at a TPS of ≧45%.In some embodiments herein, the subject's tumor has high PD-L1 expression with a TPS of ≥ 50%. In some embodiments herein, the subject's tumor expresses PD-L1 with a combined positive score (CPS) of ≥ 1%. See US2017 / 0285037. In some embodiments herein, the subject's tumor expresses PD-L1 with a CPS of ≥ 5%. In some embodiments herein, the subject's tumor expresses PD-L1 with a CPS of ≥ 10%. In some embodiments herein, the subject's tumor expresses PD-L1 with a CPS of ≥ 15%. In some embodiments herein, the subject's tumor expresses PD-L1 with a CPS of ≥ 20%. In some embodiments herein, the subject's tumor expresses PD-L1 with a CPS of ≥ 25%. In some embodiments herein, the subject's tumor expresses PD-L1 with a CPS of ≥ 30%. In some embodiments herein, the subject's tumor expresses PD-L1 with a CPS of ≥ 35%. In some embodiments herein, the subject's tumor expresses PD-L1 at a CPS of ≧40%. In some embodiments herein, the subject's tumor expresses PD-L1 at a CPS of ≧45%. In some embodiments herein, the subject's tumor expresses PD-L1 at a CPS of ≧50%. In some embodiments, the percentage of cells expressing PD-L1 is determined using immunohistochemistry (IHC). In some embodiments, the percentage of cells expressing PD-L1 is determined using flow cytometry. In some embodiments, the percentage of cells expressing PD-L1 is determined using enzyme-linked immunosorbent assay (ELISA). In some embodiments, the percentage of cells expressing PD-L1 is assessed prior to the methods or uses or products for use described herein.

[0223] IX. ARTICLES OF MANUFACTURE AND KITS In another aspect, an article of manufacture or kit is provided that includes the anti-αvβ6 antibody or anti-αvβ6 antibody-drug conjugate described herein. The article of manufacture or kit may further include instructions for using the anti-αvβ6 antibody or anti-αvβ6 antibody-drug conjugate described herein in the methods of the invention. Thus, in certain embodiments, the article of manufacture or kit comprises instructions for use of an anti-αvβ6 antibody or anti-αvβ6 antibody-drug conjugate described herein in a method for treating cancer in a subject (e.g., non-small cell lung cancer (NSCLC) (squamous and adenocarcinoma), head and neck cancer (including head and neck squamous cell carcinoma), esophageal cancer, breast cancer (including invasive breast cancer), ovarian cancer, bladder cancer (including urothelial carcinoma), skin cancer (squamous cell carcinoma, i.e., SCC), renal cancer (including renal clear cell, renal papillary cell, and renal chromophobe cell), cervical cancer, gastric cancer, prostate cancer (including prostate adenocarcinoma), endometrial cancer (including uterine carcinosarcoma and uterine corpus endometrium), rectal adenocarcinoma, thyroid cancer, colon adenocarcinoma, gastric adenocarcinoma, and pancreatic cancer (including pancreatic adenocarcinoma)), comprising administering to the subject an effective amount of an anti-αvβ6 antibody or anti-αvβ6 antibody-drug conjugate described herein. In some embodiments, the cancer is NSCLC. In some embodiments, the NSCLC is squamous cell carcinoma. In some embodiments, the NSCLC is non-squamous cell carcinoma. In some embodiments, the NSCLC is adenocarcinoma. In some embodiments, the NSCLC does not have a known mutation / alteration that qualifies it for an approved targeted therapy (e.g., epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), etc.). In some embodiments, the NSCLC has one or more known mutations / alterations that qualifies it for an approved targeted therapy (e.g., epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), etc.). In some embodiments, the NSCLC has a known EGFR mutation. In some embodiments, the NSCLC has a known ALK mutation. In some embodiments, the cancer is head and neck cancer. In some embodiments, the head and neck cancer is squamous cell carcinoma. In some embodiments, the cancer is esophageal cancer. In some embodiments, the esophageal cancer is esophageal squamous cell carcinoma. In some embodiments, the cancer is breast cancer.In some embodiments, the breast cancer is HER2-negative breast cancer. In some embodiments, the breast cancer is invasive breast cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the ovarian cancer is high-grade serous epithelial ovarian cancer. In some embodiments, the cancer is primary peritoneal cancer. In some embodiments, the cancer is fallopian tube cancer. In some embodiments, the cancer is renal cancer. In some embodiments, the renal cancer is renal clear cell carcinoma. In some embodiments, the renal cancer is renal papillary cell carcinoma. In some embodiments, the renal cancer is renal chromophobe cell carcinoma. In some embodiments, the cancer is endometrial cancer. In some embodiments, the endometrial cancer is uterine carcinosarcoma. In some embodiments, the endometrial cancer is uterine corpus endometrial carcinoma. In some embodiments, the cancer is gastric cancer. In some embodiments, the gastric cancer is gastric adenocarcinoma. In some embodiments, the cancer is bladder cancer. In some embodiments, the bladder cancer is urothelial carcinoma. In some embodiments, the cancer is skin cancer. In some embodiments, the skin cancer is cutaneous squamous cell carcinoma. In some embodiments, the cancer is prostate cancer. In some embodiments, the prostate cancer is prostate adenocarcinoma. In some embodiments, the cancer is rectal adenocarcinoma. In some embodiments, the cancer is thyroid cancer. In some embodiments, the cancer is colon adenocarcinoma. In some embodiments, the cancer is cervical cancer. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the pancreatic cancer is exocrine pancreatic adenocarcinoma. In some embodiments, the subject is a human.

[0224] The article of manufacture or kit may further comprise a container. Suitable containers include, for example, bottles, vials (e.g., dual-chamber vials), syringes (such as single- or dual-chamber syringes), and test tubes. In some embodiments, the container is a vial. The container may be formed from a variety of materials, such as glass or plastic. The container holds the formulation.

[0225] The article of manufacture or kit may further include a label or package insert on or associated with the container, which may indicate instructions for reconstitution and / or use of the formulation. The label or package insert may further indicate that the formulation is useful or intended for subcutaneous, intravenous (e.g., intravenous infusion), or other mode of administration to treat cancer in a subject (e.g., non-small cell lung cancer (NSCLC) (squamous and adenocarcinoma), head and neck cancer (including head and neck squamous cell carcinoma), esophageal cancer, breast cancer (including invasive breast cancer), ovarian cancer, bladder cancer (including urothelial carcinoma), skin cancer (squamous cell carcinoma, or SCC), kidney cancer (including renal clear cell, renal papillary cell, and renal chromophobe cell), cervical cancer, gastric cancer, prostate cancer (including prostate adenocarcinoma), endometrial cancer (including uterine carcinosarcoma and uterine corpus endometrium), rectal adenocarcinoma, thyroid cancer, colon adenocarcinoma, gastric adenocarcinoma, and pancreatic cancer (including pancreatic adenocarcinoma)). The container that holds the formulation can be a single-use vial or a multi-use vial that allows repeated administration of the reconstituted formulation.The article of manufacture or kit can further include a second container that contains a suitable diluent.The article of manufacture or kit can further include other materials that are desirable from a commercial, therapeutic, and user standpoint, including other buffers, diluents, filters, needles, syringes, and package inserts with instructions for use.

[0226] The article of manufacture or kit herein optionally further comprises a container containing a second medicament, wherein the anti-αvβ6 antibody or anti-αvβ6 antibody-drug conjugate is the first medicament, and the article or kit further comprises instructions on a label or package insert for treating a subject with an effective amount of the second medicament. In some embodiments, the second medicament is for eliminating or reducing the severity of one or more adverse events.

[0227] In some embodiments, the anti-αvβ6 antibody or anti-αvβ6 antibody-drug conjugate is present in a container as a lyophilized powder. In some embodiments, the lyophilized powder is in a sealed container, such as a vial, ampule, or sachette, indicating the quantity of active agent. If the pharmaceutical is administered by injection, an ampule of, for example, sterile water for injection or saline may optionally be provided as part of the kit so that the components can be mixed prior to administration. Such kits may further include one or more various conventional pharmaceutical components, such as, for example, a container with one or more pharmaceutically acceptable carriers, additional containers, etc., as would be readily apparent to one skilled in the art. Printed instructions, as an insert or label, indicating the quantities of the components to be administered, guidelines for administration, and / or guidelines for mixing the components may also be included in the kit.

[0228] X. Other Applications The anti-αvβ6 antibodies described herein, such as humanized anti-αvβ6 antibodies, can be used to detect αvβ6 in clinical diagnostic or therapeutic settings or in research. Expression of αvβ6 in cancer provides an indication that the cancer is amenable to treatment with the antibodies of the present invention. Antibodies can also be sold as research reagents for laboratory studies in detecting αvβ6-bearing cells and their responses to various stimuli. For such uses, monoclonal antibodies can be labeled with fluorescent molecules, spin-labeled molecules, enzymes, or radioisotopes and provided in the form of kits containing all the necessary reagents for performing assays for αvβ6. The antibodies described herein can be used to detect αvβ6 protein expression and determine whether a cancer is amenable to treatment with an αvβ6 ADC.

[0229] All patent applications, websites, other publications, accession numbers, etc., cited above or below are incorporated by reference in their entirety for all purposes to the same extent as if each individual item were specifically and individually indicated to be incorporated by reference. Where various versions of a sequence have been associated with an accession number at various times, the version associated with the accession number as of the effective filing date of this application is intended. The effective filing date means the earlier of the actual filing date or, if applicable, the filing date of the priority application referencing the accession number. Similarly, where various versions of a publication, website, etc. have been published at various times, the most recently published version as of the effective filing date of this application is intended unless otherwise indicated. Any feature, step, element, embodiment, or aspect of the invention may be used in combination with any other, unless specifically indicated otherwise. Although the invention has been described in some detail by way of illustration and example for purposes of clarity and understanding, it will be apparent that certain changes and modifications can be practiced within the scope of the appended claims. [Example]

[0230] Example 1 Phase 1 Study of SGN-B6A in Advanced Solid Tumors SGN-B6A is an antibody-drug conjugate (ADC) targeting integrin beta-6 (AVB6), a cell surface adhesion protein with high prevalence in several types of cancer. SGN-B6A consists of a humanized IgG1 anti-integrin beta-6 monoclonal antibody (h2A2) conjugated via a cleavable peptide linker to the tubulin-interfering antimitotic drug monomethyl auristatin E (MMAE). Upon binding to integrin beta-6 on the surface of malignant cells, SGN-B6A is designed to internalize and release the cytotoxic MMAE. A summary of the clinical and nonclinical data related to SGN-B6A and its studies in human subjects is provided in the Investigator's Brochure (IB).

[0231] Keytruda® (pembrolizumab) is a potent, humanized IgG4 monoclonal antibody (mAb) with high specificity for binding to the programmed death 1 (PD-1) receptor, thereby inhibiting its interaction with programmed death-ligand 1 (PD-L1) and programmed death-ligand 2 (PD-L2). Based on preclinical in vitro data, pembrolizumab has high affinity for PD-1 and potent receptor-blocking activity. Pembrolizumab has an acceptable preclinical safety profile and is also approved and in clinical development as an intravenous (IV) immunotherapy for advanced malignancies. Pembrolizumab is indicated for the treatment of patients across several indications. For detailed background, please see the pembrolizumab product information.

[0232] This first-in-human (FIH) study is designed to evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of SGN-B6A monotherapy (Parts A and B) and SGN-B6A in combination with pembrolizumab (Parts C and D) in adults with select advanced solid tumors.

[0233] This is a Phase 1, open-label, multicenter study designed to evaluate the safety, tolerability, PK, and antitumor activity of SGN-B6A in adults with selected advanced solid tumors. The study will include dose escalation and dose expansion, with multiple disease-specific and biological cohorts in the dose expansion. Biological cohorts will be gated based on data generated in other parts of the study and require additional biopsies. Upon completion of dose escalation to a specific schedule, up to nine disease-specific expansion cohorts and one biological cohort may be initiated by the sponsor in consultation with the Safety Monitoring Committee (SMC). The expansion cohorts in Part B will enroll selected tumor types eligible for enrollment in Part A.

[0234] method This is a Phase 1 dose-escalation study in subjects with advanced solid tumors. The primary objectives of Part A are to evaluate the safety and tolerability of SGN-B6A in subjects with advanced solid tumors, identify the maximum tolerated dose (MTD), and identify the recommended dose and schedule. SGN-B6A will be initially administered by intravenous (IV) infusion on days 1, 8, and 15 of a 21-day cycle. Other dosing regimens may be explored. The dose-escalation portion of the study (Part A) will be conducted using a modified toxicity probability partition (mTPI) method to determine the dose exhibiting a 25% dose-limiting toxicity (DLT) rate with a 5% margin. For the dose-escalation portion of the study (Part A), the SGN-B6A dose level and administration schedule will be defined by cohort assignment. The dose and schedule for the dose-expansion portion (Part B) will be determined based on evaluation of safety, pharmacokinetic (PK), and pharmacodynamic biomarkers. For the dose expansion portion (Part B), SGN-B6A at or below the MTD determined in Part A and / or the recommended dose and schedule.

[0235] Because integrin beta-6 is expressed in several tumor types, SGN-B6A may be active in a wide variety of malignancies. For initial clinical evaluation during dose escalation in Part A, 10 specific tumor types will be targeted: non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), advanced human epidermal growth factor receptor 2 (HER2)-negative breast cancer, esophageal squamous cell carcinoma (ESCC), high-grade serous ovarian cancer (HGSOC), cutaneous squamous cell carcinoma (cSCC), exocrine pancreatic adenocarcinoma, bladder cancer, cervical cancer, and gastric cancer. Upon completion of dose escalation to specific schedules, up to nine disease-specific expansion cohorts and one biologic cohort will be initiated in Part B to further evaluate the safety and preliminary antitumor efficacy of SGN-B6A.

[0236] The primary objective of Part C is to evaluate the safety and tolerability of SGN-B6A in combination with pembrolizumab. Upon completion of Part C, two disease-specific expansion cohorts, NSCLC and HNSCC, will be initiated to further evaluate the safety and preliminary antitumor activity of SGN-B6A in combination with pembrolizumab (Part D).

[0237] The planned dose of pembrolizumab for Parts C and D of this study is 200 mg Q3W or 400 mg Q6W. Based on the totality of data generated in the pembrolizumab development program, 200 mg Q3W and 400 mg Q6W are appropriate doses of pembrolizumab for adults across all indications. As outlined below, this dose: Clinical data from eight randomized studies in melanoma and NSCLC indications demonstrating a flat dose- and exposure-efficacy relationship over an approximately 5- to 7.5-fold exposure range from 2 mg / kg Q3W to 10 mg / kg every 2 weeks (Q2W) Population PK analysis supporting the appropriateness of 200 mg Q3W, demonstrating that both fixed-dose and weight-based dosing provide similar control of PK variability with substantial overlap in exposure distributions Clinical data demonstrating meaningful benefit-risk improvements, including overall survival, at 200 mg Q3W across multiple indications; Pharmacological data demonstrating complete target saturation in both the systemic circulation (inferred from PK data) and tumor (inferred from physiologically based PK analysis) at 200 mg Q3W is justified by

[0238] Part A - Dose Escalation Cohort The dose escalation part (Part A) of this study will be carried out in approximately 85 subjects using mTPI method.Part A is designed to evaluate the safety and tolerability of SGN-B6A and to identify its MTD.If MTD is not reached, safety, PK, pharmacodynamics and biomarker analysis, as well as preliminary antitumor activity, can be used to determine the recommended dose.

[0239] The mTPI method uses a Bayesian statistical framework and a beta-binomial hierarchical model to calculate the posterior probability of three intervals that reflect the relative distance between the toxicity rate at each dose level and the target DLT rate. The dosage decision rule is determined for a target DLT rate of 25% with a 5% margin. The three intervals are (0, 20%), (20%, 30%), and (30%, 100%), and the corresponding dose decision rule is as follows: 1. Escalate if current DLT rate is highly likely to be <20% 2. Continue if current DLT rate is highly likely to be between 20% and 30% 3. Reduce dose if current DLT rate is likely to be >30%

[0240] Dose titration decisions are shown in Table 1. "E" represents dose escalation, "S" represents staying at the same dose, and "D" represents dose decrement. A decision of "DU" means that the current dose level may be unacceptable due to high toxicity. A dose is defined as having unacceptable toxicity if the posterior probability of a DLT rate higher than 25% is greater than 95%.

[0241] Enrollment in this study will occur on a cohort-by-cohort basis. Dose escalation and subsequent cohort size decisions will be made by the sponsor in consultation with the Safety Monitoring Committee (SMC) after the completion of each cohort. At least two DLT-evaluable (DE) subjects per dose level will be treated until the first DLT is observed. After the first DLT is observed, a minimum of three DE subjects per dose level will be required before escalation to any higher dose. During initial assessment of dose levels during dose escalation, two subjects may not receive their first dose of study drug on the same day. Subjects deemed unevaluable for DLT during Cycle 1 may be replaced. A minimum of six DE subjects will be observed at the estimated MTD before the MTD is determined. The MTD is estimated based on data from all subjects across all doses evaluated. The MTD is defined as the highest evaluated dose that does not cause unacceptable side effects, as determined by the mTPI design.

[0242] Reduction to a lower dose level may be implemented at any time by the sponsor in consultation with the SMC.

[0243] During dose escalation, additional subjects may be enrolled at tested dose levels deemed tolerable (hereafter referred to as "backfilling"). DLTs observed at lower dose levels are taken into account along with the overall data; the SMC will make future escalation decisions based on the mTPI model recommendations at the current and lower dose levels where backfilled DLTs were observed.

[0244] [Table 2]

[0245] The SGN-B6A dose level and administration schedule will be determined by cohort assignment. SGN-B6A will be initially administered on days 1, 8, and 15 of a 21-day cycle at the planned doses shown in Table 2. Longer dosing intervals (e.g., only days 1 and 8 or only day 1 of a 21-day cycle, or once every two weeks in a 28-day cycle) may be evaluated during dose escalation after consultation with the SMC. The mTPI dose escalation rules apply separately to each dosing schedule. The SMC may also recommend consideration of lower and / or intermediate dose levels, in which case the mTPI dose escalation rules will continue to apply.

[0246] [Table 3]

[0247] Part B - Expansion Cohort Disease-Specific Cohorts: Upon completion of dose escalation to a specific schedule, up to 360 additional subjects may be enrolled in up to nine disease-specific expansion cohorts to further characterize the safety, PK, and antitumor activity of SGN-B6A. Each expansion cohort may enroll up to approximately 40 subjects eligible for dose escalation in the selected tumor type. For each disease-specific cohort, 15 subjects will be initially enrolled. For expansion cohorts, a baseline new tumor tissue biopsy will be required, if feasible. Optional, protocol-specified on-treatment or end-of-treatment (EOT) research biopsies may be collected for exploratory correlation studies of SGN-B6A tumor exposure and antitumor activity. A futility analysis will be performed using the predicted probability of success (PPoS) approach, with success defined as a response rate greater than the background response rate with a posterior probability of >0.70. Futility may be determined if the PPoS is <15% in the disease-specific cohorts. If the background response rate is 0.05, at least one objective response (OR) is observed among the first 15 subjects, and up to 25 additional subjects may be enrolled; if no OR is observed among the first 15 subjects, the SMC will assess the entire data set and may recommend continued enrollment of up to 25 additional subjects if there is preliminary evidence of clinical benefit among the first 15 subjects. Evidence of clinical benefit may include stabilization or improvement of disease-related symptoms as assessed by the investigator, or disease regression on imaging. The dose, schedule, and disease setting for expansion cohorts will be determined by the sponsor in consultation with the SMC and may vary between cohorts.

[0248] Biological Cohort: Up to 30 additional subjects with any of the selected tumor types who consent to protocol-specified research biopsies may be eligible to enroll in the biological cohort. Subjects in the biological cohort will be asked to provide pre- and post-treatment tumor samples to characterize the clinical mechanism of action (MOA) and correlation of sensitivity / resistance at the MTD or recommended dose.

[0249] Part C - SGN-B6A in combination with pembrolizumab Part C is designed to evaluate the safety and tolerability of SGN-B6A in combination with pembrolizumab. SGN-B6A will be administered in combination with pembrolizumab, starting at the recommended dose and schedule defined in Part A (200 mg every 3 weeks or 400 mg every 6 weeks). Part C will be conducted using the mTPI method, with a minimum cohort size of 3. If necessary, the dose will be reduced to dose level -1, as determined in Part A.

[0250] Part D - Combination Treatment Expansion Cohort To further characterize the safety, PK, and antitumor activity of SGN-B6A in combination with pembrolizumab, two expansion cohorts for NSCLC (TPS ≥ 50 by local study) and HNSCC (CPS ≥ 1 by local study) will enroll up to approximately 40 subjects each. The dose regimens evaluated in Part C will inform dose and schedule selection for the expansion cohorts, as determined by the sponsor in consultation with the SMC. The dose and schedule may vary between cohorts.

[0251] Duration of treatment In all parts, subjects may continue treatment with SGN-B6A until disease progression, unacceptable toxicity, investigator's decision, withdrawal of consent, initiation of subsequent anticancer therapy, pregnancy, or termination of study by the sponsor, whichever occurs first. In parts C and D, pembrolizumab may be administered until confirmed disease progression per iRECIST, unacceptable toxicity, investigator's decision, withdrawal of consent, initiation of subsequent anticancer therapy, pregnancy, or termination of study by the sponsor, or for up to 24 months, whichever occurs first.

[0252] Dose-limiting toxicity DLTs will be assessed during dose escalation. The DLT assessment period is the first cycle (21 or 28 days). Grading will follow the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), v5.0.

[0253] For Part A, a DLT is defined as any of the following, if assessed by the investigator as clinically significant and related to SGN-B6A treatment, during the DLT evaluation period:

[0254] For Part C, a DLT is defined as any of the following that is considered to be related to the combination with SGN-B6A or pembrolizumab and cannot be attributed to pembrolizumab alone: Grade 5 toxicity ≥ Grade 3 non-hematologic toxicity (not laboratory values), with the following exceptions: Grade 3 fatigue, fever, or constipation that resolves within 72 hours, regardless of whether intervention is given or not Grade 3 nausea, vomiting, or diarrhea in the absence of standard-of-care prophylaxis Grade 3 IRR that resolves to ≤ Grade 2 within 24 hours, with or without intervention In the event of a grade 3 IRR in ≥ 20% of subjects (i.e., ≥ 2 of the first 10 subjects), all subsequent subjects will require premedication and / or infusion technique modifications per SMC recommendations and the protocol will be amended. Any grade ≥ 3 IRR for a subsequent subject will be considered a DLT. Grade 3 or Grade 4 non-hematologic laboratory abnormalities: the abnormality requires hospitalization or clinically significant medical intervention, or Abnormality persists for >7 days, or Grade 4 anemia or thrombocytopenia Grade 4 hematologic toxicity (other than anemia / thrombocytopenia) lasting >7 days Grade 3 thrombocytopenia with clinically significant bleeding requiring platelet transfusion Grade 3 or higher febrile neutropenia ≥14-day dose delay due to toxicity

[0255] the purpose This study will evaluate the efficacy, safety, and PK of SGN-B6A in adults with the following histologically or cytologically confirmed metastatic or unresectable cancers: NSCLC, HNSCC, advanced HER2-negative breast cancer, ESCC, EAC / GEJ adenocarcinoma, HGSOC, cSCC, exocrine pancreatic adenocarcinoma, bladder cancer, cervical cancer, or gastric cancer. The study will also evaluate the efficacy, safety, and PK of SGN-B6A in combination with pembrolizumab in adults with metastatic or unresectable NSCLC or HNSCC. Specific study objectives and corresponding endpoints are summarized in Table 3.

[0256] [Table 4-1]

[0257] [Table 4-2]

[0258] Study endpoint definitions Objective response rate - ORR (confirmed or not) is defined as the proportion of subjects who achieve PR or CR according to RECIST v1.1. Confirmed ORR is defined as the proportion of subjects with a subsequently confirmed CR or PR assessed according to RECIST v1.1. Subjects whose disease response cannot be assessed according to the response criteria are scored as "unevaluable" for calculating ORR. Subjects who do not have a post-baseline response assessment or who have a response that is "unevaluable" are counted as non-responders in calculating ORR.

[0259] Progression-free survival-PFS is defined as the time from the start of any study treatment to the first documented progression (based on radiological assessment according to RECIST v1.1) or death from any cause, whichever occurs first. Subjects who are alive and have not progressed at the time of analysis are censored on the date of their last tumor assessment. Subjects who do not receive an evaluation of tumor response after their first dose are censored on day 1.

[0260] Overall survival - OS is defined as the time from the start of any study treatment to the date of death from any cause. OS = date of death - date of first dose of any study treatment + 1 OS for subjects alive at the date of their last contact, including those lost to follow-up, will be censored at the date of last contact. If the last recorded date that a subject is known to be alive is the date of first dose of any study treatment, time of survival will be censored at the date of first dose of any study treatment (i.e., 1-day OS duration).

[0261] Duration of response - DOR is defined as the time from the first documentation of an objective response (subsequently confirmed CR or PR) to the first documentation of PD or death from any cause, whichever occurs first. DOR data are censored at the date of the last adequate disease assessment documenting the absence of PD for subjects who do not have tumor progression at the time of analysis and are still on study, receive anti-tumor treatment other than the study treatment, or are removed from the study before documenting tumor progression. DOR is calculated only for subjects who achieve a confirmed response.

[0262] Study population To be eligible for this study, subjects must meet all of the enrollment criteria. Eligibility criteria cannot be waived by the investigator and are subject to review during good clinical practice audits and / or health regulatory agency inspections. Inclusion criteria 1.Disease indication a. For Part A: Subjects must have histologically or cytologically confirmed metastatic or unresectable solid malignant tumors in one of the tumor types listed below. Subjects must have disease that is relapsed or refractory, or be intolerant to standard care therapy and, in the investigator's judgment, should not have suitable standard care treatment options. If standard care therapy is available and is not being administered, the reason why the therapy is not suitable must be documented. NSCLC HNSCC Advanced HER2-negative breast cancer ·ESCC EAC / GEJ HGSOC cSCC Exocrine pancreatic adenocarcinoma Bladder cancer Cervical cancer Gastric cancer b. For Part B: Subjects may participate in up to nine disease-specific expansion cohorts. Subjects must have histologically or cytologically confirmed disease that is relapsed or refractory, unless contraindicated, or be intolerant to standard of care therapy as specified below: - NSCLC: - Subjects must have locally advanced or metastatic non-small cell lung cancer. - Prior Therapy: If applicable and available according to local standard of care, subjects must have received platinum-based therapy and a PD-1 / PD-L1 inhibitor. These agents may be administered as single agents or in combination. - Subjects with documented actionable genomic alterations should have received treatment with an approved tyrosine kinase inhibitor (TKI; e.g., ALK, ROS-1 gene rearrangement, or EGFR mutation, or other applicable targeted therapy) for the respective genomic alteration according to local guidelines. These subjects should not have received more than three lines of systemic therapy in the locally advanced or metastatic setting. Maintenance therapy should not be counted as a separate line of therapy. - HNSCC: - Subjects must have locally advanced or metastatic head and neck squamous cell carcinoma. - Prior Therapy: If eligible by biomarker status and local standard of care, subjects must have received platinum-based therapy and a PD-1 / PD-L1 inhibitor. These agents may be administered as single agents or in combination. - Advanced HER2-negative breast cancer: - Subjects must have locally advanced or metastatic HER2-negative breast cancer (per the American Society of Clinical Oncology / College of American Pathologists [ASCO / CAP] 2018 guidelines). - Subjects 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. - Hormone receptor-positive subjects must additionally be receiving CDK4 / 6 inhibitor therapy and at least one prior hormone-directed therapy, unless contraindicated. - If eligible by biomarker status and consistent with standard of care, must have received a poly-ADP ribose polymerase (PARP) inhibitor, a PD-1 / PD-L1 inhibitor, and / or a phosphoinositide 3-kinase (PI3K) inhibitor. - ESCC: - Subjects must have locally advanced or metastatic esophageal squamous cell carcinoma. - Subjects must have received prior platinum-based chemotherapy. - Must have received a prior PD-1 / PD-L1 inhibitor if eligible by biomarker status and consistent with standard of care. - EAC / GEJ adenocarcinoma: - Subjects must have locally advanced or metastatic EAC or GEJ adenocarcinoma. - Subjects must have received prior platinum-based chemotherapy. - Must have received prior PD-1 / PD-L1 inhibitor or HER-2 directed therapy if eligible by biomarker status and consistent with standard of care. - HGSOC: - Subjects must have high-grade serous epithelial ovarian, primary peritoneal, or fallopian tube cancer. - Subjects must have platinum-resistant disease, defined as progression or recurrence within 6 months of prior platinum-containing chemotherapy, if eligible, must have received a bevacizumab-containing regimen, and if eligible by biomarker status and consistent with standard of care, must have received a PARP inhibitor. - cSCC: - Subjects must have locally advanced or metastatic cutaneous squamous cell carcinoma. - Subjects must have received a PD-1 / PD-L1 inhibitor. c. For Part C: Subjects must have a histologically or cytologically confirmed metastatic or unresectable solid malignant tumor of one of the tumor types listed below. NSCLC 〇HNSCC 〇ESCC 〇cSCC Subjects must be eligible for pembrolizumab monotherapy according to local standard of care. d. With respect to Part D: Subjects may participate in up to two disease-specific expansion cohorts. Subjects must have histologically or cytologically confirmed disease and must not have received frontline systemic therapy for locally advanced or metastatic disease (prior intended curative or adjuvant therapy is permitted, with the exception of PD-[L]1). Subjects with NSCLC must have a TPS ≥ 50 according to the local study to be eligible for the cohort testing SGN-B6A in combination with pembrolizumab. Subjects with HNSCC must have a CPS ≥ 1 according to the local trial to be enrolled in the cohort testing SGN-B6A in combination with pembrolizumab. 2. Subjects enrolled in the following study parts should have an accessible tumor site for biopsy and should consent to biopsy as follows: - Disease-specific expansion cohorts (Parts B and D): A baseline new tumor tissue biopsy is required. An archived biopsy collected within 90 days may be used. This biopsy may be waived if medically not feasible (e.g., the lesion is inaccessible for minimally invasive procedures and does not pose a significant risk) after discussion with the medical monitor. - Biologic expansion cohort: Pre-treatment biopsy and on-treatment (Cycle 1) biopsy. Additional optional biopsies are required, if feasible, for all subjects in the disease-specific expansion and biologic cohorts. 3. 18 years of age or older. Eastern Cooperative Oncology Group (ECOG) performance status score of 4.0 or 1. 5. Measurable disease per RECIST v1.1 at baseline. 6. Baseline laboratory data for: - Absolute neutrophil count (ANC) ≥ 1500 / μL - Hemoglobin (Hgb) ≥ 9g / dL - Platelet count ≥100,000 / μL Serum bilirubin ≤ 1.5 x upper limit of normal (ULN), or ≤ 3 x ULN for subjects with Gilbert's disease - Estimated glomerular filtration rate (GFR) ≥ 45 mL / min / 1.73 m using the Modification of Diet in Renal Disease (MDRD) study equation, when applicable 2 Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x ULN (≤ 5 x ULN if there is evidence of liver damage due to malignant disease) 7. Subjects who may be pregnant under the following conditions: Must have a negative serum or urine pregnancy test (beta-human chorionic gonadotropin [β-hCG] with a minimum sensitivity of 25 mIU / mL or equivalent units) within 7 days prior to the first dose of SGN-B6A. Subjects with a false-positive result and documented verification that they are not pregnant are eligible to participate. b. Agree not to try to become pregnant during the study and for at least 2 months after the last dose of study medication. c. Agree not to breast-feed or donate eggs, beginning at the time of informed consent and continuing until 2 months after the last dose of study medication. d. If sexually active in a manner that could lead to pregnancy, at least two acceptable methods of birth control (contraception), at least one of which must be highly effective, must be used consistently, beginning at the time of informed consent and continuing throughout the study and for at least two months after the last dose of study drug. 8. A subject who can impregnate someone under the following conditions: a. Must agree to abstain from sperm donation beginning at the time of informed consent and continuing throughout the study period and for at least 4 months after the last study drug administration. b. If sexual activity with a person of childbearing potential occurs in a manner that could lead to pregnancy, at least two acceptable methods of birth control (contraception) must be consistently used, at least one of which must be highly effective, beginning at the time of informed consent and continuing throughout the study and for at least 4 months after the last dose of study drug. c. If sexually active with a pregnant or breastfeeding person, condoms must be used consistently, beginning at the time of informed consent and continuing throughout the study and for at least 4 months after the last dose of study medication. 9. Subject must provide written informed consent. Exclusion criteria 1. History of another malignancy within 3 years prior to the first dose of study drug, or any evidence of residual disease from a previously diagnosed malignancy. Exceptions are malignancies with a negligible risk of metastasis or death, such as adequately treated cervical intraepithelial neoplasia, non-melanoma skin cancer, localized prostate cancer, ductal carcinoma in situ, or stage I uterine cancer. 2. Known active central nervous system metastases. Subjects with previously treated brain metastases may participate provided they are clinically stable after brain metastasis treatment for at least 4 weeks prior to study entry, they have no new or expanding brain metastases, and they have been off corticosteroids prescribed for symptoms associated with brain metastases for at least 7 days prior to the first dose of study medication. 3. Cancerous meningitis. 4. Previous intake of MMAE-containing agents or agents targeting integrin beta-6. 5. Pre-existing neurological impairment ≥ Grade 2 according to NCI CTCAE v5.0. 6. Any uncontrolled ≥ Grade 3 (per NCI CTCAE, v5.0) viral, bacterial, or fungal infection within 2 weeks prior to the first dose of SGN-B6A. Routine antimicrobial prophylaxis is permitted. 7. Uncontrolled diabetes mellitus defined as hemoglobin A1C (Hgb A1c) ≥ 8.0% or Hgb A1c of 7 to < 8.0% with diabetic symptoms (polyuria or polydipsia) not otherwise described. 8. Positive for hepatitis B by surface antigen expression. Active hepatitis C infection (positive by polymerase chain reaction [PCR] or on antiviral therapy for hepatitis C within the past 6 months). Subjects being treated for hepatitis C infection will be accepted if they have documented a sustained virologic response for 12 weeks. 9. Known positive for human immunodeficiency virus (HIV). 10. Documented history of cerebrovascular event (stroke or transient ischemic attack), unstable angina, myocardial infarction, congestive heart failure, or cardiac symptoms consistent with New York Heart Association Class III-IV within 6 months prior to their first dose of SGN-B6A. 11. Congestive heart failure class III or IV according to the New York Heart Association criteria. 12. ≥ Grade 3 pulmonary disease unrelated to underlying malignancy. 13. Use of strong cytochrome P450 3A (CYP3A) inhibitors within 14 days of study drug dosing during dose escalation only. 14. Chemotherapy, immunotherapy, biologics, and / or other approved or investigational anti-neoplastic treatment that has not been completed within 4 weeks prior to the first dose of study drug, or within 2 weeks prior to the first dose of study drug if the underlying disease has progressed during treatment. 15. Localized radiotherapy or major surgery not completed 2 weeks prior to the first dose of SGN-B6A. 16. Subject is nursing, pregnant, or planning to become pregnant from the time of informed consent through 2 months after the last dose of study medication. 17. Known hypersensitivity to any excipients contained in the drug formulation of SGN-B6A. 18. Estimated life expectancy <12 weeks. 19. Any other serious underlying medical condition that, in the opinion of the investigator, impairs the subject's ability to receive or tolerate the planned treatment or follow-up. 20. Subject has received a live vaccine within 30 days of first study drug administration. Part C only: 21. Have received prior therapy with a PD-1 inhibitor, anti-PD-L1, or anti-PD-L2 agent, or with an agent directed against another stimulatory or co-inhibitory T cell receptor (e.g., CTLA-4, OX40, CD137), and had that treatment discontinued due to a grade 3 or higher immune-mediated adverse event (IMAE). Part D only: 22. Have NSCLC with actionable genomic alterations (e.g., ALK, ROS-1 gene rearrangements, or EGFR mutations). Parts C and D only: 23. Have a diagnosis of immunodeficiency or are receiving chronic systemic steroid therapy (at a dose greater than 10 mg prednisone equivalent daily) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug. 24. Have an active autoimmune disease that has required systemic treatment within the past 2 years (i.e., with disease-modifying agents, corticosteroids, or immunosuppressants). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is permitted. 25. Have a history of (non-infectious) pneumonia requiring steroids or currently have pneumonia. 26. Have a history of interstitial lung disease. 27. Have received >30 Gy of radiation therapy to the lung within 6 months of the first dose of study treatment. 28. Have had an allogeneic tissue / solid organ transplant.

[0263] Treatment administered All subjects in this protocol will receive the investigational agent under study, SGN-B6A. SGN-B6A is an ADC composed of an anti-integrin beta-6 antibody (h2A2) conjugated to the antimitotic agent MMAE, which interferes with tubulin. Subjects in Parts C and D will also receive pembrolizumab. SGN-B6A is a sterile, preservative-free, white to off-white lyophilized cake or powder for reconstitution for IV administration. SGN-B6A is supplied in single-dose glass vials. When reconstituted with Water for Injection (WFI), United States Pharmacopeia (USP), or equivalent, the reconstituted drug product is a clear to slightly opalescent, colorless to slightly yellow solution, free of visible particulate matter.

[0264] Dosage and Administration The SGN-B6A dose level and administration schedule will be determined by cohort assignment. SGN-B6A will be administered via IV infusion. The dosing frequency (continuous, intermittent, Q3W, or once every two weeks) will be outlined below. Subjects in the dose escalation phase will be required to undergo a 4-hour observation period on Day 1 of Cycle 1 after completing the infusion. To allow for rapid evaluation in the event of a delayed IRR, subjects are encouraged to remain near the medical facility for 24 hours after the SGN-B6A Cycle 1 Day 1 administration. If the first infusion is well tolerated and no IRR occurs, the observation period for subsequent infusions may be reduced according to institutional standards.

[0265] SGN-B6A is initially administered on days 1, 8, and 15 of a 21-day cycle. Reduced dosing frequency, such as dosing only on days 1 and 8, or only on day 1, of every 21-day cycle, or once every two weeks of every 28-day cycle, may be implemented if recommended by the SMC. In no case should doses of SGN-B6A be given closer than 5 days apart. Detailed medication regimen 21-day cycle Continuous Study drug will be administered to study subjects on a weekly basis (e.g., Cycle 1 Day 1, Cycle 1 Day 8, Cycle 1 Day 15, then Cycle 2 Day 1, Cycle 2 Day 8, Cycle 2 Day 15). Intermittent: Study drug will be administered to study subjects on days 1 and 8 of each cycle (e.g., cycle 1 day 1, cycle 1 day 8, then cycle 2 day 1, cycle 2 day 8) with no administration on day 15. Q3w: Study drug will be administered to study subjects once every three weeks (eg, on Day 1 of Cycle 1, then on Day 1 of Cycle 2). 28-day cycle Once every two weeks: Study drug will be administered to study subjects on a biweekly basis (eg, on days 1 and 15 of each cycle).

[0266] SGN-B6A requires dilution before administration.

[0267] Weight-based dosing is based on the subject's weight at baseline or institutional standards. The SMC may recommend implementing adjusted ideal body weight (AIBW) dosing when indicated. Dose adjustments must be made for subjects who experience a ≥10% change in weight from baseline. Other dose adjustments for <10% change in weight from baseline are acceptable according to institutional standards. Rounding to the nearest whole milligram is acceptable within 5% of the nominal dose.

[0268] The duration of the infusion will vary depending on the method of infusion administration and the dose. The rate of infusion should follow facility standards but should not exceed 250 mL / hour. In dose escalation Part A, SGN-B6A should be infused over approximately 30 minutes. Upon review of the aggregated data, the SMC may recommend or require a longer or shorter infusion duration.

[0269] If an individual subject does not tolerate an infusion, the infusion duration for that subject may be increased; the infusion duration for subsequent infusions may also be increased at the investigator's discretion in consultation with the medical monitor. Conversely, if a subject tolerates a continuous infusion without an IRR > Grade 1, the infusion duration may be shortened (i.e., administered at a faster rate) at the investigator's discretion in consultation with the medical monitor, and this implementation may be dose-cohort specific.

[0270] The injection site should be closely monitored for redness, swelling, pain, and infection at any time during and after administration. Subjects should be advised to promptly report any redness or discomfort at the time of administration or after injection. Institutional guidelines will be followed for the administration of chemotherapy, and precautions will be taken to prevent extravasation according to institutional standards.

[0271] As clinical experience with SGN-B6A progresses, alternative approaches to SGN-B6A administration and dosage may be evaluated, including, but not limited to, fixed infusion rate, weight-capped dose administration, AIBW dose administration, or flat dose administration.

[0272] When a fixed infusion rate is implemented in an SMC recommendation, the dose is administered at a fixed rate rather than over a fixed time.

[0273] For example, for a fixed infusion rate of 50 mg / hour, a 100 mg dose is infused over 2 hours. As clinical experience with fixed infusion rate administration develops, the rate may be increased or decreased based on accumulated safety data and / or SMC recommendations.

[0274] As PK, pharmacodynamic, and clinical activity data evolve, weight-limited IV dosing may be implemented in SMC recommendations. In contrast to weight-based dosing, where the total dose is calculated without an upper limit on subject weight, weight-limited dosing limits the weight to be used in total dose calculations. The upper limit to be used in dose calculations should be established based on emerging data.

[0275] For example, if the weight limit is 100 kg, a subject with a weight of ≥ 100 kg will use the weight of 100 kg to calculate the total dose to be administered. For subjects with a weight < 100 kg, the total dose to be administered will be calculated using the subject's actual weight.

[0276] AIBW provides an adjustment for a subject's actual total body weight (TBW) if it is higher or lower than their ideal body weight (IBW). Because AIBW is calculated using the subject's sex, height, and TBW, the percent adjustment for the total dose depends on the target body mass index (BMI) group.

[0277] Dose modification For SGN-B6A, dose reductions or dosing interval extensions for toxicity, including DLTs, may be approved on a subject-by-subject basis by the investigator in consultation with the medical monitor. For subjects treated at the lowest dose level, the dose may be reduced by up to 25% of the most recently administered dose, the dosing frequency may be reduced (e.g., if the initial dose is on days 1, 8, and 15, the dose may be changed to days 1 and 8 or only to day 1 in a 21-day cycle), or the subject may be discontinued from treatment.

[0278] Subjects who experience a DLT during Cycle 1 should not receive further treatment with SGN-B6A unless the toxicity is adequately managed, the investigator deems resumption of SGN-B6A appropriate, and consultation with the medical monitor is necessary. The type and severity of the observed AE will be taken into consideration to inform the decision. If the subject continues treatment after the DLT and the same dose-limiting toxicity reoccurs, treatment must be permanently discontinued. Subjects who experience an AE that meets the criteria for permanent discontinuation of SGN-B6A may not resume SGN-B6A, including at a lower or modified dose or with a reduced dosing frequency.

[0279] If a subject has a clinically significant, unresolved treatment-emergent adverse event (TEAE) on or after the next scheduled dose date in Cycle 1, the next dose may be delayed for up to 7 days. Delays due to other reasons or lasting >7 days must be discussed with the medical monitor. Subjects requiring a dose delay >7 days due to an unresolved TEAE may be dosed at a reduced dose in subsequent cycles, or the dosing frequency may be reduced in consultation with the medical monitor.

[0280] During the DLT period, growth factors and transfusion support are discouraged unless medically indicated; subjects receiving growth factors (e.g., granulocyte colony-stimulating factor [G-CSF] or granulocyte-macrophage colony-stimulating factor [GM-CSF]) or transfusion support during this period for reasons other than the DLT may not be evaluable for the DLT. Growth factor support should be considered for the prevention or treatment of cytopenias in subsequent cycles. For subjects with relapsing Grade 4 neutropenia despite growth factor use, discontinuation or dose reduction to one dose level below the current dose (see Table 2) may be considered.

[0281] During the dose delay, a comprehensive metabolic panel (CMP) and complete blood count (CBC) should be collected at least weekly. If AEs other than neutropenia reoccur despite two dose reductions, additional dose reductions may be permitted after discussion with the medical monitor.

[0282] Table 4 lists recommended dose modifications for study treatment-related toxicity. After the occurrence of any ≥ Grade 3 AE potentially related to SGN-B6A treatment, continuation of study treatment requires medical monitoring consultation.

[0283] [Table 5-1]

[0284] [Table 5-2]

[0285] Pembrolizumab Pembrolizumab is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. Pembrolizumab is an IgG4 kappa Ig with an approximate molecular weight of 149 kDa.

[0286] Pembrolizumab is 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 yellow solution that requires dilution for IV infusion. Each vial contains 100 mg of pembrolizumab in 4 mL of solution. Each mL of solution contains 25 mg of pembrolizumab and is formulated in L-histidine, polysorbate, sucrose, and WFI USP.

[0287] Pembrolizumab study treatment will be administered at doses of 200 mg or 400 mg, respectively, using a 30-minute IV infusion prior to the infusion of SGN-B6A on Day 1 of each 21-day cycle or every 6 weeks in Parts C and D cohorts. Pembrolizumab administration must be completed at least 30 minutes before the start of SGN-B6A administration. Sites should make every effort to achieve infusion timing as close to 30 minutes as possible. However, given site-specific infusion pump variability, a range of -5 minutes to +10 minutes is acceptable (i.e., infusion time is 30 minutes -5 minutes / +10 minutes).

[0288] Unless otherwise specified, administration of study treatment should be performed according to product information or institutional guidelines.

[0289] Dose modification For dose modification and toxicity management guidelines for pembrolizumab, please see the pembrolizumab EU SmPC.

[0290] For Parts C and D only: An AE may be attributable to one study treatment alone or the combination of study treatments. The final determination of causality is at the investigator's discretion. If the event is clearly related to one of the agents, follow the instructions specific to that agent. If the event is related to more than one agent, follow the instructions for all agents it is related to. There may be situations where a subject cannot tolerate combination therapy but may benefit from treatment with one agent alone. These cases must be discussed and approved by the sponsor before the subject may continue treatment. In situations where attribution to individual study treatments may be difficult, administrative measures to interrupt or discontinue study treatment should apply to both SGN-B6A and pembrolizumab.

[0291] Response / Efficacy Assessment - Clinical Response According to RECIST Response will be assessed by radiological tumor assessment on days 15–21 of 21-day cycles (cycles 2, 4, 6, and every third cycle thereafter) or every 6 weeks + / - 7 days from day 1 (C1D1) of cycle 1 through week 24 of 28-day cycles (four response assessments every 6 weeks), then every 8 weeks thereafter. Subjects who discontinue treatment before disease progression or before starting new anticancer therapy will undergo physical examinations and continue to be assessed for response according to this schedule for up to 3 years after EOT until PD is documented or new therapy is initiated. Tumor assessment will be performed by CT and / or MRI scans of the chest, abdomen, and pelvis. Neck imaging should also be obtained if there is documented or suspected involvement in this area. Scans must be of diagnostic quality, and IV contrast must be used unless medically contraindicated. The same modality should be used for each assessed lesion throughout the duration of the study.

[0292] Determination of antitumor activity will be based on assessments defined by RECIST v1.1 for all cohorts. Investigator treatment decisions will be based on RECIST v1.1 for Parts A and B and iRECIST for Parts C and D. Subjects in Parts C and D who are achieving clinical benefit according to the investigator and have not met any stopping criteria may be considered for treatment beyond disease progression according to RECIST v1.1. Subjects treated beyond disease progression according to RECIST v1.1 may continue until confirmed disease progression according to iRECIST as assessed by the investigator. A confirmatory scan must be performed 4 to 9 weeks after the first date of disease progression.

[0293] Pharmacokinetic and immunogenicity assessment Blood samples for PK and ADA assessment will be collected at the appropriate time points relative to the collection schedule.

[0294] Plasma SGN-B6A ac-MMAE, total antibody (TAb), and MMAE concentrations will be determined using validated assays. Assays may include ELISA or liquid chromatography with tandem mass spectrometry (LC-MS / MS), as well as other assays if further characterization is required. Analysis of SGN-B6A ADC concentrations may be performed in an exploratory manner on a subset of samples using unvalidated methods. The remaining PK samples will be stored for possible analysis of SGN-B6A-related species. PK and ADA samples will be collected and retained for pembrolizumab in the Part D cohort; they may be analyzed as exploratory analyses if deemed necessary.

[0295] A certified electrochemiluminescence assay is used to assess the levels of ADA against SGN-B6A in serum.

[0296] Pharmacodynamic and biomarker assessment Biomarker assessment will be performed on peripheral blood and tumor tissue as outlined in this section. Biomarker assessment will not be used for subject selection. Exploratory, predictive, and prognostic biomarkers associated with response, resistance, or safety observations will be monitored before and during treatment with SGN-B6A. Pharmacodynamic assessment will include disease burden monitoring, changes in target expression, and soluble B6 integrin in plasma. Correlation studies will be performed to gain a better understanding of target-response relationships, predictive / prognostic biomarkers, MOA, resistance mechanisms, and pharmacodynamics. On-treatment and EOT biopsies obtained in the biological cohort and potentially in disease-specific expansion cohorts (optional biopsies) will be used to investigate the mechanism of action (MOA) and resistance mechanisms of SGN-B6A.

[0297] Tumor sample requirements vary depending on the cohort the subject is enrolled in, as described below. If a biopsy is not feasible or appropriate, the biopsy may be waived after discussion with the medical monitor.

[0298] If tumor samples are obtained as part of standard care during a study, and with the subject's consent, a portion of the sample should be submitted to the sponsor for biomarker testing. Biopsies should be collected by appropriately trained clinical site personnel (e.g., interventional radiologists for internal tumor biopsies; trained personnel such as dermatologists for skin tumor biopsies). When feasible, it is strongly recommended that a pathologist be present during the biopsy to ensure adequate tumor content at the biopsy site and to ensure optimal biopsy acquisition and processing techniques.

[0299] The primary effect of SGN-B6A on tumor cells may lead to changes in the activation state of local, tumor-associated, and peripheral immune cells. To characterize malignancies and immune responses, biomarker assessments in peripheral blood may include, but are not limited to, measurements of baseline and drug-induced changes in circulating blood cell populations, immunoassays, gene expression, cytogenetics, genetic polymorphisms, cancer-associated somatic mutations, and circulating immune function and disease markers. SGN-B6A interactions with peripheral blood cells and tissues may also be monitored. Assays may include, but are not limited to, next-generation sequencing of whole blood, proteomics methodologies, immunoassays for tumor response or therapy resistance, and markers of immune function, including immune cell subsets and cytokine abundance. Analytical methods may include, but are not limited to, IHC, next-generation sequencing of RNA and DNA, and immunoassays such as flow cytometry and ELISA. These may provide insight into treatment-related changes associated with SGN-B6A.

[0300] To understand the relationship between pretreatment tumor biology and the outcome of interest, tissue from pretreatment (archived or newly obtained specimens), on-treatment, and end-of-treatment tumor biopsies will be examined. If tissue is available from standard of care biopsies collected after enrollment, it may also be examined. Biopsies will be assessed for specific pharmacodynamic, predictive, and prognostic biomarkers in the tumor. To characterize tumor SGN-B6A penetration, grade, and response to study treatment, biomarker assessment in tumor biopsies may include, but is not limited to, measurement of SGN-B6A and its potential metabolites, such as MMAE, as well as tumor microenvironment characterization, drug targeting, tumor subtyping, somatic mutations, and / or gene expression profiling. Assays may include, but are not limited to, LC-MS / MS, IHC, and next-generation sequencing of RNA and DNA.

[0301] Baseline demographics and characteristics (dose escalation) Table 5 shows the baseline demographics and characteristics of subjects enrolled in the study.

[0302] [Table 6]

[0303] result Table 6 shows the objective response rates of subjects in the dose escalation study being evaluated. Subjects with all tumor types are included.

[0304] [Table 7]

[0305] Figure 1 shows the antitumor activity of SGN-B6A in the NSCLC subset from the dose-escalation study. Subjects had received a median of 3.5 (range: 1-8) lines of prior therapy. Objective responses of NSCLC subjects from Figure 1 are shown in Table 7.

[0306] [Table 8]

[0307] Figure 2 shows the antitumor activity of SGN-B6A in the EC (esophageal cancer) subset from the dose-escalation study. Subjects had received a median of 3.0 (range: 1-5) lines of prior therapy. Objective responses of EC subjects from Figure 2 are shown in Table 8.

[0308] [Table 9]

[0309] Figure 3 shows the antitumor activity of SGN-B6A in the HNSCC subset from the dose-escalation study. Subjects had received a median of 3.0 (range: 1-4) lines of prior therapy. Objective responses of HNSCC subjects from Figure 3 are shown in Table 9.

[0310] [Table 10]

[0311] Figure 4 shows the antitumor activity of SGN-B6A in the HNSCC 2Q3W subset from the dose-expansion study. Subjects received a median of 3.0 (range: 1-6) lines of prior therapy. The efficacy-evaluable set included all treated patients who had both a baseline disease assessment and at least one evaluable post-baseline disease assessment according to RECIST v1.1 (as assessed by the investigator) or who discontinued treatment. Two subjects were not represented due to a lack of post-baseline assessments eligible for efficacy analysis. The objective responses of HNSCC subjects from Figure 4 are shown in Table 10.

[0312] [Table 11]

[0313] Example 2 Analysis of SGN-B6A treatment in subjects with NSCLC Subjects with NSCLC were treated as described in Example 1.

[0314] [Table 12]

[0315] [Table 13]

[0316] These results demonstrate that there is an approximately two-fold greater response in subjects with non-squamous cell carcinoma compared to squamous cell carcinoma, and an approximately three-fold greater response in taxane-naive subjects compared to subjects previously treated with a taxane.

[0317] [Table 14]

[0318] Example 3 A murine surrogate of SGN-B6A (mSGN-B6A) in combination with anti-mPD1 exhibits antitumor activity in a Renca syngeneic model engineered to express human integrin beta-6 BALB / c mice (n = 10 mice per group) were subcutaneously implanted with syngeneic Renca cells engineered to express human integrin beta-6. mSGN-B6A and anti-mouse PD-1 (anti-mPD1), individually or in combination, were administered three times weekly. The delayed-dose treatment group received the first dose of anti-mPD1 one week after the first mSGN-B6A dose. Figure 5A shows a Kaplan-Meier plot in which tumor growth was the survival endpoint. Figure 5B and Table 11 show that individual mice treated with mSGN-B6A showed two complete regressions observed at day 19, and one maintained a durable complete regression until the end of the study (day 58). Of the individual mice treated with mSGN-B6A and 1 mg / kg anti-mPD1, three had CTRs at day 19, and one maintained a durable complete tumor regression (dCTR). Of the individual mice treated with mSGN-B6A and 3 mg / kg mPD1, 3 had CTR and 3 maintained dCTR on day 19. Of the individual animals in the delayed-dose arm, 5 had CTR on day 19 and 4 had dCTR at the end of the study.

[0319] [Table 15]

[0320] array SEQ ID NO: 1-CDR1-H1 DYNVN SEQ ID NO:2 -CDR2-H2 VINPKYGTTRYNQKFKG SEQ ID NO: 3 -CDR3-H3 GLNAWDY SEQ ID NO: 4-CDR1-L1 GASENIYGALN SEQ ID NO:5-CDR2-L2 GATNLED SEQ ID NO:6 -CDR3-L3 QNVLTTPYT SEQ ID NO:7 -h2A2 vHC QFQLVQSGAEVKKPGASVKVSCKASGYSFTDYNVNWVRQAPGQGLEWIGVINPKYGTTRYNQKFKGRATLTVDKSTSTAYMELSSLRSEDTAVYYCTRGLNAWDYWGQGTLVTVSS SEQ ID NO:8 -h2A2 vLG DIQMTQSPSSLSASVGDRVTITCGASENIYGALNWYQQKPGKAPKLLIYGATNLEDGVPSRFSGSGSGRDYTFTISSLQPEDIATYYCQNVLTTPYTFGQGTKLEIK SEQ ID NO:9 - h2A2 HC heavy chain QFQLVQSGAEVKKPGASVKVSCKASGYSFTDYNVNWVRQAPGQGLEWIGVINPKYGTTRYNQKFKGRATLTVDKSTSTAYMELSSLRSEDTAVYYCTRGLNAWDYWGQGTL VTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH TCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT ISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 10 - h2A2 LG light chain DIQMTQSPSSLSASVGDRVTITCGASENIYGALNWYQQKPGKAPKLLIYGATNLEDGVPSRFSGSGSGRDYTFTISSLQPEDIATYYCQNVLTTPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

Claims

1. 1. A method of treating a solid tumor in a subject, comprising administering to the subject an antibody-drug conjugate or antigen-binding fragment thereof that binds to alpha-v beta-6 (αvβ6), conjugated to monomethyl auristatin, or a functional analogue or functional derivative thereof, wherein the antibody-drug conjugate is administered at a dose ranging from about 0.7 mg / kg to about 2.5 mg / kg of the subject's body weight, and wherein the anti-αvβ6 antibody or antigen-binding fragment of the antibody-drug conjugate comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region is: (i) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1; (ii) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 2; and (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 3 and the light chain variable region comprises: (i) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 4; (ii) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and (iii) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 6 A method comprising:

2. The method of claim 1, wherein the anti-αvβ6 antibody or antigen-binding fragment thereof of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO:7, and a light chain variable region comprising an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO:

8.

3. The method of claim 1 or claim 2, wherein the anti-αvβ6 antibody or antigen-binding fragment thereof of the antibody-drug conjugate comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:

8.

4. The method of any one of claims 1 to 3, wherein the anti-αvβ6 antibody or antigen-binding fragment thereof of the antibody-drug conjugate comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:9 and a light chain comprising the amino acid sequence of SEQ ID NO:

10.

5. 5. The method of any one of claims 1 to 4, wherein the monomethyl auristatin is monomethyl auristatin E (MMAE).

6. The method of any one of claims 1 to 5, wherein the anti-αvβ6 antibody or antigen-binding fragment thereof of the antibody-drug conjugate is a monoclonal antibody or monoclonal antigen-binding fragment thereof.

7. The method of any one of claims 1 to 6, wherein the antibody-drug conjugate further comprises a linker between the anti-αvβ6 antibody or antigen-binding fragment thereof and the monomethyl auristatin.

8. The method of claim 7 , wherein the linker is a cleavable peptide linker.

9. The cleavable peptide linker has the formula: -MC-vc-PAB-, wherein: a) MC is 【Chemistry 1】 and b) vc is the dipeptide valine-citrulline; c) PAB is 【Chemistry 2】 The method of claim 8, wherein

10. The method of any one of claims 7 to 9, wherein the linker is attached to a sulfhydryl residue of an anti-αvβ6 antibody obtained by partial or complete reduction of the anti-αvβ6 antibody or its antigen-binding fragment.

11. The linker is attached to monomethyl auristatin E (MMAE) and the antibody-drug conjugate has the following structure: 【Transformation 3】 11. The method of claim 10, wherein p represents a number from 1 to 8, S represents a sulfhydryl residue of an anti-αvβ6 antibody, and Ab represents an anti-αvβ6 antibody or an antigen-binding fragment thereof.

12. 12. The method of claim 11, wherein the average value of p in the population of antibody-drug conjugates is about 4.

13. 13. The method of any one of claims 1 to 12, wherein the dose is about 0.8 mg / kg, about 1.0 mg / kg, about 1.2 mg / kg, about 1.25 mg / kg, about 1.5 mg / kg, about 1.8 mg / kg, about 2.0, or about 2.4 mg / kg of the subject's body weight.

14. 13. The method of any one of claims 1 to 12, wherein the dose is 0.8 mg / kg, 1.0 mg / kg, 1.2 mg / kg, 1.25 mg / kg, 1.5 mg / kg, 1.8 mg / kg, 2.0, or 2.4 mg / kg of subject body weight.

15. 15. The method of claim 14, wherein the dose is 1.8 mg / kg of subject body weight.

16. 15. The method of claim 14, wherein the dose is 1.25 mg / kg of subject body weight.

17. 17. The method of any one of claims 1 to 16, wherein the subject's weight is the subject's ideal body weight (IBW).

18. 17. The method of any one of claims 1 to 16, wherein the subject's weight is the subject's adjusted ideal body weight (AIBW).

19. 19. The method of any one of claims 1 to 18, wherein the antibody-drug conjugate is administered about once every week, about once every two weeks, about once every three weeks, or about twice every three weeks.

20. 20. The method of claim 19, wherein the antibody-drug conjugate is administered about once every two weeks.

21. 20. The method of claim 19, wherein the antibody-drug conjugate is administered about once every week for two consecutive weeks, followed by a rest period of about one week during which the antibody-drug conjugate is not administered, so that each cycle time is about 21 days, including the rest period.

22. 22. The method of claim 21, wherein the antibody drug conjugate is administered on days 1 and 8, but not on day 15, of each 21-day cycle.

23. 23. The method of any one of claims 1 to 22, wherein the subject has previously been treated for a solid tumor with one or more therapeutic agents but has failed to respond to treatment, relapsed after treatment, or experienced disease progression during treatment, and wherein the one or more therapeutic agents are not an antibody-drug conjugate.

24. 24. The method of any one of claims 1 to 23, wherein the solid tumor is locally advanced or metastatic.

25. 25. The method of any one of claims 1 to 24, wherein the solid tumor is selected from the group consisting of lung cancer, head and neck cancer, breast cancer, esophageal cancer, gastroesophageal junction cancer, ovarian cancer, peritoneal cancer, or fallopian tube cancer, skin cancer, pancreatic cancer, bladder cancer, cervical cancer, and gastric cancer.

26. 26. The method of claim 25, wherein the lung cancer is non-small cell lung cancer.

27. 27. The method of claim 26, wherein the non-small cell lung cancer is a non-squamous cell carcinoma.

28. 27. The method of claim 26, wherein the non-small cell lung cancer is squamous cell carcinoma.

29. 29. The method of any one of claims 25 to 28, wherein the solid tumor is lung cancer, and the lung cancer does not have a known epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) mutation.

30. 29. The method of any one of claims 25 to 28, wherein the solid tumor is lung cancer, and the lung cancer has a known EGFR or ALK mutation.

31. 31. The method of any one of claims 25 to 30, wherein the solid tumor is lung cancer and the subject has received prior platinum-based therapy and prior therapy with a PD-1 / PD-L1 inhibitor.

32. 32. The method of any one of claims 25 to 31, wherein the solid tumor is lung cancer and the subject has not received prior therapy with a taxane.

33. 26. The method of claim 25, wherein the head and neck cancer is head and neck squamous cell carcinoma.

34. 34. The method of claim 25 or claim 33, wherein the solid tumor is head and neck cancer and the subject has received prior platinum-based therapy and prior therapy with a PD-1 / PD-L1 inhibitor.

35. 26. The method of claim 25, wherein the breast cancer is HER2-negative breast cancer.

36. 36. The method of claim 25 or 35, wherein the solid tumor is breast cancer and the subject has received one or more prior lines of therapy for breast cancer.

37. 37. The method of claim 36, wherein one or more prior lines of therapy included a taxane administered as a single agent or in combination with a different agent.

38. 26. The method of claim 25, wherein the esophageal cancer is esophageal squamous cell carcinoma.

39. 39. The method of claim 25 or 38, wherein the solid tumor is esophageal cancer and the subject has received prior platinum-based chemotherapy.

40. 26. The method of claim 25, wherein the esophageal cancer is esophageal adenocarcinoma.

41. 26. The method of claim 25, wherein the gastroesophageal junction cancer is gastroesophageal junction adenocarcinoma.

42. 42. The method of claim 40 or claim 41, wherein the subject has received prior platinum-based chemotherapy.

43. 26. The method of claim 25, wherein the ovarian cancer is high-grade serous epithelial ovarian cancer.

44. 26. The method of claim 25, wherein the skin cancer is cutaneous squamous cell carcinoma.

45. 45. The method of claim 25 or claim 44, wherein the solid tumor is skin cancer and the subject has received prior therapy with a PD-1 / PD-L1 inhibitor.

46. 26. The method of claim 25, wherein the pancreatic cancer is exocrine pancreatic adenocarcinoma.

47. 47. The method of any one of claims 1 to 46, wherein the solid tumor is an advanced cancer.

48. 48. The method of claim 47, wherein the advanced cancer is stage 3 or stage 4 cancer.

49. 49. The method of claim 47 or 48, wherein the advanced cancer is metastatic cancer.

50. 50. The method of any one of claims 1 to 49, wherein the route of administration of the antibody-drug conjugate is intravenous.

51. 51. The method of any one of claims 1 to 50, wherein 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 αvβ6.

52. 52. The method of any one of claims 1 to 51, wherein one or more therapeutic effects are improved in the subject after administration of the antibody-drug conjugate compared to baseline.

53. 53. The method of claim 52, wherein the one or more therapeutic effects are selected from the group consisting of size of a tumor derived from the cancer, objective response rate, duration of response, time to response, progression-free survival, and overall survival.

54. 54. The method of any one of claims 1 to 53, wherein the size of a tumor derived from the cancer is reduced by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, or at least about 80% compared to the size of a tumor derived from the cancer before administration of the antibody-drug conjugate.

55. 55. The method of any one of claims 1 to 54, wherein the objective response rate is 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%.

56. 56. The method of any one of claims 1 to 55, wherein the subject exhibits progression free survival of at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 18 months, at least about 2 years, at least about 3 years, at least about 4 years, or at least about 5 years after administration of the antibody-drug conjugate.

57. 57. The method of any one of claims 1 to 56, wherein 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 2 years, at least about 3 years, at least about 4 years, or at least about 5 years after administration of the antibody-drug conjugate.

58. 58. The method of any one of claims 1 to 57, wherein the duration of response to the antibody-drug conjugate 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 2 years, at least about 3 years, at least about 4 years, or at least about 5 years after administration of the antibody-drug conjugate.

59. 59. The method of any one of claims 1-58, wherein the subject has one or more adverse events and is further administered an additional therapeutic agent to eliminate or reduce the severity of the one or more adverse events.

60. 60. The method of any one of claims 1-59, wherein the subject is at risk of developing one or more adverse events and is further administered an additional therapeutic agent to prevent or reduce the severity of the one or more adverse events.

61. 61. The method of any one of claims 1 to 60, wherein the antibody-drug conjugate is administered as monotherapy.

62. 61. The method of any one of claims 1 to 60, further comprising administering one or more additional therapeutic agents to the subject.

63. 63. The method of claim 62, wherein the one or more additional therapeutic agents is a checkpoint inhibitor.

64. 64. The method of claim 63, wherein the checkpoint inhibitor is a PD-1 inhibitor or a PD-L1 inhibitor.

65. 65. The method of claim 64, wherein the PD-1 inhibitor is an anti-PD-1 antibody.

66. 66. The method of claim 65, wherein the anti-PD-1 antibody is pembrolizumab or a biosimilar thereof.

67. 67. The method of claim 66, wherein pembrolizumab or a biosimilar thereof is administered at a dose of about 200 mg.

68. 68. The method of claim 66 or claim 67, wherein pembrolizumab or a biosimilar thereof is administered about once every three weeks.

69. 67. The method of claim 66, wherein pembrolizumab or a biosimilar thereof is administered at a dose of about 400 mg.

70. 70. The method of claim 66 or claim 69, wherein pembrolizumab or a biosimilar thereof is administered about once every six weeks.

71. 71. The method of any one of claims 66 to 70, wherein the route of administration of pembrolizumab or a biosimilar thereof is intravenous.

72. 72. The method of any one of claims 63 to 71, wherein prior to treatment, the tumor comprises one or more cells that express PD-L1.

73. 73. The method of claim 72, wherein the subject has a tumor that expresses PD-L1 with a TPS of > 1%.

74. 73. The method of claim 72, wherein the subject has a tumor that expresses PD-L1 with a TPS of > 20%.

75. 73. The method of claim 72, wherein the subject has a tumor that expresses PD-L1 with a TPS of ≥ 50%.

76. 73. The method of claim 72, wherein the subject has a tumor that expresses PD-L1 with a CPS of ≧1.

77. 73. The method of claim 72, wherein the subject has a tumor that expresses PD-L1 with a CPS of ≥ 20.

78. 78. The method of any one of claims 62 to 77, wherein the one or more additional therapeutic agents is a platinum-based agent.

79. 79. The method of claim 78, wherein the platinum-based agent is carboplatin or cisplatin.

80. 80. The method of any one of claims 62 to 79, wherein the first dose of the antibody-drug conjugate is administered before the administration of the first dose of the one or more additional therapeutic agents.

81. 81. The method of claim 80, wherein the first dose of the antibody drug conjugate is administered at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months before the administration of the first dose of the one or more additional therapeutic agents.

82. 83. The method of any one of claims 1 to 82, wherein the subject is a human.

83. 84. The method of any one of claims 1 to 83, wherein the antibody-drug conjugate is in a pharmaceutical composition comprising the antibody-drug conjugate and a pharmaceutically acceptable carrier.

84. (a) an antibody-drug conjugate that binds to αvβ6, comprising an anti-αvβ6 antibody or antigen-binding fragment thereof conjugated to monomethyl auristatin, or a functional analog or functional derivative thereof, at a dosage ranging from about 0.7 mg / kg to about 2.5 mg / kg; and (b) instructions for using the antibody drug conjugate according to the method of any one of claims 1 to 83. Includes a kit.

85. 84. Use of an antibody-drug conjugate that binds to αvβ6 for the manufacture of a medicament for use in the method of any one of claims 1 to 83, wherein the antibody-drug conjugate comprises an anti-αvβ6 antibody or an antigen-binding fragment thereof conjugated to monomethyl auristatin or a functional analogue or functional derivative thereof.

86. An antibody-drug conjugate that binds to αvβ6 for use in the method of any one of claims 1 to 83, comprising an anti-αvβ6 antibody or an antigen-binding fragment thereof conjugated to monomethyl auristatin or a functional analogue or functional derivative thereof.

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