Methods for treating cancer using anti-tissue factor antibody-drug conjugates

Abstract

The present disclosure provides antibody-drug conjugates (e.g., tisotumab vedotin) that bind to tissue factor (TF) and their use in methods of treating cancer, such as head and neck squamous cell carcinoma or gynecological cancer, including in combination with radiation therapy. The present disclosure also provides antibody-drug conjugates that bind to TF for combination with an additional chemotherapeutic agent, such as a platinum-based agent (e.g., carboplatin or cisplatin), for the treatment of cancer, including in combination with radiation therapy.

Description

[Technical field]

[0001] Technical Field The present invention relates to methods of treating cancer with anti-tissue factor (anti-TF) antibody-drug conjugates, including in combination with radiation therapy or chemoradiotherapy. [Background technology]

[0002] background Tissue factor (TF), also known as thromboplastin, factor III, or CD142, is a protein present in subendothelial tissue, platelets, and leukocytes that is required to initiate thrombin formation from the zymogen prothrombin. The formation of thrombin ultimately leads to the clotting of blood. TF enables cells to initiate the blood coagulation cascade and serves as a high-affinity receptor for the serine protease coagulation factor VIIa (FVIIa). The resulting complex provides the catalytic activity responsible for initiating the coagulation protease cascade by limited specific proteolysis. Unlike other cofactors of these protease cascades that circulate as nonfunctional precursors, TF is a potent initiator that is fully functional when expressed on the cell surface.

[0003] TF is the cell surface receptor for the serine protease factor VIIa (FVIIa). Binding of FVIIa to TF initiates a signaling process within the cell, and said signaling function plays a role in angiogenesis. Angiogenesis is a normal process in growth and development, as well as wound healing, but is also a fundamental step in the transition of tumors from a dormant state to a malignant state. Once cancer cells acquire the ability to produce proteins involved in angiogenesis (i.e., angiogenic growth factors), these proteins are released by the tumor into nearby tissues, thereby stimulating new blood vessels to arise from existing healthy blood vessels and enter the tumor toward and into the tumor. Once new blood vessels enter the tumor, the tumor can rapidly expand its size and invade local tissues and organs. Through the new blood vessels, cancer cells can further escape into the circulation and lodge in other organs to form new tumors, also known as metastasis.

[0004] Expression of TF has been observed in many types of cancer, including head and neck squamous cell carcinoma, and is associated with more aggressive disease (see, e.g., Jacobs et al., 2012, J. Clin. Oncol. 30(15) suppl.). In addition, human TF also exists as a soluble alternatively spliced ​​form (asHTF), which has been shown to promote tumor growth (Hobbs et al., 2007, Thrombosis Res. 120(2):S13-S21).

[0005] There remains a need for improved therapies with acceptable safety profiles and high efficacy against cancer, particularly for treating cancers that express tissue factor, including gynecological and head and neck cancers. The present invention meets this need by providing a method of treating cancers, such as gynecological and head and neck cancers, with anti-tissue factor (anti-TF) antibody-drug conjugates in combination with radiation therapy.

[0006] All references cited herein, including patent applications, patent publications, and scientific literature, are incorporated by reference in their entirety as if each individual reference was specifically and individually indicated to be incorporated by reference. [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] Jacobs et al., 2012, J. Clin. Oncol. 30(15) suppl. [Non-Patent Document 2] Hobbs et al., 2007, Thrombosis Res. 120(2):S13-S21 Summary of the Invention

[0008] overview Provided herein are methods of treating cancer in a subject, the methods comprising: (i) administering radiation therapy to the subject; and (ii) administering to the subject an antibody-drug conjugate that binds tissue factor (TF), wherein the antibody-drug conjugate comprises an anti-TF antibody or an antigen-binding fragment thereof conjugated to an auristatin or a functional analog or functional derivative thereof. In some embodiments, the auristatin is monomethylauristatin or a functional analog or functional derivative thereof. In some embodiments, the auristatin is monomethylauristatin E (MMAE). In some embodiments, the antibody-drug conjugate is administered at a dose ranging from about 0.9 mg / kg to about 2.1 mg / kg. In some embodiments, the antibody-drug conjugate is administered at a dose ranging from about 0.9 mg / kg to about 1.7 mg / kg. In some embodiments, the antibody-drug conjugate is administered at a dose of about 1.3 mg / kg. In some embodiments, the antibody-drug conjugate is administered at a dose of about 1.7 mg / kg. In some embodiments, the antibody-drug conjugate is administered at a dose of about 2.0 mg / kg. In some embodiments, the antibody-drug conjugate is administered about once a week, about once every two weeks, about once every three weeks, or about once every four weeks. In some embodiments, the antibody-drug conjugate is administered about once every two weeks. In some embodiments, the antibody-drug conjugate is administered about once every three weeks. In some embodiments, the radiation therapy is administered at a dose of about 1 Gy to about 100 Gy, such as a dose of about 10 Gy to about 70 Gy, such as a dose of about 30 Gy to about 60 Gy, such as a dose of about 40 Gy to about 50 Gy.In some embodiments, the radiation therapy is selected from the group consisting of intensity-modulated radiation therapy (IMRT), image-guided radiation therapy (IGRT), tomotherapy, stereotactic radiosurgery, stereotactic body radiation therapy, photon beam, electron beam, and proton beam therapy.

[0009] In some embodiments of the method, the method further comprises administering a chemotherapeutic agent to the subject. In some embodiments, the chemotherapeutic agent is a platinum-based agent. In some embodiments, the platinum-based agent is administered at a dose of AUC=about 4 to AUC=about 6. In some embodiments, the platinum-based agent is administered at a dose of AUC=about 5. In some embodiments, the platinum-based agent is administered about once per week, about once per two weeks, about once per three weeks, or about once per four weeks. In some embodiments, the platinum-based agent is administered about once per three weeks. In some embodiments, the platinum-based agent is administered about once per four weeks.

[0010] In some embodiments of the method, the cancer is a solid tumor. In some embodiments, the cancer is head and neck squamous cell carcinoma. In some embodiments, the cancer is a gynecological cancer. In some embodiments, the cancer is selected from the list consisting of ovarian cancer, endometrial cancer, cervical cancer, perineal tissue cancer, fallopian tube cancer, uterine cancer, vaginal cancer, vulvar cancer, and gestational trophoblastic disease cancer. In some embodiments, the cancer is associated with a tissue factor positive primary tumor. In some embodiments, the cancer is an early stage cancer. In some embodiments, the cancer is a stage I or stage II cancer. In some embodiments, the cancer is not a recurrent cancer. In some embodiments, the cancer is not locally advanced. In some embodiments, the cancer is not metastatic. In some embodiments, the cancer is locally advanced.

[0011] In some embodiments of the method, the method of treatment is neoadjuvant therapy for the cancer. In some embodiments, the antibody-drug conjugate and radiation therapy are administered prior to surgical intervention for the cancer. In some embodiments, a platinum-based agent is further administered prior to surgical intervention for the cancer. In some embodiments, the antibody-drug conjugate and radiation therapy are administered prior to surgical resection of one or more tumors associated with the cancer. In some embodiments, a platinum-based agent is further administered prior to surgical resection of one or more tumors associated with the cancer. In some embodiments, the subject has not received prior therapy for the cancer.

[0012] In some embodiments of the method, the treatment method is an adjuvant therapy for cancer. In some embodiments, the antibody-drug conjugate and radiation therapy are administered after a surgical intervention for the cancer. In some embodiments, a platinum-based agent is further administered after a surgical intervention for the cancer. In some embodiments, the antibody-drug conjugate and radiation therapy are administered after a surgical resection of one or more tumors associated with the cancer. In some embodiments, a platinum-based agent is further administered after a surgical resection of one or more tumors associated with the cancer.

[0013] In some embodiments of the method, the anti-TF antibody or antigen-binding fragment thereof of the antibody-drug conjugate is a monoclonal antibody or a monoclonal antigen-binding fragment thereof. In some embodiments, the anti-TF antibody or antigen-binding fragment thereof of the antibody-drug conjugate comprises 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 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, wherein the CDRs of the anti-TF antibody or antigen-binding fragment thereof are defined according to the IMGT numbering scheme. In some embodiments, the anti-TF 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-TF antibody or antigen-binding fragment thereof of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence of SEQ ID NO:7, and a light chain variable region comprising an amino acid sequence of SEQ ID NO:8. In some embodiments, the anti-TF antibody of the antibody-drug conjugate is tisotumab. In some embodiments, the antibody-drug conjugate further comprises a linker between the anti-TF antibody or antigen-binding fragment thereof and the auristatin. In some embodiments, the linker is a cleavable peptide linker. In some embodiments, the cleavable peptide linker has the formula: -MC-vc-PAB-, where a) MC is TIFF2025515166000001.tif28128, b) vc is the dipeptide valine-citrulline; c) PAB is The file is TIFF2025515166000002.tif27128.

[0014] In some embodiments, the linker is attached to a sulfhydryl residue of an anti-TF antibody obtained by partial or complete reduction of an anti-TF antibody or antigen-binding fragment thereof. In some embodiments, the antibody-drug conjugate has the following structure: TIFF2025515166000003.tif27142, where p represents a number from 1 to 8, S represents a sulfhydryl residue of an anti-TF antibody, and Ab represents an anti-TF antibody or an antigen-binding fragment thereof.

[0015] In some embodiments, the average value of p in the population of antibody-drug conjugates is about 4. In some embodiments, the antibody-drug conjugate is tisotumab vedotin. In some embodiments, the route of administration of the antibody-drug conjugate is intravenous. In some embodiments, the platinum-based agent is selected from the group consisting of carboplatin, cisplatin, oxaliplatin, and nedaplatin. In some embodiments, the platinum-based agent is carboplatin. In some embodiments, the platinum-based agent is cisplatin. In some embodiments, the route of administration of the platinum-based agent is intravenous. In some embodiments, the platinum-based agent and the antibody-drug conjugate are administered sequentially. In some embodiments, the platinum-based agent and the antibody-drug conjugate are administered simultaneously. 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. In some embodiments, the platinum-based agent is in a pharmaceutical composition comprising the platinum-based agent and a pharmaceutically acceptable carrier. [Brief description of the drawings]

[0016] [Figure 1A]Figure 1A shows representative images of tissue factor (TF)-positive tumors (dark staining) from the indicated HNSCC patients, separated into different buckets (II-V) based on increased TF expression. Scale bars represent 100 µm.

[0017] [Figure 1B] Figure 1B shows variable expression of tissue factor (TF) in tumor biopsies from HNSCC patients. A minimum of 100 tumor cells per section were manually scored for TF expression (membrane and cytoplasmic staining were scored together). The percentage of TF-positive cells within the tumor area was classified as I = no TF-positive tumor cells (0%, open bars) or with TF-positive cells (closed bars), II = >0–25%, III = 25–50%, IV = 50–75%, and V = 75–100%.

[0018] [Diagram 2] FIG. 2 shows the degree of tissue factor expression in the indicated HNSCC cell lines. Quantitative measurements of surface expression of TF molecules on the indicated HNSCC cell lines were performed in duplicate by flow cytometry using an indirect immunofluorescence assay. The number of TF molecules expressed on the indicated cell lines in independent experiments is indicated by black circles. Each bar represents the average of independent experiments per cell type. * indicates HPV-positive cell lines.

[0019] [Diagram 3] Figure 3 shows that tisotumab can bind to HNSCC cells. Cell surface expression of TF on the indicated HNSCC cell lines was assessed by flow cytometry using the clinical anti-TF antibody tisotumab (solid black peaks) or isotype control IgG1 (IgG1-b12, solid grey peaks) with a PE-conjugated goat (Fab')2 anti-human IgG secondary antibody.

[0020] [Figure 4A] FIG. 4A shows the dose-dependent cytotoxicity of tisotumab vedotin (TV) in the indicated cell lines, assessed as percent of viable cells, compared to IgG1-vedotin (IgG1-V) control.

[0021] [Figure 4B] FIG. 4B shows dose-dependent cytotoxicity of tisotumab vedotin (TV) in the indicated cell lines, assessed as percent of viable cells, compared to IgG1-vedotin (IgG1-V) control.

[0022] [Figure 4C] Figure 4C shows the IC50 values ​​(μg / ml) of TV for each cell type indicated. The graph shows the IC50 values ​​(μg / ml) of tisotumab vedotin from independent experiments. Circles indicate IC50 from individual experiments; bars represent the mean IC50 ± SEM (standard error of the mean). Only cell lines with a minimum of n=3 experiments are included. * indicates HPV-positive cell lines.

[0023] [Diagram 5] FIG. 5 validates TF expression on HNSCC cell lines (used to induce tumor growth in mice) assessed by flow cytometry stained with 7.5 μg / ml human anti-TF antibody (anti-CD142-FITC; dark grey filled peak) or with isotype control-FITC (mouse IgG1-FITC) (light grey peak).

[0024] [Figure 6] FIG. 6 shows a schematic diagram of the mouse tumor model experiment ("TV" is tisotumab vedotin, "RT" is radiotherapy, and "CDDP" is cisplatin).

[0025] [Figure 7]Figure 7 shows that tumors derived from HNSCC cell lines express TF. Tumors from mice injected with the indicated HNSCC cell lines (without treatment) were harvested and IHC analysis was performed on formalin-fixed paraffin-embedded (FFPE) tumor sections to measure TF expression; TF expression was visualized by 3,3'-diaminobenzidine (DAB) using anti-CD142-FITC or isotype control (IgG1-FITC) with rabbit anti-FITC and BrightVision immunohistochemistry (IHC) detection kits and counterstained with hematoxylin. Scale bars represent 0-100 µm.

[0026] [Figure 8A] Figure 8A shows tumor volumes measured over time in different treatment groups of FaDu tumor-bearing mice. Mice were treated with vehicle control (PBS), the indicated concentrations of tisotumab vedotin (TV) (1, 2, or 4 mg / kg), or IgG1-vedotin (IgG1-V) (4 mg / kg) control on days 0, 7, and 13 (black arrows).

[0027] [Figure 8B] Figure 8B shows the mean tumor volume (mm3) ± SEM in different treatment groups of FaDu tumor-bearing mice. Mice were treated with vehicle control (PBS), the indicated concentrations of tisotumab vedotin (TV) (1, 2, or 4 mg / kg), or IgG1-vedotin (IgG1-V) (4 mg / kg). Results are shown when all groups were completed (day 7). Overall survival improvement was assessed using the Kaplan-Meier method, and differences between groups, indicated by brackets, were assessed by the Log-rank test (Mantel-Cox) (* p<0.05; ** p<0.01).

[0028] [Figure 8C]Figure 8C shows tumor volumes measured over time in different treatment groups of VU-SCC-OE-tumor-bearing mice. Mice were treated with vehicle control (PBS), the indicated concentrations of tisotumab vedotin (TV) (1, 2, or 4 mg / kg), or IgG1-vedotin (IgG1-V) (4 mg / kg). Days of treatment are indicated by black arrows.

[0029] [Figure 8D] Figure 8D shows the mean tumor volume (mm3) ± SEM in different treatment groups of VU-SCC-OE-tumor-bearing mice. Mice were treated with vehicle control (PBS), the indicated concentrations of tisotumab vedotin (TV) (1, 2, or 4 mg / kg), or IgG1-vedotin (IgG1-V) (4 mg / kg).

[0030] [Figure 8E] Figure 8E shows tumor volumes measured over time in different treatment groups of VU-SCC-040 tumor-bearing mice. Mice were treated with vehicle control (PBS), the indicated concentrations of tisotumab vedotin (TV) (1, 2, or 4 mg / kg), or IgG1-vedotin (IgG1-V) (4 mg / kg) on ​​days 0, 7, and 14 (indicated by black arrows).

[0031] [Figure 8F] Figure 8F shows the mean tumor volume (mm3) ± SEM in different treatment groups of VU-SCC-040 tumor-bearing mice. Mice were treated with vehicle control (PBS), the indicated concentrations of tisotumab vedotin (TV) (1, 2, or 4 mg / kg), or IgG1-vedotin (IgG1-V) (4 mg / kg). Results are shown when all groups were completed (day 6).

[0032] [Figure 9A]Figure 9A shows FaDu tumor volume measurements over time for the completed treatment groups as mean tumor (mm3) per mouse ± SEM. FaDu-bearing mice (5–6 per group) were treated with PBS, tisotumab vedotin (TV) (2 mg / kg, "TV2") or IgG1-vedotin (IgG1-V) on days 0 and 10 (black arrows). The group labeled "CRT" received chemoradiotherapy (CRT) on days 1 and 11 (indicated by light grey arrows).

[0033] [Figure 9B] Figure 9B shows the FaDu mean tumor volume (mm3) ± SEM in different treatment groups from FaDu-bearing mice (5-6 mice / group) treated with PBS, tisotumab vedotin (TV) (2 mg / kg, denoted as "TV2"), or IgG1-vedotin (IgG1-V). The group denoted as "+CRT" received chemoradiotherapy. Kruskal-Wallis test was performed to determine statistically significant differences between groups (* p<0.05).

[0034] [Figure 9C] Figure 9C shows tumor volume measurements on day 9 of VU-SCC-OE (8 mice / group) versus time for the completed treatment group as mean tumor (mm3) per mouse ± SEM. Mice were treated with PBS, tisotumab vedotin (TV) (2 mg / kg, denoted "TV2") or IgG1-vedotin on days 0 and 10 (black arrows). The group labeled "+CRT" received chemoradiotherapy (CRT) on days 1 and 11 (light grey arrows).

[0035] [Figure 9D]Figure 9D shows the mean tumor volume (mm3) ± SEM on day 14 of VU-SCC-OE (8 mice / group) in different treatment groups of VU-SCC-OE-bearing mice treated with PBS, Tisotumab vedotin (TV) (2 mg / kg) or IgG1-vedotin (IgG1-V) on days 0 and 10. The group indicated as "+CRT" received chemoradiotherapy on days 1 and 11. Kruskal-Wallis test was performed to determine statistical significance between groups (* p<0.05; **** p<0.0001).

[0036] [Figure 9E] Figure 9E shows survival plots of FaDu tumor-bearing mice after treatment with PBS, tisotumab vedotin (TV) (2 mg / kg), or IgG1-vedotin. Groups indicated as "+CRT" received chemoradiotherapy ("CRT" alone indicates PBS+CRT). Survival curves were compared by log-rank (Mantel-Cox) analysis.

[0037] [Figure 9F] Figure 9F shows survival plots of VU-SCC-OE tumor-bearing mice after treatment with PBS, tisotumab vedotin (TV) (2 mg / kg), or IgG1-vedotin (IgG1-V). The group indicated as "+CRT" received chemoradiotherapy. Survival curves were compared by log-rank (Mantel-Cox) analysis.

[0038] [Figure 10A] Figure 10A shows tumor volume measurements for the indicated treatment groups on day 7 after treatment with PBS, IgG1-vedotin, or tisotumab vedotin (TV) (1 mg / kg or 2 mg / kg) with or without 2 Gray (Gy) total body radiation therapy ("RT"), or radiation therapy alone ("RT 2Gy"). Kruskal-Wallis tests were performed to determine statistically significant differences between groups (* p<0.05; ** p<0.01).

[0039] [Figure 10B] Figure 10B shows the survival curves of the various treatment groups expressed as percentages. Survival curves were compared by log-rank (Mantel-Cox) analysis. "TV2" indicates 2 mg / kg tisotumab vedotin, and "RT" indicates 2 Gray (Gy) radiation therapy.

[0040] [Figure 10C] Figure 10C shows tumor volume measurements for the indicated treatment groups 7 days after treatment. "TV1" and "TV2" represent 1 mg / kg and 2 mg / kg tisotumab vedotin doses, respectively. CDDP represents 3 mg / kg cisplatin treatment (* p<0.05; ** p<0.01).

[0041] [Figure 10D] Figure 10D shows survival curves expressed as percentage survival for the indicated treatment groups at day 7 after treatment. "TV1" and "TV2" indicate 1 mg / kg and 2 mg / kg tisotumab vedotin doses, respectively. "CDDP" or "+CT" indicates 3 mg / kg cisplatin (CDDP, chemotherapy) treatment. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0042] Detailed Description The present disclosure provides an anti-TF antibody-drug conjugate that binds to tissue factor (TF) for use in a method of treating cancer, the method comprising administering the antibody-drug conjugate to a subject with cancer. In some embodiments, the method further comprises administering radiation therapy to the subject. In some embodiments, the method further comprises administering radiation therapy and administering an additional chemotherapeutic agent, such as a platinum-based agent (e.g., cisplatin or carboplatin). In some embodiments, the cancer is a tissue factor-positive cancer. In some embodiments, at least about 0.1%, at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, or at least about 80% of cancer cells from the subject express TF. 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 the cancer cells from the subject express TF. In some embodiments, the percentage of cells expressing TF is determined using immunohistochemistry (IHC). In some embodiments, the percentage of cells expressing TF is determined using flow cytometry. In some embodiments, the percentage of cells expressing TF is determined using enzyme-linked immunosorbent assay (ELISA). In some embodiments, the cancer is head and neck cancer, e.g., head and neck squamous cellular carcinoma (HNSCC). In some embodiments, the cancer is a gynecological cancer. In some embodiments, the subject being treated is a human.

[0043] I. Definition In order that this disclosure may be more readily understood, certain terms are first defined. As used in this application, unless otherwise defined herein, each of the following terms shall have the meaning indicated below. Additional definitions are set forth throughout this application.

[0044] The term "and / or" as used herein should be interpreted as a specific disclosure of each of the two specified features or components, with or without the other. Thus, the term "and / or" as used herein in phrases such as "A and / or B" shall include "A and B", "A or B", "A" (single), and "B" (single). Similarly, the term "and / or" as used in phrases such as "A, B, and / or C" shall include each of the following interpretations: 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 (single); B (single); C (single).

[0045] It will be understood that the aspects and embodiments of the invention described herein include "comprising," "consisting," and "consisting essentially of" aspects and embodiments.

[0046] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure pertains.For example, the following provides a general dictionary for many of the terms used in this disclosure to those skilled in the art: Concise Dictionary of Biomedicine and Molecular Biology, Juo, Pei-Show, 2nd Edition, 2002, CRC Press; 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.

[0047] Units, prefixes, and symbols are denoted in the format accepted by the Systeme International de Unites (SI). Numerical ranges are inclusive of the numbers defining the range. The headings provided herein are not limitations of the various aspects of this disclosure, which aspects can be had by reference to the specification as a whole. Thus, the terms defined immediately below are more fully defined by reference to the specification as a whole.

[0048] The terms "tissue factor," "TF," "CD142," "tissue factor antigen," "TF antigen," and "CD142 antigen" are used interchangeably herein and, unless otherwise specified, encompass variants, isoforms, and species homologs of human tissue factor that are naturally expressed by cells or expressed in cells transfected with the tissue factor gene. In some embodiments, tissue factor comprises the amino acid sequence found in Genbank accession NP_001984.

[0049] The term "immunoglobulin" refers to a class of structurally related glycoproteins that consist of two pairs of polypeptide chains, one pair of low molecular weight light (L) chains and one pair of heavy (H) chains, all four of which are interconnected by disulfide bonds. The structure of immunoglobulins has been well characterized; see, for example, 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 VH) and the heavy chain constant region (C H The heavy chain constant region is generally composed of C H 1. C H 2, and C H The heavy chains are generally interconnected via disulfide bonds at the so-called "hinge region". Each light chain typically comprises a light chain variable region (herein referred to as V L or VL) and the light chain constant region (C L The light chain constant region generally consists of one domain, C L The CL may be of kappa or lambda isotype. The terms "constant domain" and "constant region" are used interchangeably herein. Unless otherwise specified, the numbering of amino acid residues in the constant region is according to the EU index as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD. (1991). Immunoglobulins may 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 genes.

[0050] 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 divided into regions of hypervariability (i.e., hypervariable regions that may be hypervariable in sequence and / or in the form of structurally defined loops), also called complementarity determining regions (CDRs), which are interrupted by more conserved regions called framework regions (FRs). The terms "complementarity determining regions" and "CDRs" are synonymous with "hypervariable regions" or "HVRs" and are known in the art to refer to non-contiguous sequences of amino acids within antibody variable regions 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 regions" and "FRs" are known in the art to refer to the non-CDR portions of the 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 L Within a FR, the three CDRs and four FRs are usually arranged in the following order from amino-terminus to carboxy-terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4 (see also Chothia and Lesk J. Mot. Biol., 195, 901-917 (1987)).

[0051] The term "antibody" (Ab) in the context of the present invention refers to an immunoglobulin molecule, a fragment of an immunoglobulin molecule, or any derivative thereof; which has the ability to specifically bind to an antigen under normal physiological conditions and has a fairly long half-life, e.g., at least about 30 minutes, at least about 45 minutes, at least about 1 hour, at least about 2 hours, at least about 4 hours, at least about 8 hours, at least about 12 hours, about 24 hours or more, about 48 hours or more, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, or more days, or other relevant functionally defined period of time (e.g., a period of time sufficient to elicit, promote, enhance and / or modulate a physiological response associated with binding of the antibody to the antigen and / or a period of time sufficient for the antibody to recruit effector activity). The variable regions of the heavy and light chains of an immunoglobulin molecule contain the binding domains that interact with the 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 (e.g., effector cells) and components of the complement system (e.g., C1q, the first component of the classical pathway of complement activation).Antibodies may also be bispecific antibodies, diabodies, multispecific antibodies, or similar molecules.

[0052] The term "monoclonal antibody" as used herein refers to a recombinantly produced preparation of antibody molecules having a single primary amino acid sequence. A monoclonal antibody composition exhibits a single binding specificity and affinity for a particular epitope. Thus, the term "human monoclonal antibody" refers to an antibody exhibiting a single binding specificity having variable and constant regions derived from human germline immunoglobulin sequences. Human monoclonal antibodies can be made by hybridomas, which include B cells obtained from a transgenic or transchromosomal non-human animal, such as a transgenic mouse, whose genome includes human heavy and light chain transgenes, fused to an immortalized cell.

[0053] An "isolated antibody" refers to an antibody that is substantially free of other antibodies having different antigen specificities (e.g., an isolated antibody that specifically binds to TF is substantially free of antibodies that specifically bind to antigens other than TF). However, an isolated antibody that specifically binds to TF may exhibit cross-reactivity to other antigens, such as TF molecules from different species. Furthermore, an isolated antibody is substantially free of other cellular material and / or chemicals. In one embodiment, an isolated antibody comprises a conjugate conjugated to another agent (e.g., a small molecule drug). In some embodiments, an isolated anti-TF antibody comprises a conjugate of an anti-TF antibody and a small molecule drug (e.g., MMAE or MMAF).

[0054] A "human antibody" (HuMAb) refers to an antibody having a variable region 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 is also 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, the term "human antibody" as used herein 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.

[0055] The term "humanized antibody" as used herein refers to a genetically engineered non-human antibody comprising a human antibody constant domain and a non-human variable domain that has been modified to contain a high level of sequence homology to the human variable domain. This can be achieved by grafting the six non-human antibody complementarity determining regions (CDRs) that together form the antigen binding site into a homologous human acceptor framework region (FR) (see WO92 / 22653 and EP0629240). Substitution of framework residues from the parent antibody (i.e., non-human antibody) into human framework regions (back-mutations) may be required to fully reconstitute the binding affinity and specificity of the parent antibody. 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 comprise a primarily human framework region, including non-human CDR sequences and, optionally, one or more amino acid back-mutations to non-human amino acid sequences, and a fully human constant region. If necessary, additional amino acid modifications, not necessarily back-mutations, can also be applied to obtain a humanized antibody with favorable properties, such as affinity and biochemical properties.

[0056] The term "chimeric antibody" as used herein refers to an antibody whose variable region is derived from a non-human species (e.g., rodent) and whose constant region is derived from a different species (e.g., human). Chimeric antibodies can be created by antibody engineering. "Antibody engineering" is a term commonly used for various types of modification of antibodies and is a process well known to those skilled in the art. In particular, chimeric antibodies can be created using standard DNA techniques, such as those described in Sambrook et al., 1989, Molecular Cloning: A laboratory Manual, New York: Cold Spring Harbor Laboratory Press, Ch. 15. Thus, chimeric antibodies can be genetically or enzymatically created recombinant antibodies. Creating chimeric antibodies is within the knowledge of those skilled in the art, and therefore, the creation of chimeric antibodies according to the present invention may be performed by methods other than those described herein. Therapeutic chimeric monoclonal antibodies have been developed to reduce the immunogenicity of antibodies. They typically may contain non-human (e.g., murine) variable regions specific for the antigen of interest and the constant domains of human antibody heavy and light chains. The term "variable region" or "variable domain" as used in the context of a chimeric antibody refers to the region comprising the CDR and framework regions of both the heavy and light immunoglobulin chains.

[0057] "Anti-antigen antibody" refers to an antibody that binds to an antigen. For example, an anti-TF antibody is an antibody that binds to the antigen TF.

[0058] 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 results in two identical antigen-binding fragments called "Fab" fragments (each with a single antigen-binding site), and a remaining "Fc" fragment (the name reflects the ability to crystallize readily). Pepsin treatment produces an F(ab')2 fragment, which has two antigen-binding sites and is still capable of cross-linking antigen.

[0059] "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, if necessary, to achieve maximum sequence identity (any conservative substitutions are not considered as part of sequence identity). Alignment to determine percent amino acid sequence identity can be accomplished in a variety of ways that are within the skill of the art, for example, using publicly available computer software such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR, Inc.) software. Those skilled in the art can determine appropriate parameters for aligning sequences, including the algorithms required to achieve maximum alignment over the entire length of the sequences being compared. For example, the percent sequence identity of a given amino acid sequence A to a given amino acid sequence B (which can also be translated as a particular amino acid sequence A having a certain percent sequence identity to a particular amino acid sequence B) is calculated as follows: 100 x fraction X / Y where X is the number of amino acid residues recorded as perfect matches by the program in an alignment of A and B, and Y is the total number of amino acid residues in B. It will be 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.

[0060] As used herein, the terms "binding," "binding" or "specifically binding" in the context of binding of an antibody to a given antigen typically refer to a binding intensity of about 10, as measured, for example, by BioLayer Interferometry (BLI) techniques on an Octet HTX instrument using an antibody as the ligand and an antigen as the analyte. -6 K below M D , for example, about 10 -7 M or less, about 10 -8 M or less, about 10 -9 M or less, about 10 -10 M or less, or about 10 -11 K below M D and antibodies bind with an affinity corresponding to the K for binding to nonspecific antigens other than the given antigen or closely related antigens (e.g., BSA, casein). D At least 10 times lower than D , e.g., at least 100-fold lower, at least 1,000-fold lower, at least 10,000-fold lower, or at least 100,000-fold lower K D binds to a given antigen with an affinity corresponding to the K D The amount at which the antibody's K 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 lower than can be at least 10,000-fold (ie, the antibody is highly specific).

[0061] As used herein, the term "K D " (M) refers to the dissociation equilibrium constant of a particular antibody-antigen interaction. As used herein, affinity and KD is inversely related, i.e., higher affinity corresponds to lower K D and a lower affinity is intended to refer to a higher K D is intended to refer to.

[0062] The term "ADC" refers to an antibody-drug conjugate, and in the context of the present invention, refers to an anti-TF antibody linked to a drug moiety (e.g., MMAE or MMAF) as described in this application.

[0063] The abbreviations "vc" and "val-cit" refer to the dipeptide valine-citrulline.

[0064] The abbreviation "PAB" stands for self-immolative spacer: Points to TIFF2025515166000004.tif40128.

[0065] The abbreviation "MC" stands for the stretcher maleimidocaproyl: Points to TIFF2025515166000005.tif32128.

[0066] The term "Ab-MC-vc-PAB-MMAE" refers to an antibody conjugated to the drug MMAE via the MC-vc-PAB linker.

[0067] "Platinum-based drugs" refers to molecules useful as chemotherapeutic agents that contain coordination complexes with the chemical element platinum, or compositions that contain such molecules. Platinum-based drugs generally act by inhibiting DNA synthesis, and some have alkylating activity. Platinum-based drugs include drugs currently used as part of chemotherapy regimens, drugs currently in development, and drugs that will be developed in the future.

[0068] "Cancer" refers to a broad group of different diseases characterized by the uncontrolled growth of abnormal cells in the body. "Cancer" or "cancerous tissue" can include tumors. Unregulated cell division and growth leads to the formation of malignant tumors, which 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. For example, a "tumor originating from" cervical cancer refers to a tumor that is the result of the cervical cancer metastasizing.

[0069] A "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, with the goal of curing, reversing, mitigating, ameliorating, suppressing, slowing down, or preventing the onset, progression, development, severity, or recurrence of symptoms, complications, conditions, or biochemical signs associated with a disease. In some embodiments, the disease is cancer. A "neoadjuvant" treatment or therapy is one that is performed before a primary treatment (e.g., surgical intervention) to increase the chance of a favorable clinical outcome (such as a cure) from the primary treatment. In the context of cancer, for example, a neoadjuvant treatment or therapy can shrink a tumor, allowing for a curative surgical intervention. An "adjuvant" treatment or therapy is one that is performed after a primary treatment (e.g., after a surgical intervention) to increase the chance of a cure. For example, in the context of cancer, after resection of a larger primary tumor, an adjuvant treatment or therapy can prevent the growth of a secondary tumor.

[0070] 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.

[0071] An "effective amount," "therapeutically effective amount," or "therapeutically effective dose" of a drug or therapeutic agent is that amount of drug that, when used alone or in combination with another therapeutic agent, protects a subject from developing a disease or promotes regression of the disease as evidenced by a decrease in the severity of symptoms, an increase in the frequency and duration of symptom-free periods, or prevention of impairment or disability due to the affliction of the disease. The ability of a therapeutic agent to promote regression of a disease can be evaluated using a variety of methods known to those of skill in the art, for example, by assaying the activity of the therapeutic agent in human subjects during clinical trials, in animal model systems predictive of efficacy in humans, or in in vitro assays.

[0072] As an example of treating a tumor, a therapeutically effective amount of an anti-cancer agent inhibits cell proliferation or tumor growth in a treated subject (e.g., one or more treated subjects) 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%, 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% compared to an untreated subject (e.g., one or more untreated subjects). In some embodiments, a therapeutically effective amount of an anti-cancer agent inhibits cell proliferation or tumor growth in a treated subject (e.g., one or more treated subjects) by at least 100% compared to an untreated subject (e.g., one or more untreated subjects).

[0073] In other embodiments of the present disclosure, tumor regression can be observed, and regression may continue for 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. Notwithstanding these ultimate measures of therapeutic efficacy, evaluation of immunotherapeutic agents must also take into account "immune-related response patterns."

[0074] A therapeutically effective amount of a drug (e.g., an anti-TF antibody-drug conjugate or a platinum-based drug) includes a "prophylactically effective amount," which is the 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 at risk of developing a recurrence of cancer, prevents the onset or recurrence of cancer. In some embodiments, a prophylactically effective amount completely prevents the onset or recurrence of cancer. "Preventing" the onset or recurrence of cancer means reducing the likelihood of the onset or recurrence of cancer or preventing the onset or recurrence of cancer completely.

[0075] As used herein, a "sub-therapeutic dose" refers to a dose of a therapeutic compound (e.g., an anti-TF antibody-drug conjugate or a platinum-based drug) that is lower than the usual or commonly used dose of that therapeutic compound when administered alone to treat a hyperproliferative disease (e.g., cancer).

[0076] "Immune-related response pattern" refers to a clinical response pattern often observed in cancer patients treated with immunotherapeutic agents that produce antitumor effects by inducing cancer-specific immune responses or by modifying natural immune processes. This response pattern is characterized by an initial increase in tumor burden or the appearance of new lesions (which in the evaluation of conventional chemotherapeutic agents is classified as disease progression and is synonymous with drug failure) followed by a beneficial therapeutic effect. Thus, proper evaluation of immunotherapeutic agents may require long-term monitoring of the effects of these agents on the target disease.

[0077] By way of example, an "anti-cancer drug" promotes the regression of cancer in a subject. In some embodiments, a therapeutically effective amount of the drug promotes the regression of cancer to the extent that it eliminates the cancer. "Promoting the regression of cancer" means that an effective amount of the 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 symptom, an increase in the frequency and duration of symptom-free periods, or prevention of functional impairment or disability due to the affliction of the disease. Furthermore, the terms "effective" and "effectiveness" in relation to treatment include both pharmacological effectiveness and physiological safety. Pharmacological effectiveness refers to the ability of a drug to promote the regression of cancer in a patient. Physiological safety refers to the level of toxicity or other adverse physiological effects (side effects) at the cellular, organ, and / or organismal levels resulting from the administration of the drug.

[0078] "Sustained response" refers to a sustained effect on suppressing tumor growth after the cessation of treatment. For example, the tumor size is the same or smaller than the size at the beginning of the administration period. In some embodiments, the sustained response has a duration at least equal to the duration of the treatment, or at least 1.5 times, 2.0 times, 2.5 times, or 3.0 times longer than the duration of the treatment.

[0079] As used herein, a "complete response" or "CR" refers to the disappearance of all target lesions; a "partial response" or "PR" refers to at least a 30% reduction in the sum of the longest diameters (SLD) of target lesions based on baseline; and a "stable disease" or "SD" refers to neither a sufficient reduction in target lesions to qualify for PR nor a sufficient increase in the smallest SLD since treatment initiation to qualify for PD.

[0080] As used herein, "progression-free survival" or "PFS" refers to the period during and after treatment during which the disease being treated (e.g., cancer) does not worsen. Progression-free survival can include periods during which a patient experiences a complete or partial response, as well as periods during which a patient experiences stable disease.

[0081] As used herein, "overall response rate" or "ORR" refers to the combined complete response (CR) and partial response (PR) rates.

[0082] As used herein, "overall survival" or "OS" refers to the proportion of individuals in a group who are likely to be alive after a particular period of time.

[0083] The term "body weight-based dose" as used herein means that the dose administered to a subject is calculated based on the subject's body weight.For example, if a subject weighing 60 kg requires 2.0 mg / kg of platinum-based drug or anti-TF antibody-drug conjugate, the appropriate amount (i.e., 120 mg) of platinum-based drug or anti-TF antibody-drug conjugate can be calculated and used for administration to the subject.

[0084] The use of the term "fixed dose" in relation to the methods of the present disclosure means that two or more different agents (e.g., a platinum-based agent and an anti-TF antibody-drug conjugate) are administered to a subject in a specific (fixed) ratio to one another. In some embodiments, the fixed dose is based on the amount of agent (e.g., mg). In certain embodiments, the fixed dose is based on the concentration of agent (e.g., mg / ml). For example, a 3:1 ratio of platinum-based agent and anti-TF antibody-drug conjugate administered to a subject may mean that about 240 mg of platinum-based agent and about 80 mg of anti-TF antibody-drug conjugate, or about 3 mg / ml of platinum-based agent and about 1 mg / ml of anti-TF antibody-drug conjugate are administered to the subject.

[0085] The use of the term "flat dose" in relation to the methods and dosages of the present disclosure refers to a dose administered to a subject regardless of the subject's body weight or body surface area (BSA). Thus, a flat dose is provided as an absolute amount of agent (e.g., anti-TF antibody-drug conjugate and / or platinum-based agent) rather than as a mg / kg dose. For example, a subject weighing 60 kg and a subject weighing 100 kg will receive the same dose of antibody or antibody-drug conjugate (e.g., 240 mg of anti-TF antibody-drug conjugate or, e.g., 750 mg of platinum-based agent).

[0086] The phrase "pharmacologically acceptable" indicates that a substance or composition must be chemically and / or toxicologically compatible with the other ingredients that make up the formulation and / or the mammal being treated therewith.

[0087] 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, gentisinate, 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)), alkali metal (e.g., sodium and potassium), alkaline earth metal (e.g., magnesium), and ammonium salts. A pharma- ceutically acceptable salt may contain another molecule, such as an acetate ion, a succinate ion, or other counterion. A counterion may be any organic or inorganic moiety that stabilizes the charge of the parent compound. In addition, a pharma- ceutically acceptable salt may have multiple charged atoms in its structure. If multiple charged atoms are part of the pharma- ceutically acceptable salt, it may have multiple counterions. Thus, a pharma- ceutically acceptable salt may have one or more charged atoms and / or one or more counterions.

[0088] "Administering" or "administration" refers to physically introducing 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 of anti-TF antibody-drug conjugates and / or platinum-based agents include intravenous, intramuscular, subcutaneous, intraperitoneal, spinal or other parenteral routes of administration, such as by injection or infusion (e.g., intravenous infusion). As used herein, the phrase "parenteral administration" refers to a method of administration other than enteral administration and topical application, usually by injection, including, but 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, and in vivo electroporation. The therapeutic agent can be administered via a non-parenteral route or orally. Other non-parenteral routes include topical, epidermal or mucosal routes of administration, such as intranasal, intravaginal, rectal, sublingual or topical. Administration can also be, for example, once, multiple times, and / or over one or more extended periods of time.

[0089] The term "baseline" or "baseline value" as used interchangeably herein can refer to a measurement or characterization of symptoms prior to administration of a therapeutic agent (e.g., an anti-TF antibody-drug conjugate described herein and / or a platinum-based agent described herein) or at the start of administration of a therapeutic agent. The baseline value can be compared to a reference value to determine the reduction or improvement of symptoms of a disease contemplated herein, such as a TF-related disease contemplated herein (e.g., cancer). The term "reference" or "reference value" as used interchangeably herein can refer to a measurement or characterization of symptoms after administration of a therapeutic agent (e.g., an anti-TF antibody-drug conjugate described herein and / or a platinum-based agent described herein). The reference value can be measured one or more times during a dosing regimen or treatment cycle, or at the completion of a dosing regimen or treatment cycle. A "reference 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; a mean value; or a value compared to a baseline value.

[0090] 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; a mean value; or a value compared to a reference value. Reference and / or baseline values ​​can be obtained from one individual, from two different individuals, or from a population of individuals (e.g., a group of 2, 3, 4, 5 or more individuals).

[0091] The term "monotherapy" as used herein means that the anti-TF antibody-drug conjugate or platinum-based drug described herein is the only anti-cancer drug administered to the subject during the treatment cycle.However, other therapeutic agents can also be administered to the subject.For example, anti-inflammatory or other drugs administered to cancer patients to treat symptoms associated with cancer (but not the underlying cancer itself), such as inflammation, pain, weight loss, and general fatigue, can be administered during monotherapy.

[0092] As used herein, an "adverse event" (AE) is an unfavourable, generally unintended or undesirable sign (including abnormal laboratory findings), symptom, or disease associated with the use of a medical treatment. A medical treatment may exhibit one or more associated AEs, and each AE may be of the same or different levels of severity. Reference to a method that can "alter an adverse event" refers to a treatment regimen that reduces the incidence and / or severity of one or more AEs associated with the use of a different treatment regimen.

[0093] As used herein, a "serious adverse event" or "SAE" is an adverse event that meets one of the following criteria: Fatal or life-threatening (as used in the definition of a serious adverse event); "life-threatening" refers to an event in which the patient was at risk of death at the time of the adverse event; it does not refer to an event that may have caused death if it had been more severe. ·Causing permanent or significant disability / incapacity. ·Causes birth defects / abnormalities. 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 when determining whether an AE is "medically significant." Hospitalization or an extension of a current hospitalization is necessary, except for: 1) routine treatment or monitoring of an underlying disease not associated with a worsening of the condition; 2) elective or pre-planned treatment for a pre-existing condition that is unrelated to the indication under investigation and that has not worsened since signing the informed consent; and 3) social reasons and respite care in the absence of a deterioration of the patient's general condition.

[0094] The use of the alternative (e.g., "or") should be understood to mean either 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 the described or listed components.

[0095] The term "about" or "essentially consists of" refers to a value or composition that is within an acceptable error range of 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 and determined, i.e., the limitations of the measurement system. For example, "about" or "essentially consists of" can mean within 1 or more than 1 standard deviation per practice in the art. Alternatively, "about" or "essentially consists of" can mean within a range of up to 20%. Furthermore, particularly with respect to biological systems or processes, these terms can mean up to 10-fold or up to 5-fold of a value. When a particular value or composition is provided in this application and claims, unless otherwise indicated, the meaning of "about" or "essentially consists of" should be considered to be within an acceptable error range of that particular value or composition.

[0096] As used herein, the terms "about once per week," "about once per 2 weeks," "about once per 3 weeks," or other similar dosing interval terms refer to approximate numbers. "About once per week" can include every 7 days ± 1 day, i.e., every 6 to 8 days. "About once per 2 weeks" can include every 14 days ± 2 days, i.e., every 12 to 16 days. "About once per 3 weeks" can include every 21 days ± 3 days, i.e., every 18 to 24 days. Similar approximations apply, for example, to about once per 4 weeks, about once per 5 weeks, about once per 6 weeks, about once per 12 weeks, etc. In some embodiments, a dosing interval of about once per 6 weeks or about once per 12 weeks means that the first dose can be administered on any day in the first week, followed by the next dose on any day in the sixth or twelfth week, respectively. In other embodiments, a dosing interval of about once every 6 weeks or about once every 12 weeks means that a first dose is administered on a particular day (e.g., a Monday) in week 1, followed by a next dose on the same day (i.e., a Monday) in week 6 or week 12, respectively.

[0097] Any concentration range, percentage range, ratio range, or integer range described herein should be understood to include any integer value within the recited range, and fractions thereof, where appropriate (such as tenths and hundredths of integers), unless otherwise specified.

[0098] Various aspects of the disclosure are described in further detail in the following subsections.

[0099] II. Antibody-drug conjugates The present disclosure provides an anti-TF antibody-drug conjugate that binds to TF for use in the treatment of cancer, wherein the treatment comprises administering the antibody-drug conjugate to a subject with cancer, and in some embodiments, the method further comprises administering radiation therapy to the subject. In some embodiments, the addition of the antibody-drug conjugate to a treatment comprising radiation therapy enhances the efficacy of the radiation therapy. In some embodiments, the antibody-drug conjugate comprises an anti-TF antibody or an antigen-binding fragment thereof conjugated to an auristatin (such as monomethyl auristatin) or a functional analog or functional derivative thereof. In some embodiments, the cancer is associated with a tissue factor positive tumor. In some embodiments, the cancer is head and neck cancer. In some embodiments, the head and neck cancer is head and neck squamous cell carcinoma (HNSCC). In some embodiments, the cancer is a gynecological cancer. In some embodiments, the gynecological cancer is selected from ovarian cancer, endometrial cancer, cervical cancer, perineal tissue cancer, fallopian tube cancer, uterine cancer, vaginal cancer, vulvar cancer, and gestational trophoblastic disease cancer. In some embodiments, the gynecological cancer is ovarian cancer. In some embodiments, the gynecological cancer is endometrial cancer. In some embodiments, the gynecological cancer is cervical cancer. In some embodiments, the gynecological cancer is perineal tissue cancer. In some embodiments, the gynecological cancer is fallopian tube cancer. In some embodiments, the cancer is uterine cancer. In some embodiments, the gynecological cancer is vaginal cancer. In some embodiments, the gynecological cancer is vulvar cancer. In some embodiments, the gynecological cancer is gestational trophoblastic disease cancer. In some embodiments, the cancer is early stage cancer (such as stage I or stage II). In some embodiments, the cancer is not recurrent. In some embodiments, the cancer is locally advanced. In some embodiments, the cancer is not metastatic. In some embodiments, the treatment is neoadjuvant therapy (e.g., treatment prior to surgical intervention). In some embodiments, the treatment is adjuvant therapy (e.g., after surgical intervention). In some embodiments, the radiation therapy is selected from the group consisting of intensity modulated radiation therapy (IMRT), image-guided radiation therapy (IGRT), tomotherapy, stereotactic radiosurgery, stereotactic body radiation therapy, photon beam therapy, electron beam therapy, and proton beam therapy.In some embodiments, the radiation therapy is intensity modulated radiation therapy (IMRT). In some embodiments, the radiation therapy is image-guided radiation therapy (IGRT). In some embodiments, the radiation therapy is tomotherapy. In some embodiments, the radiation therapy is stereotactic radiosurgery. In some embodiments, the radiation therapy is stereotactic body radiation therapy. In some embodiments, the radiation therapy is photon beam therapy. In some embodiments, the radiation therapy is electron beam therapy. In some embodiments, the radiation therapy is proton beam therapy.

[0100] In some embodiments, the antibody-drug conjugates of the present disclosure are administered to patients who have undergone, are undergoing, or will undergo radiation therapy. In some embodiments, in external beam radiation therapy, high energy rays (e.g., gamma rays or X-rays) and / or high energy particles / charged particles can be generated outside the subject's body and irradiated to a target tumor associated with the cancer being treated. Tumor cells and normal cells that are in the path of the beam will absorb some of the radiation. In some embodiments, to avoid damage to surrounding healthy tissue (collateral tissue damage), the target tumor area can be treated with low levels of radiation administered from different points of incidence (vectors of radiation). In some embodiments, the radiation dose can be "fractionated," by administering a portion of the dose in one fraction and the remaining dose in one or more additional fractions, usually from different approach vector(s) or at different times (to allow healthy tissue time to recover). In some embodiments, stereotactic body radiotherapy is used to deliver image-guided, focused, high-dose external beam X-rays to target tumors in small areas, often in one session.In some embodiments, stereotactic radiosurgery is used as a non-surgical approach to deliver high-dose radiation, usually to the brain, head, and / or neck, using highly focused gamma or X-ray beams that converge on the specific location where the tumor is.In some embodiments, intraoperative radiation therapy is used as a focused, high-dose radiation approach to deliver using a beam of ionizing radiation that is directed to the tumor site while the tumor site is exposed during surgery.

[0101] In some embodiments, the radiation used in radiation therapy can be selected from any type suitable for treating cancer. In some embodiments, the radiation is delivered from a machine outside the body (external radiation) or from a machine placed inside the body (internal radiation). In some embodiments, the type of radiation used depends on the location within the body, the amount of healthy tissue penetrated, the particular cancer, and the particular subject. In some embodiments, more than one type of radiation can be used as part of radiation therapy.

[0102] The radiation dose irradiated in radiotherapy can be in the range of about 1 Gy to about 100 Gy, and any value and range therebetween. In some embodiments, the radiation dose irradiated is about 1 Gy to about 100 Gy, for example, about 1 Gy to about 60 Gy, about 1 Gy to about 50 Gy, about 1 Gy to about 40 Gy, about 1 Gy to about 30 Gy, about 1 Gy to about 20 Gy, about 1 Gy to about 10 Gy, about 10 Gy to about 90 Gy, about 10 Gy to about 80 Gy, about 10 Gy to about 70 Gy, about 10 Gy to about 60 Gy, about 10 Gy to about 50 Gy, about 10 Gy to about 40 Gy, about 10 Gy to about 30 Gy, about 20 Gy to about 90 Gy, about 20 Gy to about 80 Gy. , about 20Gy to about 70Gy, about 20Gy to about 60Gy, about 20Gy to about 50Gy, about 20Gy to about 40Gy, about 30Gy to about 90Gy, about 30Gy to about 80Gy, about 30Gy to about 70Gy, about 30Gy to about 60Gy, about 40Gy to about 90Gy, about 40Gy to about 80Gy, about 40Gy to about 70Gy, about 40Gy to about 60Gy, about 40Gy to about 50Gy, about 50Gy to about 90Gy, about 50Gy to about 80Gy, or about 50Gy to about 70Gy, and any value and range therebetween. In some embodiments, the dose of radiation administered is less than about 100 Gy, e.g., less than about 90 Gy, less than about 80 Gy, less than about 70 Gy, less than about 60 Gy, less than about 50 Gy, less than about 40 Gy, less than about 30 Gy, less than about 20 Gy, and less than about 10 Gy. In some embodiments, the dose of radiation administered is less than about 90 Gy. In some embodiments, the dose of radiation administered is less than about 80 Gy. In some embodiments, the dose of radiation administered is less than about 70 Gy. In some embodiments, the dose of radiation administered is less than about 60 Gy. In some embodiments, the dose of radiation administered is less than about 50 Gy. In some embodiments, the dose of radiation administered is less than about 40 Gy. In some embodiments, the dose of radiation administered is less than about 30 Gy. In some embodiments, the dose of radiation administered is less than about 20 Gy. In some embodiments, the dose of radiation administered is less than about 10 Gy. In some embodiments, the dose of radiation administered is about 5 Gy. In some embodiments, the dose of radiation administered is about 10 Gy. In some embodiments, the dose of radiation administered is about 15 Gy.In some embodiments, the dose of radiation administered is about 20 Gy. In some embodiments, the dose of radiation administered is about 25 Gy. In some embodiments, the dose of radiation administered is about 30 Gy. In some embodiments, the dose of radiation administered is about 35 Gy. In some embodiments, the dose of radiation administered is about 40 Gy. In some embodiments, the dose of radiation administered is about 45 Gy. In some embodiments, the dose of radiation administered is about 50 Gy. In some embodiments, the dose of radiation administered is about 55 Gy. In some embodiments, the dose of radiation administered is about 60 Gy. In some embodiments, the dose of radiation administered is about 65 Gy. In some embodiments, the dose of radiation administered is about 70 Gy. In some embodiments, the dose of radiation administered is about 75 Gy. In some embodiments, the dose of radiation administered is about 80 Gy. In some embodiments, the dose of radiation administered is about 85 Gy. In some embodiments, the dose of radiation administered is about 90 Gy. In some embodiments, the dose of radiation administered is about 95 Gy. In some embodiments, the dose of radiation administered is about 100 Gy. In some embodiments, the dose of radiation administered is 5 Gy. In some embodiments, the dose of radiation administered is 10 Gy. In some embodiments, the dose of radiation administered is 15 Gy. In some embodiments, the dose of radiation administered is 20 Gy. In some embodiments, the dose of radiation administered is 25 Gy. In some embodiments, the dose of radiation administered is 30 Gy. In some embodiments, the dose of radiation administered is 35 Gy. In some embodiments, the dose of radiation administered is 40 Gy. In some embodiments, the dose of radiation administered is 45 Gy. In some embodiments, the dose of radiation administered is 50 Gy. In some embodiments, the dose of radiation administered is 55 Gy. In some embodiments, the dose of radiation administered is 60 Gy. In some embodiments, the dose of radiation administered is 65 Gy. In some embodiments, the dose of radiation administered is 70 Gy. In some embodiments, the dose of radiation administered is 75 Gy.In some embodiments, the dose of radiation administered is 80 Gy. In some embodiments, the dose of radiation administered is 85 Gy. In some embodiments, the dose of radiation administered is 90 Gy. In some embodiments, the dose of radiation administered is 95 Gy. In some embodiments, the dose of radiation administered is 100 Gy. In some embodiments, the dose of radiation administered is the sum of fractionated doses administered as part of the dose. In some embodiments, the dose of radiation can be reduced by delivering a radiosensitizer to the target tumor or to the target tumor site.

[0103] In some embodiments, the radiation dose can be administered in one to about 60 divided doses. In some embodiments, the radiation dose is administered in one dose. In some embodiments, the radiation dose is fractionated and administered in about 2 to about 10 divided doses. In some embodiments, the radiation dose is fractionated and administered in about 5 to about 60 divided doses. In some embodiments, the radiation dose is fractionated and administered in divided doses of about 1 Gy to about 20 Gy. In some embodiments, the interval between divided doses can be as little as minutes, hours, days, or weeks. In some embodiments, the divided doses are administered at intervals of less than 10 minutes. In some embodiments, the divided doses are administered at intervals of about 1 hour to about 1 week. In some embodiments, the divided doses are administered at intervals of about 1 week to about 26 weeks.

[0104] In some embodiments, the radiation source can be selected from gamma rays and X-rays. X-rays can be generated by a linear accelerator. In some embodiments, gamma rays can be generated by selecting a radioisotope, such as cobalt 60. In some embodiments, the radiation source is gamma rays. In some embodiments, the radiation source is X-rays. In some embodiments, the radiation source can be a particle beam. The particle beam is generated by a linear accelerator, a synchrotron, a betatron, a cyclotron, etc., each accelerator accelerating particles for delivery to a subject. In some embodiments, the particle beam can be generated by a linear accelerator. In some embodiments, the particle beam can be generated by a synchrotron. In some embodiments, the particle beam can be generated by a betatron. In some embodiments, the particle beam can be generated by a cyclotron. In some embodiments, the particle beam can be generated by electrons or neutrons.

[0105] In some embodiments, radiation therapy includes stereotactic radiosurgery. In stereotactic radiosurgery, the subject's head can be placed in a device that delivers high-dose radiation beams directly to the tumor in the subject's head. In some embodiments, imaging systems can be used in conjunction with the accelerator's motion to deliver radiation precisely to the target tumor site. In some embodiments, radiation therapy can be stereotactic body radiotherapy; this treatment uses a similar approach to stereotactic radiosurgery, except that multiple small fractionated doses of radiation are typically used to deliver potential target sites in the body, rather than a single large dose.

[0106] In some embodiments, radiation therapy includes intensity modulated radiation therapy (IMRT). In IMRT, radiation beams, such as X-ray beams, of varying intensity are used to simultaneously deliver different doses of radiation to small tissue areas. This approach allows for a higher dose to be delivered to the tumor and a lower dose to the surrounding healthy tissue.

[0107] III. Anti-TF antibody In general, the anti-TF antibodies of the present disclosure bind to tissue factor (TF, e.g., human TF, CD142) and exert cytostatic and cytotoxic effects on malignant cells, such as head and neck cancer cells or gynecological cancer cells. The anti-TF antibodies of the present disclosure are preferably monoclonal and can be multispecific, human, humanized or chimeric antibodies, single chain antibodies, Fab fragments, F(ab') fragments, fragments generated by a Fab expression library, and TF-binding fragments of any of the above. In some embodiments, the anti-TF antibodies of the present disclosure specifically bind to TF. The 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.

[0108] In certain embodiments of the disclosure, the anti-TF antibody is an antigen-binding fragment (e.g., a human antigen-binding fragment) as described herein, including, but not limited to, Fab, Fab' and F(ab')2, Fd, single-chain Fv (scFv), single-chain antibodies, disulfide-linked Fv (sdFv), and VFv. L or V H Antigen-binding fragments include fragments that contain any of the variable regions. Antigen-binding fragments, such as single chain antibodies, may contain the variable region alone or in combination with all or a portion of the hinge region, CH1, CH2, CH3 and CL domains. The disclosure also includes antigen-binding fragments that contain any combination of the variable region with the hinge region, CH1, CH2, CH3 and CL domains. In some embodiments, the anti-TF antibody or antigen-binding fragment thereof is a human, murine (e.g., mouse and rat), donkey, sheep, rabbit, goat, guinea pig, camel, horse, or chicken antibody.

[0109] The anti-TF antibodies of the present disclosure may be monospecific, bispecific, trispecific, or of higher multispecificity. Multispecific antibodies may be specific for different epitopes of TF or specific for both TF and heterologous proteins. See, for example, PCT Publications WO 93 / 17715; WO 92 / 08802; WO 91 / 00360; WO 92 / 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.

[0110] The anti-TF antibodies of the disclosure may be described or specified in terms of the particular CDRs they contain. The precise amino acid sequence boundaries of a given CDR or FR can be readily determined using any of a number of well-known schemes, including those described in: Kabat et al. (1991), "Sequences of Proteins of Immunological Interest," 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD (the "Kabat" numbering scheme); Al-Lazikani et al., (1997) JMB 273,927-948 (the "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 (the "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 Jan;27(1):55-77 ("IMGT" numbering scheme); Honegger A and Plueckthun A, "Yet another numbering scheme for immunoglobulin variable domains: an automatic modeling and analysis tool," J Mol Biol, 2001 Jun 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 "CDR" or "complementarity determining region" of a given antibody or region thereof (e.g., its variable region) or individual identified CDRs (e.g., CDR-H1, CDR-H2, CDR-H3) will be understood to encompass the CDRs (or specific CDRs) defined by any of the foregoing schemes. For example, a specific CDR (e.g., CDR-H3) may be defined as a CDR that is specific to a given V. H or V L When a statement is made that the amino acid sequence of a corresponding CDR in the amino acid sequence of a region is included, it is understood that such CDR has the sequence of the corresponding CDR (e.g., CDR-H3) in the variable region defined by any of the above schemes. Schemes for identifying particular CDRs can be specified, for example, CDRs defined by the Kabat, Chothia, AbM, or IMGT methods.

[0111] Numbering of amino acid residues in the CDR sequences provided herein is according to the IMGT numbering scheme described in Lefranc, MP et al., Dev. Comp. Immunol., 2003, 27, 55-77. The CDR sequences provided herein for the anti-TF antibodies of the anti-TF antibody-drug conjugates are according to the IMGT method described in Lefranc, MP et al., Dev. Comp. Immunol., 2003, 27, 55-77.

[0112] In certain embodiments, the antibody of the disclosure comprises one or more CDRs of antibody 011. See WO 2011 / 157741 and WO 2010 / 066803. The disclosure encompasses an antibody or derivative thereof comprising a heavy or light chain variable domain; the variable domain comprises (a) a set of three CDRs, the set of CDRs being derived from monoclonal antibody 011, and (b) a set of four framework regions, the set of framework regions being different from the set of framework regions of monoclonal antibody 011, and the antibody or derivative thereof binds to TF. In some embodiments, the antibody or derivative thereof specifically binds to TF. In certain embodiments, the anti-TF antibody is 011. Antibody 011 is also known as tisotumab.

[0113] In one aspect, also provided herein are anti-TF antibodies that compete with tisotumab for binding to TF. Also provided herein are anti-TF antibodies that bind to the same epitope as tisotumab.

[0114] In one aspect, provided herein is an anti-TF antibody that comprises one, two, three, four, five, or six of the CDR sequences of tisotumab.

[0115] In one aspect, provided herein is an anti-TF antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises (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) a CDR-H3 comprising the amino acid sequence of SEQ ID NO:3, and / or 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) a CDR-L3 comprising the amino acid sequence of SEQ ID NO:6, wherein the CDRs of the anti-TF antibody are defined according to the IMGT numbering scheme.

[0116] The anti-TF antibodies described herein may comprise any suitable framework variable domain sequence, provided that the antibody retains the ability to bind to TF (e.g., human TF). As used herein, the heavy chain framework regions are designated "HC-FR1-FR4" and the light chain framework regions are designated "LC-FR1-FR4". In some embodiments, the anti-TF antibodies comprise the heavy chain variable domain framework sequence of SEQ ID NOs:9, 10, 11, and 12 (HC-FR1, HC-FR2, HC-FR3, and HC-FR4, respectively). In some embodiments, the anti-TF antibodies comprise the light chain variable domain framework sequence of SEQ ID NOs:13, 14, 15, and 16 (LC-FR1, LC-FR2, LC-FR3, and LC-FR4, respectively).

[0117] In some embodiments of the anti-TF antibodies described herein, the heavy chain variable domain has the following amino acid sequence: TIFF2025515166000006.tif18149, and the light chain variable domain comprises the following amino acid sequence: Includes TIFF2025515166000007.tif18148.

[0118] In some embodiments of the anti-TF antibodies described herein, the heavy chain CDR sequences are Includes TIFF2025515166000008.tif18128.

[0119] In some embodiments of the anti-TF antibodies described herein, the heavy chain FR sequence is Includes TIFF2025515166000009.tif31148.

[0120] In some embodiments of the anti-TF antibodies described herein, the light chain CDR sequences are Includes TIFF2025515166000010.tif17128.

[0121] In some embodiments of the anti-TF antibodies described herein, the light chain FR sequence is Includes TIFF2025515166000011.tif31136.

[0122] In some aspects, provided herein is an anti-TF antibody that binds to TF (e.g., human TF); wherein the antibody comprises a heavy chain variable region and a light chain variable region, the antibody comprising: (a)(1) HC-FR1 comprising the amino acid sequence of SEQ ID NO:9; (2) CDR-H1 comprising the amino acid sequence of SEQ ID NO:1; (3) HC-FR2 comprising the amino acid sequence of SEQ ID NO:10; (4) CDR-H2 comprising the amino acid sequence of SEQ ID NO:2; (5) HC-FR3 comprising the amino acid sequence of SEQ ID NO:11; (6) a CDR-H3 comprising the amino acid sequence of SEQ ID NO:3; and (7) HC-FR4 comprising the amino acid sequence of SEQ ID NO:12; a heavy chain variable domain comprising and / or (b)(1) LC-FR1 comprising the amino acid sequence of SEQ ID NO:13; (2) a CDR-L1 comprising the amino acid sequence of SEQ ID NO:4; (3) LC-FR2 comprising the amino acid sequence of SEQ ID NO:14; (4) CDR-L2 comprising the amino acid sequence of SEQ ID NO:5; (5) LC-FR3 comprising the amino acid sequence of SEQ ID NO:15; (6) a CDR-L3 comprising the amino acid sequence of SEQ ID NO:6; and (7) LC-FR4 comprising the amino acid sequence of SEQ ID NO:16; a light chain variable domain comprising Includes.

[0123] In one aspect, an anti-TF antibody comprises a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO:7, or comprises a light chain variable domain comprising the amino acid sequence of SEQ ID NO:8. In one aspect, provided herein is an anti-TF 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.

[0124] In some embodiments, provided herein is an anti-TF antibody 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, 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 contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence and retains the ability to bind to TF (e.g., human TF). In certain embodiments, a total of 1-10 amino acids are 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) are in the regions outside the CDRs (i.e., FRs). In some embodiments, the anti-TF antibody comprises a heavy chain variable domain sequence of SEQ ID NO:7, including its post-translational modifications. In particular 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.

[0125] In some embodiments, provided herein is an anti-TF antibody 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, 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 comprises substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence and retains the ability to bind to TF (e.g., human TF). In certain embodiments, a total of 1-10 amino acids are 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) are in the regions outside the CDRs (i.e., FRs). In some embodiments, the anti-TF antibody comprises a light chain variable domain sequence of SEQ ID NO:8, including its post-translational modifications. In particular 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.

[0126] In some embodiments, the anti-TF antibody comprises a heavy chain variable domain according to any of the embodiments provided above and a light chain variable domain according to 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 these sequences.

[0127] In some embodiments, the anti-TF antibody of the anti-TF 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, 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, wherein the CDRs of the anti-TF antibody are defined according to the IMGT numbering scheme.

[0128] In some embodiments, the anti-TF antibody of the anti-TF 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.

[0129] In some embodiments, the anti-TF antibody of the anti-TF antibody-drug conjugate is a monoclonal antibody.

[0130] In some embodiments, the anti-TF antibody of the anti-TF antibody-drug conjugate is tisotumab, also known as antibody 011, described in WO 2011 / 157741 and WO 2010 / 066803.

[0131] The anti-TF antibodies of the invention may also be described or specified in terms of their binding affinity to TF (e.g., human TF, CD142). Preferred binding affinities include those with a dissociation constant or Kd of 5×10 -2 M, 10 -2 M, 5×10 -3 M, 10 -3 M, 5×10 -4 M, 10 -4 M, 5×10 -5 M, 10 -5 M, 5×10 -6 M, 10 -6 M, 5×10 -7 M, 10 -7 M, 5×10-8 M, 10 -8 M, 5×10 -9 M, 10 -9 M, 5×10 -10 M, 10 -10 M, 5×10 -11 M, 10 -11 M, 5×10 -12 M, 10 -12 M, 5×10 -13 M, 10 -13 M, 5×10 -14 M, 10 -14 M, 5×10 -15 M, or 10 -15 Includes items smaller than M.

[0132] 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 as multiple polymorphic variants called allotypes (reviewed in Jefferis and Lefranc 2009. mAbs Vol 1 Issue 4 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 a, f, n, z, or combinations thereof. In any of the embodiments herein, the antibody may comprise a heavy chain Fc region that comprises a human IgG Fc region. In a further embodiment, the human IgG Fc region comprises a human IgG1.

[0133] The antibodies also include modified derivatives, i.e., derivatives modified by the covalent attachment of any type of molecule to the antibody, provided that the covalent attachment does not prevent the antibody from binding to TF or exerting a cytostatic or cytotoxic effect on HD cells. For example, but not limited to, antibody derivatives include antibodies modified by glycosylation, acetylation, PEGylation, phosphorylation, amidation, derivatization with known protecting / blocking groups, proteolytic cleavage, conjugation 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, the derivatives may include one or more non-classical amino acids.

[0134] IV. Structure of Antibody-Drug Conjugates In some aspects, the anti-TF antibody-drug conjugate described herein comprises a linker between the anti-TF antibody or antigen-binding fragment thereof described herein and the cytostatic or cytotoxic drug. In some embodiments, the linker is a non-cleavable linker. In some embodiments, the linker is a cleavable linker.

[0135] In some embodiments, the linker is a cleavable peptide linker comprising maleimidocaproyl (MC), the dipeptide valine-citrulline (vc) and p-aminobenzyl carbamate (PAB). In some embodiments, the cleavable peptide linker has the formula: MC-vc-PAB-, where: a) MC is TIFF2025515166000012.tif34128, b) vc is the dipeptide valine-citrulline; c) PAB is The file is TIFF2025515166000013.tif38128.

[0136] In some embodiments, the linker is a cleavable peptide linker comprising maleimidocaproyl (MC). In some embodiments, the cleavable peptide linker has the formula: MC-, where: a) MC is The file is TIFF2025515166000014.tif34128.

[0137] In some embodiments, the linker is attached to a sulfhydryl residue of an anti-TF antibody or antigen-binding fragment thereof obtained by partial or complete reduction of the anti-TF antibody or antigen-binding fragment thereof. In some embodiments, the linker is attached to a sulfhydryl residue of an anti-TF antibody or antigen-binding fragment thereof obtained by partial reduction of the anti-TF antibody or antigen-binding fragment thereof. In some embodiments, the linker is attached to a sulfhydryl residue of an anti-TF antibody or antigen-binding fragment thereof obtained by complete reduction of the anti-TF antibody or antigen-binding fragment thereof.

[0138] In some aspects, the anti-TF antibody-drug conjugate described herein comprises a linker described herein between the anti-TF antibody or antigen-binding fragment thereof described herein and the cytostatic or cytotoxic drug. Auristatins have been shown to interfere with microtubule dynamics, GTP hydrolysis, and nuclear and cytotoxic division (see Woyke et al (2001) Antimicrob. Agents and Chemother. 45(12): 3580-3584), and to have anticancer activity (see U.S. Pat. No. 5,663,149) and antifungal activity (see Pettit et al., (1998) Antimicrob. Agents and Chemother. 42: 2961-2965). For example, auristatin E can be reacted with p-acetylbenzoic acid or benzoylvaleric acid to produce AEB and AEVB, respectively. Other exemplary auristatin derivatives include AFP, MMAF (monomethylauristatin F), and MMAE (monomethylauristatin E). Suitable auristatins, auristatin analogs, derivatives and prodrugs, and linkers suitable for conjugating auristatins to Abs are described, for example, in U.S. Patent Nos. 5,635,483, 5,780,588, 6,214,345, and International Patent Publications WO02088172, WO2004010957, WO2005081711, WO2005084390, WO2006132670, WO03026577, WO200700860, WO207011968, WO205082023. In some embodiments of the anti-TF antibody-drug conjugates described herein, the cytostatic or cytotoxic drug is an auristatin or a functional analogue (e.g., a functional peptide thereof) or a functional derivative thereof. In some embodiments, the auristatin is monomethylauristatin or a functional analogue (e.g., a functional peptide thereof) or a functional derivative thereof.

[0139] In one embodiment, the auristatin is monomethylauristatin E (MMAE): TIFF2025515166000015.tif35150, where the wavy line indicates the attachment site to the linker.

[0140] In one embodiment, the auristatin is monomethylauristatin F (MMAF): TIFF2025515166000016.tif35149, where the wavy line indicates the attachment site to the linker.

[0141] In one embodiment, the cleavable peptide linker has the formula: MC-vc-PAB- and is attached to MMAE. The resulting linker-auristatin, MC-vc-PAB-MMAE, is also designated vcMMAE. vcMMAE drug linker moieties and conjugation methods are disclosed in WO2004010957, US7659241, US7829531 and US7851437. When vcMMAE is attached to an anti-TF antibody or antigen-binding fragment thereof described herein, the resulting structure is: TIFF2025515166000017.tif28147, where p represents a number from 1 to 8 (e.g., 1, 2, 3, 4, 5, 6, 7, or 8), e.g., p can be 3 to 5, S represents a sulfhydryl residue of an anti-TF antibody, and Ab represents an anti-TF antibody or antigen-binding fragment thereof described herein. In one embodiment, the average value of p in a population of antibody-drug conjugates is about 4. In some embodiments, p is measured by hydrophobic interaction chromatography (HIC), e.g., by partitioning drug-loaded species based on increasing hydrophobicity, with the least hydrophobic unconjugated form eluting first and the most hydrophobic 8 drug form eluting last; in this case, the area percentage of the peak represents the relative distribution of antibody-drug conjugate species loaded with a particular drug. See Ouyang, J., 2013, Antibody-Drug Conjugates, Methods in Molecular Biology (Methods and Protocols). In some embodiments, p is measured by reversed-phase high performance liquid chromatography (RP-HPLC), e.g., by first performing a reduction reaction to completely dissociate the heavy and light chains of the ADC, and then separating the light and heavy chains and their corresponding drug-loaded forms on a RP column; in this case, the peak percentage is obtained from the integration of the light and heavy chain peaks and used in combination with the drug load assigned to each peak to calculate a weighted average drug-to-antibody ratio. See Ouyang, J., 2013, Antibody-Drug Conjugates, Methods in Molecular Biology (Methods and Protocols).

[0142] In one embodiment, the cleavable peptide linker has the formula: MC-vc-PAB- and is attached to MMAF. The resulting linker-auristatin, MC-vc-PAB-MMAF, is also designated as vcMMAF. In another embodiment, the non-cleavable linker MC is attached to MMAF. The resulting linker-auristatin MC-MMAF is also designated as mcMMAF. Both vcMMAF and mcMMAF drug linker moieties and conjugation methods are disclosed in WO2005081711 and US7498298. When vcMMAF or mcMMAF is attached to an anti-TF antibody or antigen-binding fragment thereof described herein, the resulting structure is: TIFF2025515166000018.tif81146, where p represents a number from 1 to 8 (e.g., 1, 2, 3, 4, 5, 6, 7, or 8), e.g., p can be 3 to 5, S represents a sulfhydryl residue of an anti-TF antibody, and Ab or mAb represents an anti-TF antibody or antigen-binding fragment thereof described herein. In one embodiment, the average value of p in a population of antibody-drug conjugates is about 4. In some embodiments, p is measured by hydrophobic interaction chromatography (HIC), e.g., by partitioning drug-loaded species based on increasing hydrophobicity, with the least hydrophobic unconjugated form eluting first and the most hydrophobic 8 drug form eluting last; in this case, the area percentage of the peak represents the relative distribution of antibody-drug conjugate species loaded with a particular drug. See Ouyang, J., 2013, Antibody-Drug Conjugates, Methods in Molecular Biology (Methods and Protocols). In some embodiments, p is measured by reversed-phase high performance liquid chromatography (RP-HPLC), e.g., by first performing a reduction reaction to completely dissociate the heavy and light chains of the ADC, and then separating the light and heavy chains and their corresponding drug-loaded forms on a RP column; in this case, the peak percentage is obtained from the integration of the light and heavy chain peaks and used in combination with the drug load assigned to each peak to calculate a weighted average drug-to-antibody ratio. See Ouyang, J., 2013, Antibody-Drug Conjugates, Methods in Molecular Biology (Methods and Protocols).

[0143] In one embodiment, the antibody-drug conjugate is tisotumab vedotin.

[0144] Anti-TF antibodies, linkers, and methods for making anti-TF antibody-drug conjugates are described in US Pat. No. 9,168,314.

[0145] The anti-TF antibodies described herein can be produced by well-known recombinant techniques using well-known expression vector systems and host cells. In one embodiment, the antibodies are produced in CHO cells using the GS expression vector system as disclosed in De la Cruz Edmunds et al., 2006, Molecular Biotechnology 34; 179-190; EP216846; U.S. Pat. No. 5,981,216; WO 87 / 04462; EP323997; U.S. Pat. No. 5,591,639; U.S. Pat. No. 5,658,759; EP338841; U.S. Pat. No. 5,879,936; and U.S. Pat. No. 5,891,693.

[0146] After isolation and purification of the anti-TF antibodies from the cell culture medium using techniques well known in the art, they are conjugated to an auristatin via a linker as described in US Pat. No. 9,168,314.

[0147] The monoclonal anti-TF antibodies described herein can be produced by the hybridoma method, for example, first described in Kohler et al., Nature, 256, 495 (1975), or by recombinant DNA methods. Monoclonal antibodies can also be isolated from phage antibody libraries, for example, using the techniques described in Clackson et al., Nature, 352, 624-628 (1991) and Marks et al., JMol, 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 mouse splenic B cells from mice immunized with an antigen of interest, for example, in the form of cells expressing the antigen on their surface, or in the form of 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, and the like.

[0148] In one embodiment, the antibodies of the invention (e.g., anti-TF antibodies) are human antibodies. Human monoclonal antibodies against TF can be generated using transgenic or transchromosomal mice carrying parts of the human immune system rather than the mouse system. Such transgenic and transchromosomal mice include those referred to herein as HuMAb mice and KM mice, respectively, and collectively referred to herein as "transgenic mice."

[0149] HuMAb mice contain a human immunoglobulin gene minilocus encoding unrearranged human heavy (μ and γ) and κ light chain immunoglobulin sequences, together with targeted mutations that inactivate the endogenous μ and κ chain loci (Lonberg, N. et al., Nature, 368, 856-859 (1994)). As a result, the mice exhibit reduced expression of mouse IgM or κ, and in response to immunization, the introduced human heavy and light chain transgenes undergo class switching and somatic mutation to generate high affinity human IgG, κ monoclonal antibodies (Lonberg, N. et al. (1994), supra; Lonberg, N. published in Handbook of Experimental Pharmacology 113, 49-101 (1994); Lonberg, N. and Huszar. D., Intern. Rev. Immunol, Vol. 13 65-93 (1995) and Harding, F. and Lonberg, N. Ann, NY Acad. Sci 764:536-546 (1995)). The generation of HuMAb mice is described in detail in the following references: Taylor, L. et al., Nucleic Acids Research. 20:6287-6295 (1992); Chen, J. et al., International Immunology. 5:647-656 (1993); Tuaillon at al., J. Immunol, 152:2912-2920 (1994); Taylor, L. et al., International Immunology, 6:579-591 (1994); Fishwild, D. et al., Nature Biotechnology, 14:845-851 (1996).See also U.S. Patent Nos. 5,545,806, 5,569,825, 5,625,126, 5,633,425, 5,789,650, 5,877,397, 5,661,016, 5,814,318, 5,874,299, 5,770,429, 5,545,807, WO 98 / 24884, WO 94 / 25585, WO 93 / 1227, WO 92 / 22645, WO 92 / 03918, and WO 01 / 09187.

[0150] The HCo7 mouse has a JKD disruption in its endogenous light chain (κ) gene (described in Chen et al, EMBO J. 12:821-830 (1993)), a CMD disruption in its endogenous heavy chain gene (described in Example 1 of WO 01 / 14424), a KCo5 human κ light chain transgene (described in Fishwild et al., Nature Biotechnology, 14:845-851 (1996)), and an HCo7 human heavy chain transgene (described in U.S. Pat. No. 5,770,429).

[0151] The HCo12 mouse has a JKD disruption in its endogenous light chain (κ) gene (described in Chen et al, EMBO J. 12:821-830 (1993)), a CMD disruption in its endogenous heavy chain gene (described in Example 1 of WO 01 / 14424), a KCo5 human κ light chain transgene (described in Fishwild et al., Nature Biotechnology, 14:845-851 (1996)), and an HCo12 human heavy chain transgene (described in Example 2 of WO 01 / 14424).

[0152] The HCo17 transgenic mouse line (see also US 2010 / 0077497) was generated by co-injection of an 80 kb insert of pHC2 (Taylor et al. (1994) Int. Immunol., 6:579-591), a Kb insert of pVX6, and a -460 kb yeast artificial chromosome fragment of the yIgH24 chromosome. This line was designated (HCo17) 25950. The (HCo17) 25950 strain was then crossed with mice containing the CMD mutation (described in Example 1 of PCT Publication WO 01109187), the JKD mutation (Chen et al, (1993) EMBO J. 12:811-820), and the (KCo5) 9272 transgene (Fishwild et al. (1996) Nature Biotechnology, 14:845-851). The resulting mice express human immunoglobulin heavy and kappa light chain transgenes in a background homozygous for disruption of the endogenous mouse heavy and kappa light chain loci.

[0153] The HCo20 transgenic mouse line is the result of co-injection of the minilocus 30 heavy chain transgene pHC2, the germline variable region (Vh)-containing YAC yIgH10, and the minilocus construct pVx6 (described in WO09097006). This (HCo20) line was then crossed with mice containing the CMD mutation (described in Example 1 of PCT Publication WO 01 / 09187), the JKD mutation (Chen et al, (1993) EMBO J. 12:811-820), and the (KCo5) 9272 transgene (Fishwild et al. (1996) Nature Biotechnology, 14:845-851). The resulting mice express human 10 immunoglobulin heavy and kappa light chain transgenes in a background homozygous for the disruption of the endogenous mouse heavy and kappa light chain loci.

[0154] To generate HuMab mice with the beneficial properties of the Balb / c strain, HuMab mice were crossed with Kco05 [MIK] (Balb) mice, which were generated by backcrossing the KCo5 strain (described in Fishwild et al, (1996) Nature Biotechnology, 14:845-851) to wild-type Balb / c mice, to generate the mice described in WO09097006. This cross was used to generate Balb / c hybrids for the HCo12, HCo17, and HCo20 strains.

[0155] In the KM mouse strain, the endogenous mouse kappa light chain gene is homozygously disrupted as described in Chen et al., EMBO J. 12:811-820 (1993), and the endogenous mouse heavy chain gene is homozygously disrupted as described in Example 1 of WO 01 / 09187. This mouse strain carries a human kappa light chain transgene as described in Fishwild et al., Nature Biotechnology, 14:845-851 (1996). This mouse strain also carries a human heavy chain transchromosome consisting of chromosome 14 fragment hCF(SC20) as described in WO 02 / 43478.

[0156] Spleen cells from these transgenic mice can be used to generate hybridomas secreting human monoclonal antibodies according to well-known techniques. Human monoclonal or polyclonal antibodies of the invention, or antibodies of the invention derived from other species, can also be produced recombinantly by creating another non-human mammal or plant transgenic for the desired immunoglobulin heavy and light chain sequences and producing the antibody in a recoverable form therefrom. In connection with transgenic production in mammals, antibodies can be produced in goats, cows, or other mammals and recovered from their milk. See, for example, U.S. Patent Nos. 5,827,690, 5,756,687, 5,750,172, and 5,741,957.

[0157] Additionally, human antibodies of the invention or antibodies of the invention derived from other species can be generated by display-type technologies, including but not limited to, phage display, retroviral display, ribosome display, and other technologies, using methods well known in the art; the resulting molecules can be subjected to further maturation techniques, such as affinity maturation, which are well known in the art (e.g., Hoogenboom et al., J. Mol. Biol. 227(2):381-388 (1992) (phage display); Vaughan et al., Nature Biotech, 14:309 (1996) (phage display); Hanes and Plucthau, PNAS USA 94:4937-4942 (1997) (ribosome display); Parmley and Smith, Gene, 73:305-318 (1988) (phage display); Scott, TIBS. 17:241-245 (1992); Cwirla et al., PNAS (See, e.g., J. Immunol., 1992, 11:111-113 (1992); Hogenboom et al., Immunol., Reviews, 130:43-68 (1992); Chiswell and McCafferty, TIBTECH, 10:80-84 (1992); and U.S. Patent No. 5,733,743.) Where display techniques have been used to generate antibodies that are not human, such antibodies may be humanized.

[0158] V. Additional Chemotherapeutic Agents In addition to administering the antibody-drug conjugate and performing radiation therapy, the method of the present disclosure may further include administering an additional chemotherapeutic agent in some embodiments. In some embodiments, the additional chemotherapeutic agent is selected from the group consisting of pemetrexed, nab-paclitaxel, vinorelbine, bevacizumab, cisplatin, carboplatin, paclitaxel, topotecan, a combination of bevacizumab and paclitaxel, a combination of bevacizumab and cisplatin, a combination of bevacizumab and carboplatin, a combination of paclitaxel and topotecan, a combination of bevacizumab and topotecan, a combination of bevacizumab, cisplatin and paclitaxel, a combination of bevacizumab, carboplatin and paclitaxel, and a combination of bevacizumab, paclitaxel and topotecan. In some preferred embodiments, the additional chemotherapeutic agent is a platinum-based agent. In general, the platinum-based agents of the present disclosure are molecules or compositions comprising such molecules having coordination complexes containing the chemical element platinum that are useful as chemotherapeutic agents. In some embodiments, the platinum-based agents covalently bind to DNA to crosslink the strand, inhibit DNA synthesis, and / or inhibit transcription. Platinum-based agents include those currently used as part of chemotherapy regimens, those currently under development, and those that may be developed in the future. Platinum-based agents include, but are not limited to, carboplatin, cisplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, and satraplatin. In some preferred embodiments, the platinum-based agent is carboplatin, cisplatin, oxaliplatin, or nedaplatin. In a particularly preferred embodiment, the platinum-based agent is carboplatin. In other particularly preferred embodiments, the platinum-based agent is cisplatin. In some embodiments, the platinum-based agent is oxaliplatin. In some embodiments, the platinum-based agent is nedaplatin.

[0159] VI. Route of Administration The anti-TF antibody-drug conjugate or antigen-binding fragment thereof described herein, and the additional chemotherapeutic agent, if used, can be administered by any suitable route and method. Suitable routes of administration are well known in the art and can be selected by the skilled artisan. In one embodiment, the anti-TF antibody-drug conjugate and / or the additional chemotherapeutic agent are administered parenterally. Parenteral administration refers to a method of administration other than enteral and topical administration, usually by injection, and includes epidermal, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, intratendinous, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspinal, intracranial, intrathoracic, epidural and intrasternal injection and infusion. In some embodiments, the route of administration of the anti-TF antibody-drug conjugate or antigen-binding fragment thereof described herein is intravenous injection or infusion. In some embodiments, the route of administration of the anti-TF antibody-drug conjugate or antigen-binding fragment thereof described herein is intravenous infusion (infusion). In some embodiments, the route of administration of the platinum-based agents described herein is intravenous injection or infusion. In some embodiments, the route of administration of the additional chemotherapeutic agents described herein is intravenous infusion (infusion).

[0160] VII. Dosage and Frequency of Administration The present disclosure provides methods of treating a subject having a cancer as described herein with a particular dose of an anti-TF antibody-drug conjugate or antigen-binding fragment thereof as described herein and a particular dose of radiation therapy as described herein, where the subject is administered the antibody-drug conjugate or antigen-binding fragment thereof as described herein, and optionally an additional chemotherapeutic agent, at a particular frequency.

[0161] In one embodiment of the methods or uses or products for use provided herein, the anti-TF antibody-drug conjugate or antigen-binding fragment thereof described herein is administered to the subject at a dose ranging from about 0.9 mg / kg to about 2.1 mg / kg (of the subject's body weight). In certain embodiments, the dose is about 0.9 mg / kg, about 1.0 mg / kg, about 1.1 mg / kg, about 1.2 mg / kg, about 1.3 mg / kg, about 1.4 mg / kg, about 1.5 mg / kg, about 1.6 mg / kg, about 1.7 mg / kg, about 1.8 mg / kg, about 1.9 mg / kg, about 2.0 mg / kg or about 2.1 mg / kg. In one embodiment, the dose is about 2.0 mg / kg. In certain embodiments, the dose is 0.9 mg / kg, 1.0 mg / kg, 1.1 mg / kg, 1.2 mg / kg, 1.3 mg / kg, 1.4 mg / kg, 1.5 mg / kg, 1.6 mg / kg, 1.7 mg / kg, 1.8 mg / kg, 1.9 mg / kg, 2.0 mg / kg or 2.1 mg / kg. In one embodiment, the dose is 2.0 mg / kg. In some preferred embodiments, the dose is 2.0 mg / kg and the anti-TF antibody-drug conjugate is tisotumab vedotin. In one embodiment, the dose is about 1.3 mg / kg. In other preferred embodiments, the dose is 1.3 mg / kg. In some embodiments, the dose is 1.3 mg / kg and the anti-TF antibody-drug conjugate is tisotumab vedotin. In other preferred embodiments, the dose is about 1.7 mg / kg. In some embodiments, the dose is 1.7 mg / kg. In some embodiments, the dose is 1.7 mg / kg and the anti-TF antibody-drug conjugate is tisotumab vedotin. In some embodiments, for subjects weighing more than 100 kg, the dose of anti-TF antibody-drug conjugate administered is the amount that would be administered if the subject weighed 100 kg. In some embodiments, for subjects weighing more than 100 kg, the dose of anti-TF antibody-drug conjugate administered is 65 mg, 90 mg, 130 mg, or 200 mg.

[0162] In one embodiment of the methods or uses or products for use provided herein, the anti-TF antibody-drug conjugate or antigen-binding fragment thereof described herein is administered to the subject about once every 1-4 weeks. In some embodiments, the treatment is an adjuvant treatment after surgery and can be combined with radiation therapy. In some embodiments, the treatment is a neoadjuvant treatment before surgery and can be combined with radiation therapy. In some embodiments, the treatment can be combined with a platinum-based agent, such as carboplatin or cisplatin. In certain embodiments, the anti-TF antibody-drug conjugate or antigen-binding fragment thereof described herein is administered about once per week, about once per 2 weeks, about once per 3 weeks, or about once per 4 weeks. In one embodiment, the anti-TF antibody-drug conjugate or antigen-binding fragment thereof described herein is administered about once per 3 weeks. In one embodiment, the anti-TF antibody-drug conjugate or antigen-binding fragment thereof described herein is administered about once per 3 weeks. In some embodiments, the dose is about 0.9 mg / kg and is administered about once a week. In some embodiments, the dose is about 0.9 mg / kg and is administered about once every two weeks. In some embodiments, the dose is about 0.9 mg / kg and is administered about once every three weeks. In some embodiments, the dose is about 0.9 mg / kg and is administered about once every four weeks. In some embodiments, the dose is about 1.0 mg / kg and is administered about once a week. In some embodiments, the dose is about 1.0 mg / kg and is administered about once every two weeks. In some embodiments, the dose is about 1.0 mg / kg and is administered about once every three weeks. In some embodiments, the dose is about 1.0 mg / kg and is administered about once every four weeks. In some embodiments, the dose is about 1.1 mg / kg and is administered about once a week. In some embodiments, the dose is about 1.1 mg / kg and is administered about once every two weeks. In some embodiments, the dose is about 1.1 mg / kg and is administered about once every 3 weeks. In some embodiments, the dose is about 1.1 mg / kg and is administered about once every 4 weeks. In some embodiments, the dose is about 1.2 mg / kg and is administered about once a week.In some embodiments, the dose is about 1.2 mg / kg and is administered about once every two weeks. In some embodiments, the dose is about 1.2 mg / kg and is administered about once every three weeks. In some embodiments, the dose is about 1.2 mg / kg and is administered about once every four weeks. In some embodiments, the dose is about 1.3 mg / kg and is administered about once per week. In some embodiments, the dose is about 1.3 mg / kg and is administered about once per two weeks. In some embodiments, the dose is about 1.3 mg / kg and is administered about once per three weeks. In some embodiments, the dose is about 1.3 mg / kg and is administered about once per four weeks. In some embodiments, the dose is about 1.4 mg / kg and is administered about once per week. In some embodiments, the dose is about 1.4 mg / kg and is administered about once per two weeks. In some embodiments, the dose is about 1.4 mg / kg and is administered about once per three weeks. In some embodiments, the dose is about 1.4 mg / kg and is administered about once every 4 weeks. In some embodiments, the dose is about 1.5 mg / kg and is administered about once every week. In some embodiments, the dose is about 1.5 mg / kg and is administered about once every 2 weeks. In some embodiments, the dose is about 1.5 mg / kg and is administered about once every 3 weeks. In some embodiments, the dose is about 1.5 mg / kg and is administered about once every 4 weeks. In some embodiments, the dose is about 1.6 mg / kg and is administered about once every week. In some embodiments, the dose is about 1.6 mg / kg and is administered about once every 2 weeks. In some embodiments, the dose is about 1.6 mg / kg and is administered about once every 3 weeks. In some embodiments, the dose is about 1.6 mg / kg and is administered about once every 4 weeks. In some embodiments, the dose is about 1.7 mg / kg and is administered about once every week. In some embodiments, the dose is about 1.7 mg / kg and is administered about once every two weeks. In some embodiments, the dose is about 1.7 mg / kg and is administered about once every three weeks. In some embodiments, the dose is about 1.7 mg / kg and is administered about once every four weeks. In some embodiments, the dose is about 1.8 mg / kg and is administered about once a week. In some embodiments, the dose is about 1.8 mg / kg and is administered about once every two weeks.In some embodiments, the dose is about 1.8 mg / kg and is administered about once every 3 weeks. In some embodiments, the dose is about 1.8 mg / kg and is administered about once every 4 weeks. In some embodiments, the dose is about 1.9 mg / kg and is administered about once per week. In some embodiments, the dose is about 1.9 mg / kg and is administered about once per 2 weeks. In some embodiments, the dose is about 1.9 mg / kg and is administered about once per 3 weeks. In some embodiments, the dose is about 1.9 mg / kg and is administered about once per 4 weeks. In some embodiments, the dose is about 2.0 mg / kg and is administered about once per week. In some embodiments, the dose is about 2.0 mg / kg and is administered about once per 2 weeks. In some embodiments, the dose is about 2.0 mg / kg and is administered about once per 3 weeks. In some embodiments, the dose is about 2.0 mg / kg and is administered about once per 4 weeks. In some embodiments, the dose is about 2.1 mg / kg and is administered about once a week. In some embodiments, the dose is about 2.1 mg / kg and is administered about once every two weeks. In some embodiments, the dose is about 2.1 mg / kg and is administered about once every three weeks. In some embodiments, the dose is about 2.1 mg / kg and is administered about once every four weeks. In some embodiments, the dose is 0.9 mg / kg and is administered about once a 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 once every three weeks. In some embodiments, the dose is 0.9 mg / kg and is administered about once every four weeks. In some embodiments, the dose is 1.0 mg / kg and is administered about once a 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 once every 3 weeks. In some embodiments, the dose is 1.0 mg / kg and is administered about once every 4 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 2 weeks. In some embodiments, the dose is 1.1 mg / kg and is administered about once every 3 weeks.In some embodiments, the dose is 1.1 mg / kg and is administered about once every 4 weeks. In some embodiments, the dose is 1.2 mg / kg and is administered about once per week. In some embodiments, the dose is 1.2 mg / kg and is administered about once per 2 weeks. In some embodiments, the dose is 1.2 mg / kg and is administered about once per 3 weeks. In some embodiments, the dose is 1.2 mg / kg and is administered about once per 4 weeks. In some embodiments, the dose is 1.3 mg / kg and is administered about once per week. In some embodiments, the dose is 1.3 mg / kg and is administered about once per 2 weeks. In some embodiments, the dose is 1.3 mg / kg and is administered about once per 3 weeks. In some embodiments, the dose is 1.3 mg / kg and is administered about once per 4 weeks. In some embodiments, the dose is 1.4 mg / kg and is administered about once per week. In some embodiments, the dose is 1.4 mg / kg and is administered about once every 2 weeks. In some embodiments, the dose is 1.4 mg / kg and is administered about once every 3 weeks. In some embodiments, the dose is 1.4 mg / kg and is administered about once every 4 weeks. In some embodiments, the dose is 1.5 mg / kg and is administered about once per week. In some embodiments, the dose is 1.5 mg / kg and is administered about once per 2 weeks. In some embodiments, the dose is 1.5 mg / kg and is administered about once per 3 weeks. In some embodiments, the dose is 1.5 mg / kg and is administered about once per 4 weeks. In some embodiments, the dose is 1.6 mg / kg and is administered about once per week. In some embodiments, the dose is 1.6 mg / kg and is administered about once per 2 weeks. In some embodiments, the dose is 1.6 mg / kg and is administered about once per 3 weeks. In some embodiments, the dose is 1.6 mg / kg and is administered about once every 4 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 2 weeks. In some embodiments, the dose is 1.7 mg / kg and is administered about once every 3 weeks. In some embodiments, the dose is 1.7 mg / kg and is administered about once every 4 weeks.In some embodiments, the dose is 1.8 mg / kg and is administered about once a 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 once every three weeks. In some embodiments, the dose is 1.8 mg / kg and is administered about once every four weeks. In some embodiments, the dose is 1.9 mg / kg and is administered about once a 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 once every three weeks. In some embodiments, the dose is 1.9 mg / kg and is administered about once every four weeks. In some embodiments, the dose is 2.0 mg / kg and is administered about once a 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 once every 3 weeks. In some embodiments, the dose is 2.0 mg / kg and is administered about once every 4 weeks. In some embodiments, the dose is 2.1 mg / kg and is administered about once per week. In some embodiments, the dose is 2.1 mg / kg and is administered about once per 2 weeks. In some embodiments, the dose is 2.1 mg / kg and is administered about once per 3 weeks. In some embodiments, the dose is 2.1 mg / kg and is administered about once per 4 weeks. In some embodiments, the dose is 2.0 mg / kg and is administered about once per 3 weeks (e.g., ±3 days). In some embodiments, the dose is 2.0 mg / kg and is administered about once per 3 weeks. In some embodiments, the dose is 2.0 mg / kg and is administered about once per 3 weeks and the antibody-drug conjugate is tisotumab vedotin. In some embodiments, the dose is 2.0 mg / kg and is administered once every three weeks, the antibody-drug conjugate is tisotumab vedotin, and if one or more adverse events occur, the dose is reduced to 1.3 mg / kg. In some embodiments, the dose is 1.3 mg / kg and is administered once every three weeks. In some embodiments, the dose is 1.3 mg / kg and is administered once every three weeks, and the antibody-drug conjugate is tisotumab vedotin.In some embodiments, the dose is 1.3 mg / kg and is administered once every three weeks, the antibody-drug conjugate is tisotumab vedotin, and if one or more adverse events occur, the dose is reduced to 0.9 mg / kg. In some embodiments, the dose is 1.7 mg / kg and is administered once every two weeks. In some embodiments, the dose is 1.7 mg / kg and is administered once every two weeks, the antibody-drug conjugate is tisotumab vedotin. In some embodiments, the dose is 1.7 mg / kg and is administered once every two weeks, the antibody-drug conjugate is tisotumab vedotin, and if one or more adverse events occur, the dose is reduced to 1.3 mg / kg. In some embodiments, the dose is 1.7 mg / kg and is administered once every two weeks. In some embodiments, the dose is 1.7 mg / kg, administered once every two weeks, and the antibody-drug conjugate is tisotumab vedotin. In some embodiments, such administration of the antibody-drug conjugate is provided as a neoadjuvant therapy before surgical intervention. In some embodiments, such administration of the antibody-drug conjugate is provided as an adjuvant therapy after surgical intervention. In some embodiments, such administration of the antibody-drug conjugate is combined with radiation therapy and provided as a neoadjuvant therapy before surgical intervention. In some embodiments, such administration of the antibody-drug conjugate is combined with radiation therapy and provided as an adjuvant therapy after surgical intervention. In some embodiments, such administration of the antibody-drug conjugate is combined with radiation therapy and a platinum-based agent (such as cisplatin or carboplatin) and provided as a neoadjuvant therapy before surgical intervention. In some embodiments, such administration of the above antibody-drug conjugates is in combination with radiation therapy and platinum-based drugs (cisplatin). It is often combined with chemotherapy (such as chemotherapy with rivaroxaban or carboplatin) and offered as adjuvant therapy after surgical intervention.

[0163] In one embodiment of the methods or uses or products for use provided herein, the anti-TF antibody-drug conjugate or antigen-binding fragment thereof described herein is administered to a subject at a fixed dose ranging from about 50 mg to about 200 mg, e.g., about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, or about 200 mg. In some embodiments, the fixed dose is administered to the subject about once every 1 to 4 weeks. In certain embodiments, the fixed dose is administered to the subject about once per week, about once per two weeks, about once per three weeks, or about once per four weeks. In some embodiments, the fixed dose is administered to the subject about once per three weeks (e.g., ±3 days). In some embodiments, the fixed dose is administered to the subject once per three weeks. In some embodiments, the fixed dose is administered to the subject once per three weeks and the antibody-drug conjugate is tisotumab vedotin.

[0164] In one embodiment of the methods or uses or products for use provided herein, the anti-TF antibody-drug conjugate or antigen-binding fragment thereof described herein is administered to the subject at a fixed dose ranging from 50 mg to 200 mg, e.g., a fixed dose of 50 mg, a fixed dose of 60 mg, a fixed dose of 70 mg, a fixed dose of 80 mg, a fixed dose of 90 mg, a fixed dose of 100 mg, a fixed dose of 110 mg, a fixed dose of 120 mg, a fixed dose of 130 mg, a fixed dose of 140 mg, a fixed dose of 150 mg, a fixed dose of 160 mg, a fixed dose of 170 mg, a fixed dose of 180 mg, a fixed dose of 190 mg, or a fixed dose of 200 mg. In some embodiments, the fixed dose is administered to the subject about once every 1 to 4 weeks. In certain embodiments, the fixed dose is administered to the subject about once a week, about once every 2 weeks, about once every 3 weeks, or about once every 4 weeks. In some embodiments, the fixed dose is administered to the subject about once every three weeks (e.g., ±3 days). In some embodiments, the fixed dose is administered to the subject once every three weeks. In some embodiments, the fixed dose is administered to the subject once every three weeks and the antibody-drug conjugate is tisotumab vedotin.

[0165] In one embodiment of the methods or uses or products for use provided herein, a platinum-based agent described herein, e.g., carboplatin, is administered to a subject at a dose based on the Calvert formula: Dose of platinum-based drug (mg) = (target AUC) x (GFR + 25) where AUC stands for "area under the concentration-time curve" (AUC is expressed in mg / mL·min) and GFR stands for "glomerular filtration rate" (GFR is expressed in mL / min). In some embodiments, GFR is estimated by calculated creatinine clearance. In some embodiments, serum creatine is measured by IDMS method. In some embodiments, a platinum-based agent, such as carboplatin, described herein is administered (in addition to administering an antibody-drug conjugate described herein, or administering an antibody-drug conjugate described herein and administering radiation therapy) at a dose of AUC=about 4 to about 6. In some embodiments, the dose of a platinum-based agent, such as carboplatin, described herein is either AUC=about 4, AUC=about 4.5, AUC=about 5, AUC=about 5.5, or AUC=about 6. In some embodiments, the dose of a platinum-based agent, such as carboplatin, described herein is AUC=about 5. In some embodiments, the dose of a platinum-based agent, such as carboplatin, described herein has an AUC=5. In some embodiments, the dose has an AUC=about 4 and is administered about once per week. In some embodiments, the dose has an AUC=about 4 and is administered about once per two weeks. In some embodiments, the dose has an AUC=about 4 and is administered about once per three weeks. In some embodiments, the dose has an AUC=about 4 and is administered about once per four weeks. In some embodiments, the dose has an AUC=about 4.5 and is administered about once per week. In some embodiments, the dose has an AUC=about 4.5 and is administered about once per two weeks. In some embodiments, the dose has an AUC=about 4.5 and is administered about once per three weeks. In some embodiments, the dose has an AUC=about 4.5 and is administered about once per four weeks. In some embodiments, the dose has an AUC=about 5 and is administered about once per week. In some embodiments, the dose has an AUC=about 5 and is administered about once every 2 weeks. In some embodiments, the dose has an AUC=about 5 and is administered about once every 3 weeks. In some embodiments, the dose has an AUC=about 5 and is administered about once every 4 weeks. In some embodiments, the dose has an AUC=about 5.5 and is administered about once a week.In some embodiments, the dose is AUC=about 5.5 and is administered about once every 2 weeks. In some embodiments, the dose is AUC=about 5.5 and is administered about once every 3 weeks. In some embodiments, the dose is AUC=about 5.5 and is administered about once every 4 weeks. In some embodiments, the dose is AUC=about 6 and is administered about once every week. In some embodiments, the dose is AUC=about 6 and is administered about once every 2 weeks. In some embodiments, the dose is AUC=about 6 and is administered about once every 3 weeks. In some embodiments, the dose is AUC=about 6 and is administered about once every 4 weeks. In some embodiments, the dose of the platinum-based agent, such as carboplatin, described herein is AUC=4, AUC=4.5, AUC=5, AUC=5.5, or AUC=6. In some embodiments, the dose of the platinum-based agent, such as carboplatin, described herein is AUC=5. In some embodiments, the dose of a platinum-based agent, such as carboplatin, described herein has an AUC=5. In some embodiments, the dose has an AUC=4 and is administered about once per week. In some embodiments, the dose has an AUC=4 and is administered about once per two weeks. In some embodiments, the dose has an AUC=4 and is administered about once per three weeks. In some embodiments, the dose has an AUC=4 and is administered about once per four weeks. In some embodiments, the dose has an AUC=4.5 and is administered about once per week. In some embodiments, the dose has an AUC=4.5 and is administered about once per two weeks. In some embodiments, the dose has an AUC=4.5 and is administered about once per three weeks. In some embodiments, the dose has an AUC=4.5 and is administered about once per four weeks. In some embodiments, the dose has an AUC=5 and is administered about once per week. In some embodiments, the dose has an AUC=5 and is administered about once every two weeks. In some embodiments, the dose has an AUC=5 and is administered about once every three weeks. In some embodiments, the dose has an AUC=5 and is administered about once every four weeks. In some embodiments, the dose has an AUC=5.5 and is administered about once a week.In some embodiments, the dose is AUC=5.5 and is administered about once every 2 weeks. In some embodiments, the dose is AUC=5.5 and is administered about once every 3 weeks. In some embodiments, the dose is AUC=5.5 and is administered about once every 4 weeks. In some embodiments, the dose is AUC=6 and is administered about once every week. In some embodiments, the dose is AUC=6 and is administered about once every 2 weeks. In some embodiments, the dose is AUC=6 and is administered about once every 3 weeks. In some embodiments, the dose is AUC=6 and is administered about once every 4 weeks. In some embodiments, the dose is AUC=5 and is administered about once every 3 weeks (e.g., ±3 days). In some embodiments, the dose is AUC=5 and is administered about once every 3 weeks. In some embodiments, the dose is AUC=5 and is administered about once every 3 weeks and the platinum-based agent is carboplatin.

[0166] In one embodiment of the methods or uses or products for use provided herein, the platinum-based agent described herein is administered to a subject at a fixed dose ranging from about 50 mg to about 900 mg, e.g., a fixed dose of about 50 mg, a fixed dose of about 60 mg, a fixed dose of about 70 mg, a fixed dose of about 80 mg, a fixed dose of about 90 mg, a fixed dose of about 100 mg, a fixed dose of about 120 mg, a fixed dose of about 140 mg, a fixed dose of about 160 mg, a fixed dose of about 180 mg, a fixed dose of about 200 mg, a fixed dose of about 220 mg, a fixed dose of about 240 mg, a fixed dose of about 260 mg, a fixed dose of about 280 mg, a fixed dose of about 300 mg, a fixed dose of about 320 mg, a fixed dose of about 340 mg, a fixed dose of about 360 mg, a fixed dose of about 380 mg, a fixed dose of about 400 mg, or a fixed dose of about 500 mg. g fixed dose, about 420 mg fixed dose, about 440 mg fixed dose, about 460 mg fixed dose, about 480 mg fixed dose, about 500 mg fixed dose, about 520 mg fixed dose, about 540 mg fixed dose, about 560 mg fixed dose, about 580 mg fixed dose, about 600 mg fixed dose, about 620 mg fixed dose, about 640 mg fixed dose, about 660 mg fixed dose, about 680 mg fixed dose, about 700 mg fixed dose, about 720 mg fixed dose, about 740 mg fixed dose, about 750 mg fixed dose, about 760 mg fixed dose, about 780 mg fixed dose, about 800 mg fixed dose, about 820 mg fixed dose, about 840 mg fixed dose, about 860 mg fixed dose, about 880 mg fixed dose, or about 900 mg fixed dose.In one embodiment of the methods or uses or products for use provided herein, the platinum-based agent described herein is administered to a subject in a fixed dose ranging from 50 mg to 900 mg, e.g., a 50 mg fixed dose, a 60 mg fixed dose, a 70 mg fixed dose, a 80 mg fixed dose, a 90 mg fixed dose, a 100 mg fixed dose, a 120 mg fixed dose, a 140 mg fixed dose, a 160 mg fixed dose, a 180 mg fixed dose, a 200 mg fixed dose, a 220 mg fixed dose, a 240 mg fixed dose, a 260 mg fixed dose, a 280 mg fixed dose, a 300 mg fixed dose, a 320 mg fixed dose, a 340 mg fixed dose, a 360 mg fixed dose, a 380 mg fixed dose, a 400 mg fixed dose, a 50 ...500 mg fixed dose, a 600 mg fixed dose, a 700 mg fixed dose, a 800 mg fixed dose, a 900 mg fixed dose, a 1000 mg fixed dose, a 1000 mg fixed dose, a 1000 mg fixed dose, a 1000 mg fixed dose The fixed dose is 750 mg. In some embodiments, the fixed dose is 750 mg and the platinum-based agent is carboplatin. In some embodiments, the fixed dose is about 600 mg and is administered about once a week. In some embodiments, the fixed dose is about 600 mg and is administered about once every two weeks. In some embodiments, the fixed dose is about 600 mg and is administered about once every three weeks. In some embodiments, the fixed dose is about 600 mg and is administered about once every four weeks. In some embodiments, the fixed dose is about 750 mg and is administered about once a week. In some embodiments, the fixed dose is about 750 mg and is administered about once every two weeks. In some embodiments, the fixed dose is about 750 mg and is administered about once every three weeks. In some embodiments, the fixed dose is about 750 mg and is administered about once every four weeks.In some embodiments, the fixed dose is 600 mg and is administered about once a week. In some embodiments, the fixed dose is 600 mg and is administered about once every two weeks. In some embodiments, the fixed dose is 600 mg and is administered about once every three weeks. In some embodiments, the fixed dose is 600 mg and is administered about once every four weeks. In some embodiments, the fixed dose is 750 mg and is administered about once a week. In some embodiments, the fixed dose is 750 mg and is administered about once every two weeks. In some embodiments, the fixed dose is 750 mg and is administered about once every three weeks. In some embodiments, the fixed dose is 750 mg and is administered about once every four weeks. In some embodiments, the fixed dose is 750 mg and is administered about once every three weeks (e.g., ±3 days). In some embodiments, the fixed dose is 750 mg and is administered about once every three weeks. In some embodiments, the fixed dose is 750 mg administered once every three weeks and the platinum-based agent is carboplatin.

[0167] In some embodiments of the methods or uses or products for use provided herein, the platinum-based agent described herein and the anti-TF antibody-drug conjugate or antigen-binding fragment thereof described herein are administered to the subject in fixed doses. In some embodiments, the fixed dose is based on the amount (e.g., mg) of these agents. In certain embodiments, the fixed dose is based on the concentration (e.g., mg / ml) of these agents. In some embodiments, the ratio of the amount (e.g., mg) of the platinum-based agent to the amount (e.g., mg) of the anti-TF antibody-drug conjugate or antigen-binding fragment thereof is about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, about 1:10, about 1:15, about 1:20, about 1:30, about 1:40, about 1:50, about 1:60, about 1:70, about 1:80, about 1:90, about 1:100 , about 1:120, about 1:140, about 1:160, about 1:180, about 1:200, about 200:1, about 180:1, about 160:1, about 140:1, about 120:1, about 100:1, about 90:1, about 80:1, about 70:1, about 60:1, about 50:1, about 40:1, about 30:1, about 20:1, about 15:1, about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1, or about 2:1. In some embodiments, the ratio of the concentration (e.g., mg / ml) of the platinum-based agent to the concentration (e.g., mg / ml) of the anti-TF antibody-drug conjugate or antigen-binding fragment thereof is about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, about 1:10, about 1:15, about 1:20, about 1:30, about 1:40, about 1:50, about 1:60, about 1:70, about 1:80, about 1:90 ...0, about 1:10, about 1:10, about 1:10, about 1:10, about 1:10, about 1:10, about 1:10, about 1:10, about 1:10, about 1:10, about 1:10, about 1:10, about 1:10, about 1:10, about 1:10, about 1:100, about 1:120, about 1:140, about 1:160, about 1:180, about 1:200, about 200:1, about 180:1, about 160:1, about 140:1, about 120:1, about 100:1, about 90:1, about 80:1, about 70:1, about 60:1, about 50:1, about 40:1, about 30:1, about 20:1, about 15:1, about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1, or about 2:1.In some embodiments, the ratio of the amount (e.g., mg) of platinum-based drug to the amount (e.g., mg) of anti-TF antibody-drug conjugate or antigen-binding fragment thereof is 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:15, 1:20, 1:30, 1:40, 1:50, 1:60, 1:70, 1:80, 1:90, 1:100, 1:150 ... :100, 1:120, 1:140, 1:160, 1:180, 1:200, 200:1, 180:1, 160:1, 140:1, 120:1, 100:1, 90:1, 80:1, 70:1, 60:1, 50:1, 40:1, 30:1, 20:1, 15:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, or 2:1. In some embodiments, the ratio of the concentration (e.g., mg / ml) of the platinum-based drug to the concentration (e.g., mg / ml) of the anti-TF antibody-drug conjugate or antigen-binding fragment thereof is 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:15, 1:20, 1:30, 1:40, 1:50, 1:60, 1:70, 1:80, 1: 90, 1:100, 1:120, 1:140, 1:160, 1:180, 1:200, 200:1, 180:1, 160:1, 140:1, 120:1, 100:1, 90:1, 80:1, 70:1, 60:1, 50:1, 40:1, 30:1, 20:1, 15:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, or 2:1.

[0168] In some embodiments, the dose of the anti-TF antibody-drug conjugate is 2.0 mg / kg administered once every 3 weeks (e.g., ±3 days) and the dose of the platinum-based agent is AUC=5 administered once every 3 weeks (e.g., ±3 days). In some embodiments, the dose of the anti-TF antibody-drug conjugate is 2.0 mg / kg administered once every 3 weeks and the dose of the platinum-based agent is AUC=5 administered once every 3 weeks. In some embodiments, the dose of the anti-TF antibody-drug conjugate is 2.0 mg / kg administered once every 3 weeks, the antibody-drug conjugate is tisotumab vedotin, and the dose of the platinum-based agent is AUC=5 administered once every 3 weeks and the platinum-based agent is carboplatin. In some embodiments, the dose of the anti-TF antibody-drug conjugate is 2.0 mg / kg administered once every three weeks, the antibody-drug conjugate is tisotumab vedotin, and the dose of the platinum-based drug is AUC=5 administered once every three weeks, the platinum-based drug is cisplatin. In some embodiments, the antibody-drug conjugate and the platinum-based drug are provided as adjuvant therapy following radiation and / or surgery.

[0169] In some embodiments, the dose of the anti-TF antibody-drug conjugate is 1.3 mg / kg administered once every 3 weeks (e.g., ±3 days) and the dose of the platinum-based agent is AUC=5 administered once every 3 weeks (e.g., ±3 days). In some embodiments, the dose of the anti-TF antibody-drug conjugate is 1.3 mg / kg administered once every 3 weeks and the dose of the platinum-based agent is AUC=5 administered once every 3 weeks. In some embodiments, the dose of the anti-TF antibody-drug conjugate is 1.3 mg / kg administered once every 3 weeks, the antibody-drug conjugate is tisotumab vedotin, and the dose of the platinum-based agent is AUC=5 administered once every 3 weeks and the platinum-based agent is carboplatin. In some embodiments, the dose of the anti-TF antibody-drug conjugate is 1.3 mg / kg administered once every three weeks, the antibody-drug conjugate is tisotumab vedotin, and the dose of the platinum-based drug is AUC=5 administered once every three weeks, the platinum-based drug is cisplatin. In some embodiments, the antibody-drug conjugate and the platinum-based drug are provided as adjuvant therapy following radiation and / or surgery.

[0170] In some embodiments, the dose of the anti-TF antibody-drug conjugate is 1.7 mg / kg administered about once every 2 weeks (e.g., ±3 days), and the dose of the platinum-based agent is AUC=5 administered about once every 3 weeks (e.g., ±3 days). In some embodiments, the dose of the anti-TF antibody-drug conjugate is 1.7 mg / kg administered about once every 2 weeks, and the dose of the platinum-based agent is AUC=5 administered about once every 3 weeks. In some embodiments, the dose of the anti-TF antibody-drug conjugate is 1.7 mg / kg administered about once every 2 weeks, the antibody-drug conjugate is tisotumab vedotin, and the dose of the platinum-based agent is AUC=5 administered about once every 3 weeks, and the platinum-based agent is carboplatin. In some embodiments, the dose of the anti-TF antibody-drug conjugate is 1.7 mg / kg administered once every two weeks, the antibody-drug conjugate is tisotumab vedotin, and the dose of the platinum-based drug is AUC=5 administered once every three weeks, the platinum-based drug is cisplatin. In some embodiments, the antibody-drug conjugate and the platinum-based drug are provided as adjuvant therapy following radiation and / or surgery.

[0171] In some embodiments, the anti-TF antibody-drug conjugate or antigen-binding fragment thereof described herein and the platinum-based agent described herein are co-administered. In some embodiments, the co-administration is simultaneous or sequential. In some embodiments, the anti-TF antibody-drug conjugate described herein is administered simultaneously with the platinum-based agent described herein. In some embodiments, simultaneous means that the anti-TF antibody-drug conjugate and the platinum-based agent are administered to a subject less than one hour apart, for example, less than about 30 minutes, less than about 15 minutes, less than about 10 minutes, or less than about 5 minutes apart. In some embodiments, the anti-TF antibody-drug conjugate described herein is administered sequentially with the platinum-based agent described herein. In some embodiments, sequential administration means that the anti-TF antibody-drug conjugate and the platinum-based agent 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 2 days apart, at least 3 days apart, at least 4 days apart, at least 5 days apart, at least 5 days apart, at least 7 days apart, at least 2 weeks apart, at least 3 weeks apart, or at least 4 weeks apart.

[0172] The therapeutic methods described herein may be neoadjuvant or adjuvant in various aspects. "Neoadjuvant" therapy refers to a treatment that is administered as a first treatment before a main treatment, for example, to shrink a tumor before surgical intervention. "Adjuvant" therapy refers to an additional treatment that is administered after a main treatment, for example, to reduce the risk of cancer recurrence.

[0173] In some embodiments, the method comprises administering an antibody-drug conjugate as neoadjuvant therapy. In some embodiments, the method comprises administering radiation therapy as neoadjuvant therapy. In some embodiments, the method comprises administering an antibody-drug conjugate and administering radiation therapy as neoadjuvant therapy. In some embodiments, the method comprises administering an antibody-drug conjugate and administering chemoradiotherapy as neoadjuvant therapy. In some embodiments, the antibody-drug conjugate and radiation therapy are administered and administered to a subject in need thereof and who has not been previously treated for cancer. In some embodiments, the antibody-drug conjugate and chemoradiotherapy are administered and administered to a subject in need thereof and who has not been previously treated for cancer. In some embodiments, the antibody-drug conjugate and radiation therapy are administered and administered prior to a surgical intervention for the cancer. In some embodiments, the antibody-drug conjugate and chemoradiotherapy are administered and administered prior to a surgical intervention for the cancer. In some embodiments, the surgical intervention comprises a surgical resection of one or more tumors associated with the cancer. In some embodiments, the method comprises administering and performing tisotumab vedotin and chemoradiotherapy (wherein the chemotherapy is cisplatin) as neoadjuvant therapy. In some embodiments, the method comprises administering and performing tisotumab vedotin and chemoradiotherapy (wherein the chemotherapy is carboplatin) as neoadjuvant therapy. In some embodiments of any of the foregoing embodiments, the chemoradiotherapy is a combination of chemotherapy (e.g., a platinum-based agent such as cisplatin or carboplatin) and radiation therapy (as described elsewhere herein).

[0174] In some embodiments, the method comprises administering an antibody-drug conjugate as an adjuvant therapy. In some embodiments, the method comprises administering radiation therapy as an adjuvant therapy. In some embodiments, the method comprises administering an antibody-drug conjugate and administering radiation therapy as an adjuvant therapy. In some embodiments, the antibody-drug conjugate and radiation therapy are administered and administered after a surgical intervention for cancer. In some embodiments, the method comprises administering an antibody-drug conjugate and administering chemoradiotherapy as an adjuvant therapy. In some embodiments, the antibody-drug conjugate and chemoradiotherapy are administered and administered to a subject in need thereof and who has not been previously treated for cancer. In some embodiments, the surgical intervention comprises surgical resection of one or more tumors associated with cancer. In some embodiments, the method comprises administering and administering tisotumab vedotin and chemoradiotherapy (wherein the chemotherapy is cisplatin) as an adjuvant therapy. In some embodiments, the method includes administering and performing tisotumab vedotin and chemoradiotherapy (wherein the chemotherapy is carboplatin) as an adjuvant therapy. In some embodiments of any of the foregoing embodiments, the chemoradiotherapy is a combination of chemotherapy (e.g., a platinum-based agent such as cisplatin or carboplatin) and radiation therapy (as described elsewhere herein).

[0175] In some embodiments, the method of treatment or use or product for use described herein further comprises administration of one or more additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are administered simultaneously with the anti-TF antibody-drug conjugate or antigen-binding fragment thereof described herein (such as tisotumab vedotin) and the platinum-based agent described herein (such as carboplatin or cisplatin). In some embodiments, the one or more additional therapeutic agents, the anti-TF antibody-drug conjugate or antigen-binding fragment thereof described herein (such as tisotumab vedotin) and the platinum-based agent described herein (such as carboplatin or cisplatin) are administered sequentially, administered before or after radiation therapy. In some embodiments, the method of treatment or use or product for use described herein comprises treatment of the anti-TF antibody-drug conjugate described herein (such as tisotumab vedotin) in combination with a platinum-based agent (such as cisplatin or carboplatin) and further in combination with radiation therapy.

[0176] VIII. Treatment results In one aspect, a method of treating cancer using an anti-TF antibody-drug conjugate or antigen-binding fragment thereof described herein (e.g., tisotumab vedotin, etc.) and radiation therapy described herein, further comprising, in some embodiments, an additional chemotherapeutic agent, such as a platinum-based drug, improves one or more therapeutic effects in a subject after administration of the antibody-drug conjugate and radiation therapy. In some embodiments, the one or more therapeutic effects are a size of a tumor resulting from the cancer, an objective response rate, a duration of response, a time to response, a progression-free survival, an overall survival (overall survival rate), or any combination thereof. In one embodiment, the one or more therapeutic effects are a size of a tumor resulting 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 a duration of response. In one embodiment, the one or more therapeutic benefits is time to response. In one embodiment, the one or more therapeutic benefits is progression-free survival. In one embodiment, the one or more therapeutic benefits is overall survival (overall survival rate). In one embodiment, the one or more therapeutic benefits is regression of cancer.

[0177] In one embodiment of the methods or uses or products for use provided herein, the response to treatment with an anti-TF antibody-drug conjugate or antigen-binding fragment thereof (e.g., tisotumab vedotin) described herein and radiation therapy described herein can include the following criteria (RECIST criteria 1.1): TIFF2025515166000019.tif116150

[0178] In one embodiment of the methods or uses or products for use provided herein, the efficacy of treatment with an anti-TF antibody-drug conjugate or antigen-binding fragment thereof (e.g., tisotumab vedotin) described herein and radiation therapy is assessed by measuring the objective response rate. In some embodiments, the objective response rate is the percentage of patients who show a predetermined amount of reduction in tumor size in the shortest period of time. 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%-80%. In one embodiment, the objective response rate is at least about 30%-80%. In one embodiment, the objective response rate is at least about 40%-80%. In one embodiment, the objective response rate is at least about 50%-80%. In one embodiment, the objective response rate is at least about 60%-80%. In one embodiment, the objective response rate is at least about 70%-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%-80%. In one embodiment, the objective response rate is at least 30%-80%. In one embodiment, the objective response rate is at least 40%-80%. In one embodiment, the objective response rate is at least 50%-80%. In one embodiment, the objective response rate is at least 60%-80%. In one embodiment, the objective response rate is at least 70%-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%.

[0179] In one embodiment of the methods or uses or products for use provided herein, the response to treatment with an anti-TF antibody-drug conjugate or antigen-binding fragment thereof (e.g., tisotumab vedotin) and radiation therapy 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 a tumor derived from the cancer prior to administration of the anti-TF antibody-drug conjugate and / or administration of radiation therapy. In one embodiment, the size of a tumor derived from the cancer is reduced by at least about 10%-80%. In one embodiment, the size of a tumor derived from the cancer is reduced by at least about 20%-80%. In one embodiment, the size of a tumor derived from the cancer is reduced by at least about 30%-80%. In one embodiment, the size of a tumor derived from the cancer is reduced by at least about 40%-80%. In one embodiment, the size of a tumor derived from a cancer is reduced by at least about 50%-80%. In one embodiment, the size of a tumor derived from a cancer is reduced by at least about 60%-80%. In one embodiment, the size of a tumor derived from a cancer is reduced by at least about 70%-80%. In one embodiment, the size of a tumor derived from a cancer is reduced by at least about 80%. In one embodiment, the size of a tumor derived from a cancer is reduced by at least about 85%. In one embodiment, the size of a tumor derived from a cancer is reduced by at least about 90%. In one embodiment, the size of a tumor derived from a cancer is reduced by at least about 95%. In one embodiment, the size of a tumor derived from a cancer is reduced by at least about 98%. In one embodiment, the size of a tumor derived from a 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 a tumor derived from the cancer before administration of the anti-TF antibody-drug conjugate and / or administration of radiation therapy.In one embodiment, the size of a tumor derived from a cancer is reduced by at least 10% to 80%. In one embodiment, the size of a tumor derived from a cancer is reduced by at least 20% to 80%. In one embodiment, the size of a tumor derived from a cancer is reduced by at least 30% to 80%. In one embodiment, the size of a tumor derived from a cancer is reduced by at least 40% to 80%. In one embodiment, the size of a tumor derived from a cancer is reduced by at least 50% to 80%. In one embodiment, the size of a tumor derived from a cancer is reduced by at least 60% to 80%. In one embodiment, the size of a tumor derived from a cancer is reduced by at least 70% to 80%. In one embodiment, the size of a tumor derived from a cancer is reduced by at least 80%. In one embodiment, the size of a tumor derived from a cancer is reduced by at least 85%. In one embodiment, the size of a tumor derived from a cancer is reduced by at least 90%. In one embodiment, the size of a tumor derived from a cancer is reduced by at least 95%. In one embodiment, the size of a tumor derived from a cancer is reduced by at least 98%. In one embodiment, the size of a tumor derived from a cancer is reduced by at least 99%. In one embodiment, the size of a tumor derived from a cancer is reduced by 100%. In one embodiment, the size of the tumor derived from the cancer is measured by magnetic resonance imaging (MRI). In one embodiment, the size of the tumor derived from the cancer is measured by computed tomography (CT). In some embodiments, the size of the tumor derived from the cancer is reduced compared to the size of the tumor before administration of the anti-TF antibody-drug conjugate and administration of radiation therapy. In some embodiments, the size of the tumor derived from the cancer is reduced compared to the size of the tumor before administration of the anti-TF antibody-drug conjugate. In some embodiments, the size of the tumor derived from the cancer is reduced compared to the size of the tumor before administration of radiation therapy.

[0180] In one embodiment of the methods or uses or products for use provided and described herein, the response to treatment with the antibody-drug conjugate or antigen-binding fragment thereof (e.g., tisotumab vedotin) described herein and radiation therapy promotes regression of a tumor derived from a cancer. In one embodiment, the tumor derived from a cancer regresses by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, or at least about 80% compared to the size of the tumor derived from a cancer before administration of the anti-TF antibody-drug conjugate and / or administration of radiation therapy. In one embodiment, the tumor derived from a cancer regresses by at least about 10% to about 80%. In one embodiment, the tumor derived from a cancer regresses by at least about 20% to about 80%. In one embodiment, the tumor derived from a cancer regresses 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 cancer-derived tumor 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 cancer-derived tumor before administration of the anti-TF antibody-drug conjugate and / or administration of radiation therapy. In one embodiment, the cancer-derived tumor shrinks by at least 10%-80%. In one embodiment, the cancer-derived tumor shrinks by at least 20%-80%. In one embodiment, the cancer-derived tumor shrinks by at least 30%-80%.In one embodiment, the tumor of cancer origin regresses by at least 40% to 80%. In one embodiment, the tumor of cancer origin regresses by at least 50% to 80%. In one embodiment, the tumor of cancer origin regresses by at least 60% to 80%. In one embodiment, the tumor of cancer origin regresses by at least 70% to 80%. In one embodiment, the tumor of cancer origin regresses by at least 80%. In one embodiment, the tumor of cancer origin regresses by at least 85%. In one embodiment, the tumor of cancer origin regresses by at least 90%. In one embodiment, the tumor of cancer origin regresses by at least 95%. In one embodiment, the tumor of cancer origin regresses by at least 98%. In one embodiment, the tumor of cancer origin regresses by at least 99%. In one embodiment, the tumor of cancer origin regresses by 100%. In one embodiment, the tumor of cancer origin is determined by measuring the size of the tumor with magnetic resonance imaging (MRI). In one embodiment, the tumor of cancer origin is determined by measuring the size of the tumor with computed tomography (CT). In some embodiments, the tumor derived from the cancer regresses compared to the size of the tumor before administration of the anti-TF antibody-drug conjugate and administration of radiation therapy. In some embodiments, the tumor derived from the cancer regresses compared to the size of the tumor before administration of the anti-TF antibody-drug conjugate. In some embodiments, the tumor derived from the cancer regresses compared to the size of the tumor before administration of radiation therapy.

[0181] In one embodiment of the methods or uses or products for use described herein, the response to treatment with an anti-TF antibody-drug conjugate or antigen-binding fragment thereof (such as, for example, tisotumab vedotin) described herein and radiation therapy described herein is assessed by measuring progression-free survival after administration of the anti-TF antibody-drug conjugate and / or radiation therapy. In some embodiments, the subject exhibits a progression-free survival of at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 18 months, at least about 2 years, at least about 3 years, at least about 4 years, or at least about 5 years after administration of the anti-TF antibody-drug conjugate and / or radiation therapy. In some embodiments, the subject exhibits a progression-free survival of at least about 6 months after administration of the anti-TF antibody-drug conjugate and / or radiation therapy. In some embodiments, the subject exhibits a progression-free survival of at least about 1 year after administration of the anti-TF antibody-drug conjugate and / or radiation therapy. In some embodiments, the subject exhibits a progression-free survival of at least about 2 years after administration of the anti-TF antibody-drug conjugate and / or radiation therapy. In some embodiments, the subject exhibits a progression-free survival of at least about 3 years after administration of the anti-TF antibody-drug conjugate and / or radiation therapy. In some embodiments, the subject exhibits a progression-free survival of at least about 4 years after administration of the anti-TF antibody-drug conjugate and / or radiation therapy. In some embodiments, the subject exhibits a progression-free survival of at least about 5 years after administration of the anti-TF antibody-drug conjugate and / or radiation therapy.In some embodiments, the subject exhibits a progression-free 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 administering the anti-TF antibody-drug conjugate and / or administering radiation therapy. In some embodiments, the subject exhibits a progression-free survival of at least 6 months after administering the anti-TF antibody-drug conjugate and / or administering radiation therapy. In some embodiments, the subject exhibits a progression-free survival of at least 1 year after administering the anti-TF antibody-drug conjugate and / or administering radiation therapy. In some embodiments, the subject exhibits a progression-free survival of at least 2 years after administering the anti-TF antibody-drug conjugate and / or administering radiation therapy. In some embodiments, the subject exhibits a progression-free survival of at least 3 years after administration of the anti-TF antibody-drug conjugate and / or radiation therapy. In some embodiments, the subject exhibits a progression-free survival of at least 4 years after administration of the anti-TF antibody-drug conjugate and / or radiation therapy. In some embodiments, the subject exhibits a progression-free survival of at least 5 years after administration of the anti-TF antibody-drug conjugate and / or radiation therapy. In some embodiments, the response to the treatment is assessed by measuring the progression-free survival after administration of the anti-TF antibody-drug conjugate and radiation therapy. In some embodiments, the response to the treatment is assessed by measuring the progression-free survival after administration of the anti-TF antibody-drug conjugate. In some embodiments, the response to the treatment is assessed by measuring the progression-free survival after radiation therapy.

[0182] In one embodiment of the methods or uses or products for use described herein, the response to treatment with an anti-TF antibody-drug conjugate or antigen-binding fragment thereof (such as, for example, tisotumab vedotin) described herein and radiation therapy described herein is assessed by measuring overall survival after administration of the anti-TF antibody-drug conjugate and / or radiation therapy. 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 anti-TF antibody-drug conjugate and / or radiation therapy. In some embodiments, the subject exhibits an overall survival of at least about 6 months after administration of the anti-TF antibody-drug conjugate and / or radiation therapy. In some embodiments, the subject exhibits an overall survival time of at least about 1 year after administration of the anti-TF antibody-drug conjugate and / or radiation therapy. In some embodiments, the subject exhibits an overall survival time of at least about 2 years after administration of the anti-TF antibody-drug conjugate and / or radiation therapy. In some embodiments, the subject exhibits an overall survival time of at least about 3 years after administration of the anti-TF antibody-drug conjugate and / or radiation therapy. In some embodiments, the subject exhibits an overall survival time of at least about 4 years after administration of the anti-TF antibody-drug conjugate and / or radiation therapy. In some embodiments, the subject exhibits an overall survival time of at least about 5 years after administration of the anti-TF antibody-drug conjugate and / or radiation therapy.In some embodiments, the subject exhibits an 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 administering the anti-TF antibody-drug conjugate and / or administering radiation therapy. In some embodiments, the subject exhibits an overall survival of at least 6 months after administering the anti-TF antibody-drug conjugate and / or administering radiation therapy. In some embodiments, the subject exhibits an overall survival of at least 1 year after administering the anti-TF antibody-drug conjugate and / or administering radiation therapy. In some embodiments, the subject exhibits an overall survival of at least 2 years after administering the anti-TF antibody-drug conjugate and / or administering radiation therapy. In some embodiments, the subject exhibits an overall survival of at least 3 years after administering the anti-TF antibody-drug conjugate and / or administering radiation therapy. In some embodiments, the subject exhibits an overall survival of at least 4 years after administration of the anti-TF antibody-drug conjugate and / or radiation therapy. In some embodiments, the subject exhibits an overall survival of at least 5 years after administration of the anti-TF antibody-drug conjugate and / or radiation therapy. In some embodiments, the response to the treatment is assessed by measuring the overall survival after administration of the anti-TF antibody-drug conjugate and radiation therapy. In some embodiments, the response to the treatment is assessed by measuring the overall survival after administration of the anti-TF antibody-drug conjugate. In some embodiments, the response to the treatment is assessed by measuring the overall survival after radiation therapy.

[0183] In one embodiment of the methods or uses or products for use described herein, the response to treatment with an anti-TF antibody-drug conjugate or antigen-binding fragment thereof described herein (such as, for example, tisotumab vedotin) and radiation therapy described herein is assessed by measuring the duration of response to the anti-TF antibody-drug conjugate and radiation therapy after administration of the anti-TF antibody-drug conjugate and / or administration of radiation therapy. In some embodiments, the duration of response to the anti-TF antibody-drug conjugate and radiation therapy 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 anti-TF antibody-drug conjugate and / or administration of radiation therapy. In some embodiments, the duration of response to the anti-TF antibody-drug conjugate and radiation therapy is at least about 6 months after administration of the antibody-drug conjugate and / or administration of radiation therapy. In some embodiments, the duration of response to the anti-TF antibody-drug conjugate and radiation therapy is at least about 1 year after administration of the antibody-drug conjugate and / or administration of radiation therapy. In some embodiments, the duration of response to the anti-TF antibody-drug conjugate and radiation therapy is at least about 2 years after administration of the antibody-drug conjugate and / or administration of radiation therapy. In some embodiments, the duration of response to the anti-TF antibody-drug conjugate and radiation therapy is at least about 3 years after administration of the antibody-drug conjugate and / or administration of radiation therapy. In some embodiments, the duration of response to the anti-TF antibody-drug conjugate and radiation therapy is at least about 4 years after administration of the antibody-drug conjugate. In some embodiments, the duration of response to the anti-TF antibody-drug conjugate and radiation therapy is at least about 5 years after administration of the antibody-drug conjugate and / or radiation therapy.In some embodiments, the duration of response to the anti-TF antibody-drug conjugate and radiation therapy 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 the anti-TF antibody-drug conjugate and / or administration of radiation therapy. In some embodiments, the duration of response to the anti-TF antibody-drug conjugate and radiation therapy is at least 6 months after administration of the antibody-drug conjugate and / or administration of radiation therapy. In some embodiments, the duration of response to the anti-TF antibody-drug conjugate and radiation therapy is at least 1 year after administration of the antibody-drug conjugate and / or administration of radiation therapy. In some embodiments, the duration of response to the anti-TF antibody-drug conjugate and radiation therapy is at least 2 years after administration of the antibody-drug conjugate and / or administration of radiation therapy. In some embodiments, the duration of response to the anti-TF antibody-drug conjugate and radiation therapy is at least 3 years after administration of the antibody-drug conjugate and / or administration of radiation therapy. In some embodiments, the duration of response to the anti-TF antibody-drug conjugate and radiation therapy is at least 4 years after administration of the antibody-drug conjugate. In some embodiments, the duration of response to the anti-TF antibody-drug conjugate and radiation therapy is at least 5 years after administration of the antibody-drug conjugate and / or administration of radiation therapy. In some embodiments, the duration of response is measured after administration of the anti-TF antibody-drug conjugate and administration of radiation therapy. In some embodiments, the duration of response is measured after administration of the anti-TF antibody-drug conjugate. In some embodiments, the duration of response is measured after administration of radiation therapy.

[0184] IX. Composition In some aspects, also provided herein are compositions (e.g., pharmaceutical compositions and therapeutic formulations) comprising any of the anti-TF antibody-drug conjugates or antigen-binding fragments thereof described herein, such as tisotumab vedotin, which are useful in methods of treating cancer in combination with radiation therapy, and for the manufacture of medicaments for use in methods of treating cancer in combination with radiation therapy.

[0185] Therapeutic formulations are prepared for storage by mixing the active ingredient having the desired purity with a pharma- ceutically acceptable carrier, excipient, or stabilizer (Remington: The Science and Practice of Pharmacy, 20th ed., published by Lippincott Williams & Wiklins, edited by Gennaro, Philadelphia, PA, 2000).

[0186] Acceptable carriers, excipients, or stabilizers are non-toxic to recipients at the dosages and concentrations employed and include: buffers; antioxidants, e.g., ascorbic acid, methionine, vitamin E, sodium metabisulfite; preservatives; tonicity agents; stabilizers; metal complexes (e.g., Zn-protein complexes); chelating agents, e.g., EDTA; and / or non-ionic surfactants.

[0187] Buffers may be used to adjust the pH to a range that optimizes therapeutic efficacy, especially if the stability is pH dependent. Buffers may be present at concentrations ranging from about 50 mM to about 250 mM. Buffers suitable for use in the present invention include both organic and inorganic acids and their salts. For example, citric acid, phosphoric acid, succinic acid, tartaric acid, fumaric acid, gluconic acid, oxalic acid, lactic acid, acetic acid and their salts. Additionally, buffers may be comprised of trimethylamine salts such as histidine and Tris.

[0188] Preservatives can be added to prevent microbial growth and are typically present in the range of about 0.2% to 1.0% (w / v). Preservatives suitable for use in the present invention include: octadecyldimethylbenzylammonium chloride; hexamethonium chloride; benzalkonium halides (e.g., chloride, bromide, iodide), benzethonium chloride; thimerosal, phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol, 3-pentanol, and m-cresol.

[0189] Tonicity agents, sometimes also known as "stabilizers", may be present to adjust or maintain the osmotic pressure of the liquid in the composition. When used with large charged biomolecules such as proteins and antibodies, they are often referred to as "stabilizers" because they interact with the charged groups of the amino acid side chains, thereby reducing the possibility of inter- and intra-molecular interactions. Tonicity agents can be present in an amount of about 0.1% to about 25% by weight or about 1% to about 5% by weight, taking into account the relative amounts of other components. In some embodiments, tonicity agents include polyhydric sugar alcohols, trihydric or higher sugar alcohols, such as glycerin, erythritol, arabitol, xylitol, sorbitol, and mannitol.

[0190] Additional excipients include additives that may function as one or more of the following: (1) bulking agents, (2) solubility enhancers, (3) stabilizers, and (4) additives that prevent denaturation or adhesion to container walls. Such excipients include: polyhydric sugar alcohols (listed above); amino acids, such as alanine, glycine, glutamine, asparagine, histidine, arginine, lysine, ornithine, leucine, 2-phenylalanine, glutamic acid, threonine, and the like; organic sugars or sugar alcohols, such as sucrose, lactose, lactitol, trehalose, stachyose, mannose, sorbose, xylose, ribose, ribitol, myoinisitose, myoinositol, galactose, galactitol, glycerol, cyclitols (e.g., : inositol), polyethylene glycol; sulfur-containing reducing agents, e.g., urea, glutathione, thioctic acid, sodium thioglycolate, thioglycerol, α-monothioglycerol, sodium thiosulfate; low molecular weight proteins, e.g., human serum albumin, bovine serum albumin, gelatin or other immunoglobulins; hydrophilic polymers, e.g., polyvinylpyrrolidone; monosaccharides (e.g., xylose, mannose, fructose, glucose); disaccharides (e.g., lactose, maltose, sucrose); trisaccharides, e.g., raffinose; polysaccharides, e.g., dextrin or dextran.

[0191] A non-ionic surfactant or detergent (also known as a "wetting agent") can be present to aid in solubilization of the therapeutic agent as well as to protect the therapeutic protein from agitation-induced aggregation, which also allows the formulation to be exposed to shear surface stresses without causing denaturation of the active therapeutic protein or antibody. The non-ionic surfactant is present in the range of about 0.05 mg / ml to about 1.0 mg / ml or about 0.07 mg / ml to about 0.2 mg / ml. In some embodiments, the non-ionic surfactant is present in the range of about 0.001% to about 0.1% w / v or about 0.01% to about 0.1% w / v or about 0.01% to about 0.025% w / v.

[0192] Suitable nonionic surfactants include polysorbates (20, 40, 60, 65, 80, etc.), poloxamers (184, 188, etc.), PLURONIC® polyols, TRITON®, polyoxyethylene sorbitan monoethers (TWEEN®-20, TWEEN®-80, etc.), lauromacrogol 400, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil 10, 50 and 60, glycerol monostearate, sucrose fatty acid esters, methylcellulose and carboxymethylcellulose. Anionic detergents that can be used include sodium lauryl sulfate, dioctyl sodium sulfosuccinate and dioctyl sodium sulfonate. Cationic detergents include benzalkonium chloride or benzethonium chloride.

[0193] Formulations comprising the anti-TF antibody conjugates described herein for use in the therapeutic methods provided herein are described in WO2015 / 075201. In some embodiments, the anti-TF antibody-drug conjugates described herein are present in a formulation comprising the anti-TF antibody-drug conjugate, histidine, sucrose, and D-mannitol, the formulation having a pH of about 6.0. In some embodiments, the anti-TF antibody-drug conjugates described herein are present in a formulation comprising the anti-TF antibody-drug conjugate at a concentration of about 10 mg / ml, histidine at a concentration of about 30 mM, sucrose at a concentration of about 88 mM, and D-mannitol at a concentration of about 165 mM, the formulation having a pH of about 6.0. In some embodiments, the anti-TF antibody-drug conjugate described herein is present in a formulation comprising the anti-TF antibody-drug conjugate at a concentration of 10 mg / ml, histidine at a concentration of 30 mM, sucrose at a concentration of 88 mM, D-mannitol at a concentration of 165 mM, and the formulation has a pH of 6.0. In some embodiments, the formulation comprises tisotumab vedotin at a concentration of 10 mg / ml, histidine at a concentration of 30 mM, sucrose at a concentration of 88 mM, D-mannitol at a concentration of 165 mM, and has a pH of 6.0.

[0194] In some embodiments provided herein, the formulations comprising the anti-TF antibody conjugates described herein do not contain surfactants (i.e., are surfactant-free).

[0195] For the preparation to be used for in vivo administration, they must be sterile.The preparation can be sterilized by filtering through a sterile filtration membrane.The therapeutic composition herein is generally placed in a container with a sterile access port, for example, an intravenous infusion bag or vial with a stopper that can be pierced by a hypodermic injection needle.

[0196] Routes of administration will be in accordance with known and accepted methods, for example, by single or multiple bolus administration, or by infusion over time in an appropriate manner, such as injection or infusion by subcutaneous, intravenous, intraperitoneal, intramuscular, intraarterial, intralesional or intraarticular routes, topical administration, inhalation, or by sustained or sustained release means.

[0197] The formulations described herein may also contain multiple active compounds as necessary for the particular indication being treated, preferably those with complementary activities that do not adversely affect each other. Alternatively, or in addition, the compositions may contain cytotoxic drugs, cytokines, or growth inhibitors. Such molecules are suitably present in combination in amounts effective for the intended purpose.

[0198] The present invention provides compositions comprising a population of anti-TF antibody-drug conjugates or antigen-binding fragments thereof as described herein for use in the methods of treating cancer as described herein. In some aspects, provided herein are compositions comprising a population of antibody-drug conjugates, wherein the antibody-drug conjugates comprise a linker attached to MMAE, and the antibody-drug conjugates have the following structure: TIFF2025515166000020.tif28147, where p represents a number from 1 to 8 (e.g., 1, 2, 3, 4, 5, 6, 7, or 8), S represents a sulfhydryl residue of an anti-TF antibody or antigen-binding fragment thereof, and Ab represents an anti-TF antibody or antigen-binding fragment thereof described herein, e.g., tisotumab. In some embodiments, p represents a number from 3 to 5. In some embodiments, the average value of p in the composition is about 4. In some embodiments, the population is a mixed population of antibody-drug conjugates, where p varies from 1 to 8 for each antibody-drug conjugate. In some embodiments, the population is a homogenous population of antibody-drug conjugates, where each antibody-drug conjugate has the same value for p.

[0199] In some embodiments, a composition comprising an anti-TF antibody-drug conjugate or an antigen-binding fragment thereof, such as tisotumab vedotin, as described herein, is co-administered with a composition comprising an additional chemotherapeutic agent, such as a platinum-based agent, as described herein. In some embodiments, the co-administration is simultaneous or sequential. In some embodiments, the anti-TF antibody-drug conjugate described herein is administered simultaneously with the platinum-based agent. In some embodiments, simultaneous means that the anti-TF antibody-drug conjugate and the platinum-based agent are administered to a subject less than about 1 hour apart, e.g., 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, simultaneous means that the anti-TF antibody-drug conjugate and the platinum-based agent are administered to a subject less than 1 hour apart, e.g., less than 30 minutes apart, less than 15 minutes apart, less than 10 minutes apart, or less than 5 minutes apart. In some embodiments, the anti-TF antibody-drug conjugate is administered sequentially with the platinum-based agent. In some embodiments, sequential administration means that the anti-TF antibody-drug conjugate and the platinum-based agent are administered to a subject 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 2 days apart, at least 3 days apart, at least 4 days apart, at least 5 days apart, at least 5 days apart, at least 7 days apart, at least 2 weeks apart, at least 3 weeks apart, or at least 4 weeks apart.In some embodiments, a composition comprising an anti-TF antibody-drug conjugate described herein and / or a platinum-based agent described herein is co-administered with one or more therapeutic agents to eliminate or reduce the severity of one or more adverse events. In some embodiments, a composition comprising an anti-TF antibody-drug conjugate described herein and / or a platinum-based agent described herein is co-administered with one or more therapeutic agents to prevent the onset of or reduce the severity of an adverse event.

[0200] In some embodiments, a composition comprising an anti-TF antibody-drug conjugate described herein, such as tisotumab vedotin, is co-administered with one or more additional therapeutic agents. In some embodiments, the co-administration is simultaneous or sequential. In some embodiments, the anti-TF antibody-drug conjugate described herein is administered simultaneously with one or more additional therapeutic agents. In some embodiments, simultaneous means that the anti-TF antibody-drug conjugate and one or more therapeutic agents are administered to a subject less than about one hour apart, for example, 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, the anti-TF antibody-drug conjugate is administered sequentially with one or more additional therapeutic agents. In some embodiments, simultaneous means that the anti-TF antibody-drug conjugate and one or more therapeutic agents are administered to a subject less than one hour apart, for example, less than 30 minutes apart, less than 15 minutes apart, less than 10 minutes apart, or less than 5 minutes apart. In some embodiments, the anti-TF antibody-drug conjugate is administered sequentially with one or more additional therapeutic agents. In some embodiments, sequential administration means that the anti-TF antibody-drug conjugate and the one or more additional therapeutic agents are administered to a subject 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 2 days apart, at least 3 days apart, at least 4 days apart, at least 5 days apart, at least 5 days apart, at least 7 days apart, at least 2 weeks apart, at least 3 weeks apart, or at least 4 weeks apart.

[0201] X. Articles of Manufacture and Kits In another aspect, an article of manufacture or kit is provided that includes an anti-TF antibody-drug conjugate as described herein, such as tisotumab vedotin. The article of manufacture or kit may further include an additional chemotherapeutic agent, such as a platinum-based agent. The article of manufacture or kit may further include instructions for using the anti-TF antibody-drug conjugate in the method of the invention. Thus, in certain embodiments, the article of manufacture or kit includes instructions for using the anti-TF antibody-drug conjugate in a method of treating cancer in a subject, comprising administering an effective amount of the anti-TF antibody-drug conjugate and administering radiation therapy. In some embodiments, the cancer is tissue factor positive. In some embodiments, the cancer is head and neck cancer, such as head and neck squamous cell carcinoma. In some embodiments, the cancer is a gynecological cancer. In some embodiments, the gynecological cancer is selected from the list consisting of ovarian cancer, endometrial cancer, cervical cancer, perineal tissue cancer, fallopian tube cancer, uterine cancer, vaginal cancer, vulvar cancer, and gestational trophoblastic disease cancer. In some embodiments, the gynecological cancer is ovarian cancer. In some aspects, the gynecological cancer is endometrial cancer. In some aspects, the gynecological cancer is cervical cancer. In some aspects, the gynecological cancer is perineal tissue cancer. In some aspects, the gynecological cancer is fallopian tube cancer. In some aspects, the gynecological cancer is uterine cancer. In some aspects, the gynecological cancer is vaginal cancer. In some aspects, the gynecological cancer is vulvar cancer. In some aspects, the gynecological cancer is gestational trophoblastic disease cancer.

[0202] The article of manufacture or kit may further comprise a container. Suitable containers include, for example, bottles, vials (e.g., dual-chamber vials), syringes (e.g., single- 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, plastic, etc. The container holds the formulation.

[0203] 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 administration methods for treating cancer in a subject. The container holding the formulation may be a single-use vial, or a multi-use vial that allows for repeated administration of the reconstituted formulation. The article of manufacture or kit may further include a second container that includes a suitable diluent. The article of manufacture or kit may further include other materials desirable from commercial, therapeutic, and user standpoints, such as other buffers, diluents, filters, needles, syringes, and package inserts with instructions for use.

[0204] The article of manufacture or kit herein optionally further comprises a container containing a second agent, where the anti-TF antibody-drug conjugate is the first agent; the article of manufacture or kit further comprises instructions on a label or package insert for treating a subject with an effective amount of the second agent. In some embodiments, the second agent is a platinum-based agent as described herein. In some embodiments, the label or package insert indicates that the first agent and the second agent should be administered sequentially or simultaneously as described herein.

[0205] In some embodiments, the anti-TF 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, an ampoule, a sachet, etc., indicating the amount of active agent. If the agent is administered by injection, an ampoule of, for example, sterile water for injection or saline can be provided, optionally as part of the kit, so that the components can be mixed before administration. Such a kit can further include one or more of various conventional pharmaceutical components, such as, for example, a container containing one or more pharma- ceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art. Printed instructions, such as a package insert or label, indicating the amount of components to be administered, guidelines for administration, and / or guidelines for mixing the components, can also be included in the kit.

[0206] VII. Exemplary Embodiments Aspects provided herein include the following:

[0207] A. Treatment method Aspect 1A. A method of treating cancer in a subject, comprising: (i) administering radiation therapy to the subject; and (ii) administering to the subject an antibody-drug conjugate that binds to tissue factor (TF). wherein the antibody-drug conjugate comprises an anti-TF antibody, or an antigen-binding fragment thereof, conjugated to an auristatin, or a functional analogue or functional derivative thereof.

[0208] Aspect 2A. The method of Aspect 1A, wherein said auristatin is monomethylauristatin or a functional analog or derivative thereof.

[0209] Aspect 3A. The method of aspect 1A or 2A, wherein said auristatin is monomethylauristatin E (MMAE).

[0210] Aspect 4A. The method of any one of Aspects 1A to 3A, wherein the antibody-drug conjugate is administered at a dose ranging from about 0.9 mg / kg to about 2.1 mg / kg.

[0211] Aspect 5A. The method of any one of Aspects 1A to 4A, wherein the antibody-drug conjugate is administered at a dose ranging from about 0.9 mg / kg to about 1.7 mg / kg.

[0212] Embodiment 6A. The method of embodiment 4A or 5A, wherein said antibody-drug conjugate is administered at a dose of about 1.3 mg / kg.

[0213] Embodiment 7A. The method of embodiment 4A or 5A, wherein said antibody-drug conjugate is administered at a dose of about 1.7 mg / kg.

[0214] The method of embodiment 4A, wherein said antibody-drug conjugate is administered at a dose of about 2.0 mg / kg.

[0215] Aspect 9A. The method of any one of Aspects 1A-8A, wherein the antibody-drug conjugate is administered about once per week, about once per two weeks, about once per three weeks, or about once per four weeks.

[0216] Aspect 10A. The method of any one of Aspects 1A-9A, wherein the antibody-drug conjugate is administered about once every two weeks.

[0217] Aspect 11A. The method of any one of Aspects 1A-9A, wherein the antibody-drug conjugate is administered about once every three weeks.

[0218] Aspect 12A. The method of any one of Aspects 1A to 11A, wherein the radiation therapy is administered at a dose of about 1 Gy to about 100 Gy, such as at a dose of about 10 Gy to about 70 Gy, such as at a dose of about 30 Gy to about 60 Gy, such as at a dose of about 40 Gy to about 50 Gy.

[0219] Aspect 13A. The method of any one of Aspects 1A-12A, wherein the radiation therapy is selected from the group consisting of intensity modulated radiation therapy (IMRT), image guided radiation therapy (IGRT), tomotherapy, stereotactic radiosurgery, stereotactic body radiation therapy, photon beam, electron beam, and proton beam therapy.

[0220] Embodiment 14A. The method of any one of Embodiments 1A-13A, further comprising administering to the subject a chemotherapeutic agent.

[0221] Embodiment 15A. The method of embodiment 14A, wherein said chemotherapeutic agent is a platinum-based agent.

[0222] The method of embodiment 15A, wherein the platinum-based drug is administered at a dose of AUC=about 4 to AUC=about 6.

[0223] The method of embodiment 15A or 16A, wherein said platinum-based agent is administered at a dose of AUC=about 5.

[0224] Embodiment 18A. The method of any one of Embodiments 15A-17A, wherein the platinum-based agent is administered about once per week, about once every two weeks, about once every three weeks, or about once every four weeks.

[0225] Embodiment 19A. The method of any one of embodiments 15A-18A, wherein the platinum-based agent is administered about once every three weeks.

[0226] The method of any one of embodiments 15A-18A, wherein the platinum-based agent is administered about once every four weeks.

[0227] Embodiment 21A. The method of any one of embodiments 1A to 20A, wherein the cancer is a solid tumor.

[0228] Embodiment 22A. The method of any one of embodiments 1A to 21A, wherein the cancer is head and neck squamous cell carcinoma.

[0229] Embodiment 23A. The method of any one of embodiments 1A to 21A, wherein the cancer is a gynecological cancer.

[0230] Embodiment 24A. The method of any one of embodiments 1A-21A, wherein said cancer is selected from the list consisting of ovarian cancer, endometrial cancer, cervical cancer, perineal cancer, fallopian tube cancer, uterine cancer, vaginal cancer, vulvar cancer, and gestational trophoblastic disease cancer.

[0231] Embodiment 25A. The method of any one of embodiments 1A to 24A, wherein the cancer is associated with a tissue factor positive primary tumor.

[0232] Embodiment 26A. The method of any one of embodiments 1A to 25A, wherein the cancer is an early stage cancer.

[0233] Embodiment 27A. The method of embodiment 26A, wherein the cancer is stage I or stage II cancer.

[0234] Embodiment 28A. The method of embodiment 26A or 27A, wherein the cancer is not a recurrent cancer.

[0235] Embodiment 29A. The method of any one of embodiments 26A to 28A, wherein the cancer is not locally advanced.

[0236] Embodiment 30A. The method of any one of embodiments 26A to 29A, wherein the cancer is not metastatic.

[0237] Embodiment 31A. The method of any one of embodiments 26A to 28A, wherein the cancer is locally advanced.

[0238] Aspect 32A. The method according to any one of Aspects 1A to 31A, which is a neoadjuvant treatment for said cancer.

[0239] Embodiment 33A. The method of embodiment 32A, wherein the antibody-drug conjugate is administered and the radiation therapy is performed prior to surgical intervention for the cancer.

[0240] Embodiment 34A. The method of embodiment 32A or 33A, wherein a platinum-based agent is further administered prior to the surgical intervention for said cancer.

[0241] Embodiment 35A. The method of embodiment 33A or 34A, wherein the antibody-drug conjugate is administered and the radiation therapy is performed prior to surgical resection of one or more tumors associated with the cancer.

[0242] Embodiment 36A. The method of any one of embodiments 33A-35A, wherein a platinum-based agent is further administered prior to surgical resection of one or more tumors associated with said cancer.

[0243] Embodiment 37A. The method of any one of Embodiments 1A-36A, wherein the subject has not undergone prior treatment for the cancer.

[0244] The method of any one of embodiments 1A to 31A, which is an adjuvant therapy for said cancer.

[0245] Embodiment 39A. The method of embodiment 38A, wherein the antibody-drug conjugate is administered and the radiation therapy is performed after surgical intervention for the cancer.

[0246] Embodiment 40A. The method of embodiment 38A or 39A, wherein a platinum-based agent is further administered after the surgical intervention for said cancer.

[0247] Embodiment 41A. The method of any one of embodiments 38A-40A, wherein the antibody-drug conjugate is administered and the radiation therapy is performed after surgical resection of one or more tumors associated with the cancer.

[0248] Embodiment 42A. The method of any one of embodiments 38A-41A, wherein a platinum-based agent is further administered following surgical resection of one or more tumors associated with said cancer.

[0249] Embodiment 43A. The method of any one of embodiments 1A to 42A, wherein the anti-TF antibody or antigen-binding fragment thereof of the antibody-drug conjugate is a monoclonal antibody or a monoclonal antigen-binding fragment thereof.

[0250] Embodiment 44A. The anti-TF antibody or antigen-binding fragment thereof of the antibody-drug conjugate comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising: (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 wherein the CDRs of the anti-TF antibody or antigen-binding fragment thereof are defined according to the IMGT numbering scheme.

[0251] Embodiment 45A. The method of any one of embodiments 1A to 44A, wherein the anti-TF 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.

[0252] Embodiment 46A. The method of any one of embodiments 1A to 45A, wherein the anti-TF 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.

[0253] Embodiment 47A. The method according to any one of embodiments 1A to 46A, wherein the anti-TF antibody of the antibody-drug conjugate is tisotumab.

[0254] Embodiment 48A. The method of any one of embodiments 1A to 47A, wherein the antibody-drug conjugate further comprises a linker between the anti-TF antibody or antigen-binding fragment thereof and the auristatin.

[0255] Embodiment 49A. The method of embodiment 48A, wherein the linker is a cleavable peptide linker.

[0256] Embodiment 50A. The cleavable peptide linker has the formula: -MC-vc-PAB-, wherein: a) MC is TIFF2025515166000021.tif28128, b) vc is the dipeptide valine-citrulline; c) PAB is The method of embodiment 49A, wherein the image is TIFF2025515166000022.tif27128.

[0257] Embodiment 51A. The method according to any one of embodiments 48A to 50A, wherein the linker is attached to a sulfhydryl residue of the anti-TF antibody obtained by partial or complete reduction of the anti-TF antibody or antigen-binding fragment thereof.

[0258] Embodiment 52A. The linker is attached to MMAE and the antibody-drug conjugate has the following structure: TIFF2025515166000023.tif27142, wherein p represents a number from 1 to 8, S represents a sulfhydryl residue of said anti-TF antibody, and Ab represents said anti-TF antibody or an antigen-binding fragment thereof.

[0259] Embodiment 53A. The method of embodiment 52A, wherein the average value of p in the population of antibody-drug conjugates is about 4.

[0260] Embodiment 54A. The method of any one of embodiments 1A to 53A, wherein the antibody-drug conjugate is tisotumab vedotin.

[0261] Embodiment 55A. The method according to any one of embodiments 1A to 54A, wherein the route of administration of the antibody-drug conjugate is intravenous.

[0262] Embodiment 56A. The method of any one of Embodiments 15A to 55A, wherein the platinum-based agent is selected from the group consisting of carboplatin, cisplatin, oxaliplatin, and nedaplatin.

[0263] Embodiment 57A. The method of any one of embodiments 15A to 56A, wherein the platinum-based agent is carboplatin.

[0264] Embodiment 58A. The method of any one of embodiments 15A to 56A, wherein the platinum-based agent is cisplatin.

[0265] Embodiment 59A. The method of any one of embodiments 15A to 58A, wherein the route of administration of the platinum-based agent is intravenous.

[0266] Embodiment 60A. The method of any one of embodiments 15A to 59A, wherein the platinum-based drug and the antibody-drug conjugate are administered sequentially.

[0267] Embodiment 61A. The method of any one of embodiments 15A to 59A, wherein the platinum-based drug and the antibody-drug conjugate are administered simultaneously.

[0268] Embodiment 62A. The method of any one of embodiments 1A to 61A, wherein the subject is a human.

[0269] Embodiment 63A. The method of any one of embodiments 1A to 62A, wherein the antibody-drug conjugate is in a pharmaceutical composition comprising the antibody-drug conjugate and a pharma- ceutically acceptable carrier.

[0270] Embodiment 64A. The method of any one of Embodiments 15A to 63A, wherein the platinum-based drug is in a pharmaceutical composition comprising the platinum-based drug and a pharma- ceutically acceptable carrier.

[0271] B. Antibody-Drug Conjugates for Use Embodiment 1B. An antibody-drug conjugate that binds TF for use in treating cancer in a subject, wherein the antibody-drug conjugate is or is to be administered in combination with radiation therapy, and wherein the antibody-drug conjugate comprises an anti-TF antibody, or antigen-binding fragment thereof, conjugated to an auristatin, or a functional analogue or derivative thereof.

[0272] Aspect 2B. The antibody-drug conjugate for use according to aspect 1B, wherein said auristatin is monomethylauristatin or a functional analogue or a functional derivative thereof.

[0273] Embodiment 3B. The antibody-drug conjugate for use according to embodiment 1B or 2B, wherein said auristatin is monomethylauristatin E (MMAE).

[0274] Aspect 4B. The antibody-drug conjugate for use according to any one of Aspects 1B to 3B, wherein said antibody-drug conjugate is administered at a dose ranging from about 0.9 mg / kg to about 2.1 mg / kg.

[0275] Aspect 5B. The antibody-drug conjugate for use according to any one of Aspects 1B to 4B, wherein said antibody-drug conjugate is administered at a dose ranging from about 0.9 mg / kg to about 1.7 mg / kg.

[0276] Embodiment 6B. An antibody-drug conjugate for use according to embodiment 4B or 5B, wherein said antibody-drug conjugate is administered at a dose of about 1.3 mg / kg.

[0277] Embodiment 7B. An antibody-drug conjugate for use according to embodiment 4B or 5B, wherein said antibody-drug conjugate is administered at a dose of about 1.7 mg / kg.

[0278] Embodiment 8B. An antibody-drug conjugate for use according to embodiment 4B, wherein said antibody-drug conjugate is administered at a dose of about 2.0 mg / kg.

[0279] Embodiment 9B. The antibody-drug conjugate for use according to any one of embodiments 1B to 8B, wherein said antibody-drug conjugate is administered about once per week, about once per two weeks, about once per three weeks, or about once per four weeks.

[0280] Embodiment 10B. An antibody-drug conjugate for use according to any one of embodiments 1B to 9B, wherein said antibody-drug conjugate is administered about once every two weeks.

[0281] Embodiment 11B. An antibody-drug conjugate for use according to any one of embodiments 1B to 9B, wherein said antibody-drug conjugate is administered about once every three weeks.

[0282] Aspect 12B. The antibody-drug conjugate for use according to any one of Aspects 1B to 11B, wherein the radiation therapy is administered at a dose of about 1 Gy to about 100 Gy, such as at a dose of about 10 Gy to about 70 Gy, such as at a dose of about 30 Gy to about 60 Gy, such as at a dose of about 40 Gy to about 50 Gy.

[0283] Embodiment 13B. The antibody-drug conjugate for use according to any one of embodiments 1B to 12B, wherein said radiation therapy is selected from the group consisting of intensity modulated radiation therapy (IMRT), image guided radiation therapy (IGRT), tomotherapy, stereotactic radiosurgery, stereotactic body radiation therapy, photon beam, electron beam, and proton beam therapy.

[0284] Embodiment 14B. The antibody-drug conjugate for use according to any one of Embodiments 1B to 13B, wherein said method further comprises administering to said subject a chemotherapeutic agent.

[0285] Embodiment 15B. The antibody-drug conjugate for use according to embodiment 14B, wherein said chemotherapeutic agent is a platinum-based agent.

[0286] Embodiment 16B. The antibody-drug conjugate for use according to embodiment 15B, wherein said platinum-based drug is administered at a dose of AUC=about 4 to AUC=about 6.

[0287] Embodiment 17B. The antibody-drug conjugate for use according to embodiment 15B or 16B, wherein said platinum-based drug is administered at a dose of AUC=about 5.

[0288] Embodiment 18B. The antibody-drug conjugate for use according to any one of embodiments 15B to 17B, wherein said platinum-based agent is administered about once per week, about once per two weeks, about once per three weeks, or about once per four weeks.

[0289] Embodiment 19B. The antibody-drug conjugate for use according to any one of embodiments 15B to 18B, wherein said platinum-based drug is administered about once every three weeks.

[0290] Embodiment 20B. The antibody-drug conjugate for use according to any one of embodiments 15B to 18B, wherein said platinum-based drug is administered about once every four weeks.

[0291] Embodiment 21B. The antibody-drug conjugate for use according to any one of embodiments 1B to 20B, wherein the cancer is a solid tumor.

[0292] Embodiment 22B. The antibody-drug conjugate for use according to any one of embodiments 1B to 21B, wherein said cancer is head and neck squamous cell carcinoma.

[0293] Embodiment 23B. The antibody-drug conjugate for use according to any one of embodiments 1B to 21B, wherein said cancer is a gynecological cancer.

[0294] Embodiment 24B. The antibody-drug conjugate for use according to any one of embodiments 1B to 21B, wherein said cancer is selected from the list consisting of ovarian cancer, endometrial cancer, cervical cancer, perineal tissue cancer, fallopian tube cancer, uterine cancer, vaginal cancer, vulvar cancer, and gestational trophoblastic disease cancer.

[0295] Embodiment 25B. The antibody-drug conjugate for use according to any one of embodiments 1B to 24B, wherein the cancer is associated with a tissue factor positive primary tumor.

[0296] Embodiment 26B. The antibody-drug conjugate for use according to any one of embodiments 1B to 25B, wherein the cancer is an early stage cancer.

[0297] Embodiment 27B. The antibody-drug conjugate for use according to embodiment 26B, wherein said cancer is stage I or stage II cancer.

[0298] Embodiment 28B. The antibody-drug conjugate for use according to embodiment 26B or 27B, wherein said cancer is not a recurrent cancer.

[0299] Embodiment 29B. The antibody-drug conjugate for use according to any one of embodiments 26B to 28B, wherein the cancer is not locally advanced.

[0300] Embodiment 30B. The antibody-drug conjugate for use according to any one of embodiments 26B to 29B, wherein the cancer is not metastatic.

[0301] Embodiment 31B. The antibody-drug conjugate for use according to any one of embodiments 26B to 28B, wherein the cancer is locally advanced.

[0302] Embodiment 32B. The antibody-drug conjugate for use according to any one of embodiments 1B to 31B, wherein said method of treatment is a neoadjuvant treatment for said cancer.

[0303] Embodiment 33B. An antibody-drug conjugate for use according to embodiment 32B, wherein said antibody-drug conjugate is administered and said radiation therapy is performed prior to surgical intervention against said cancer.

[0304] Embodiment 34B. The antibody-drug conjugate for use according to embodiment 32B or 33B, further comprising administering a platinum-based agent prior to surgical intervention for said cancer.

[0305] Embodiment 35B. The antibody-drug conjugate for use according to embodiment 33B or 34B, wherein the antibody-drug conjugate is administered and the radiation therapy is performed prior to surgical resection of one or more tumors associated with said cancer.

[0306] Embodiment 36B. The antibody-drug conjugate for use according to any one of Embodiments 33B to 35B, further comprising administering a platinum-based agent prior to surgical resection of one or more tumors associated with said cancer.

[0307] Embodiment 37B. The antibody-drug conjugate for use according to any one of embodiments 1B to 36B, wherein the subject has not undergone prior treatment for the cancer.

[0308] Embodiment 38B. The antibody-drug conjugate for use according to any one of embodiments 1B to 31B, wherein said method of treatment is an adjuvant treatment for said cancer.

[0309] Embodiment 39B. An antibody-drug conjugate for use according to embodiment 38B, wherein said antibody-drug conjugate is administered and radiation therapy is performed after surgical intervention against said cancer.

[0310] Embodiment 40B. The antibody-drug conjugate for use according to embodiment 38B or 39B, further wherein said platinum-based agent is administered after a surgical intervention for said cancer.

[0311] Embodiment 41B. The antibody-drug conjugate for use according to any one of embodiments 38B to 40B, wherein the antibody-drug conjugate is administered and the radiation therapy is performed after surgical resection of one or more tumors associated with the cancer.

[0312] Embodiment 42B. The antibody-drug conjugate for use according to any one of embodiments 38B to 41B, further comprising administering a platinum-based agent following surgical resection of one or more tumors associated with said cancer.

[0313] Embodiment 43B. An antibody-drug conjugate for use according to any one of embodiments 1B to 42B, wherein said anti-TF antibody or antigen-binding fragment thereof of said antibody-drug conjugate is a monoclonal antibody or a monoclonal antigen-binding fragment thereof.

[0314] Embodiment 44B. The anti-TF antibody or antigen-binding fragment thereof of the antibody-drug conjugate comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising: (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) a 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) a CDR-L3 comprising the amino acid sequence of SEQ ID NO:6; and the CDRs of the anti-TF antibody or antigen-binding fragment thereof are defined according to the IMGT numbering scheme.

[0315] Embodiment 45B. An antibody-drug conjugate for use in any one of embodiments 1B to 44B, wherein the anti-TF antibody or antigen-binding fragment thereof of said 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.

[0316] Embodiment 46B. An antibody-drug conjugate for use in any one of embodiments 1B to 45B, wherein said anti-TF antibody or antigen-binding fragment thereof of said 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.

[0317] Embodiment 47B. An antibody-drug conjugate for use according to any one of embodiments 1B to 46B, wherein said anti-TF antibody of said antibody-drug conjugate is tisotumab.

[0318] Embodiment 48B. The antibody-drug conjugate for use of any one of embodiments 1B to 47B, wherein said antibody-drug conjugate further comprises a linker between said anti-TF antibody or antigen-binding fragment thereof and said auristatin.

[0319] Embodiment 49B. The antibody-drug conjugate for use in embodiment 48B, wherein said linker is a cleavable peptide linker.

[0320] Embodiment 50B. The cleavable peptide linker has the formula: -MC-vc-PAB-, wherein a) MC is TIFF2025515166000024.tif28128, b) vc is the dipeptide valine-citrulline; c) PAB is The antibody-drug conjugate for use in embodiment 49B, which is TIFF2025515166000025.tif27128.

[0321] Embodiment 51B. An antibody-drug conjugate for use according to any one of embodiments 48B to 50B, wherein the linker is attached to a sulfhydryl residue of the anti-TF antibody obtained by partial or complete reduction of the anti-TF antibody or antigen-binding fragment thereof.

[0322] Embodiment 52B. The linker is attached to MMAE and the antibody-drug conjugate has the following structure: TIFF2025515166000026.tif27142, wherein p represents a number from 1 to 8, S represents a sulfhydryl residue of said anti-TF antibody, and Ab represents said anti-TF antibody or an antigen-binding fragment thereof.

[0323] Embodiment 53B. An antibody-drug conjugate for use in embodiment 52B, wherein the average value of p in the population of said antibody-drug conjugates is about 4.

[0324] Embodiment 54B. The antibody-drug conjugate for use in any one of embodiments 1B to 53B, wherein said antibody-drug conjugate is tisotumab vedotin.

[0325] Embodiment 55B. An antibody-drug conjugate for use in any one of embodiments 1B to 54B, wherein the route of administration of said antibody-drug conjugate is intravenous.

[0326] Embodiment 56B. The antibody-drug conjugate for use of any one of Embodiments 15B to 55B, wherein said platinum-based agent is selected from the group consisting of carboplatin, cisplatin, oxaliplatin, and nedaplatin.

[0327] Embodiment 57B. The antibody-drug conjugate for use of any one of embodiments 15B to 56B, wherein said platinum-based agent is carboplatin.

[0328] Embodiment 58B. The antibody-drug conjugate for use in any one of embodiments 15B to 56B, wherein said platinum-based agent is cisplatin.

[0329] Embodiment 59B. The antibody-drug conjugate for use in any one of embodiments 15B to 58B, wherein the route of administration of said platinum-based agent is intravenous.

[0330] Embodiment 60B. The antibody-drug conjugate for use in any one of embodiments 15B to 59B, wherein said platinum-based drug and said antibody-drug conjugate are administered sequentially.

[0331] Embodiment 61B. The antibody-drug conjugate for use in any one of embodiments 15B to 59B, wherein said platinum-based agent and said antibody-drug conjugate are administered simultaneously.

[0332] Embodiment 62B. The antibody-drug conjugate for use of any one of embodiments 1B to 61B, wherein the subject is a human.

[0333] Embodiment 63B. The antibody-drug conjugate for use of any one of Embodiments 1B to 62B, wherein said antibody-drug conjugate is present as a pharmaceutical composition comprising the antibody-drug conjugate and a pharma- ceutically acceptable carrier.

[0334] Embodiment 64B. The antibody-drug conjugate for use of any one of Embodiments 15B to 63B, wherein said platinum-based drug is present as a pharmaceutical composition comprising said platinum-based drug and a pharma- ceutically acceptable carrier.

[0335] C. Use of Antibody-Drug Conjugates Embodiment 1C. Use of an antibody-drug conjugate that binds TF for the manufacture of a medicament for treating cancer in a subject, the medicament for use in combination with radiation therapy, the antibody-drug conjugate comprising an anti-TF antibody, or an antigen-binding fragment thereof, conjugated to an auristatin, or a functional analogue or functional derivative thereof.

[0336] Aspect 2C. The use of Aspect 1C, wherein said auristatin is monomethylauristatin or a functional analog or derivative thereof.

[0337] Aspect 3C. The use of Aspect 1C or 2C, wherein said auristatin is monomethylauristatin E (MMAE).

[0338] Aspect 4C. The use of any one of Aspects 1C to 3C, wherein the antibody-drug conjugate is administered at a dose ranging from about 0.9 mg / kg to about 2.1 mg / kg.

[0339] Aspect 5C. The use of any one of Aspects 1C to 4C, wherein the antibody-drug conjugate is administered at a dose ranging from about 0.9 mg / kg to about 1.7 mg / kg.

[0340] Embodiment 6C. The use of embodiment 4C or 5C, wherein said antibody-drug conjugate is administered at a dose of about 1.3 mg / kg.

[0341] Embodiment 7C. The use of embodiment 4C or 5C, wherein said antibody-drug conjugate is administered at a dose of about 1.7 mg / kg.

[0342] The use of embodiment 4C, wherein the antibody-drug conjugate is administered at a dose of about 2.0 mg / kg.

[0343] Embodiment 9C. The use of any one of embodiments 1C to 8C, wherein the antibody-drug conjugate is administered about once per week, about once per two weeks, about once per three weeks, or about once per four weeks.

[0344] Embodiment 10C. The use of any one of embodiments 1C to 9C, wherein the antibody-drug conjugate is administered about once every two weeks.

[0345] Embodiment 11C. The use of any one of embodiments 1C to 9C, wherein the antibody-drug conjugate is administered about once every three weeks.

[0346] Aspect 12C. The use according to any one of Aspects 1C to 11C, wherein the radiation therapy is administered at a dose of about 1 Gy to about 100 Gy, such as at a dose of about 10 Gy to about 70 Gy, such as at a dose of about 30 Gy to about 60 Gy, such as at a dose of about 40 Gy to about 50 Gy.

[0347] Aspect 13C. The use of any one of Aspects 1C to 12C, wherein the radiation therapy is selected from the group consisting of intensity modulated radiation therapy (IMRT), image guided radiation therapy (IGRT), tomotherapy, stereotactic radiosurgery, stereotactic body radiation therapy, photon beam, electron beam, and proton beam therapy.

[0348] Embodiment 14C. The use of any one of embodiments 1C to 13C, wherein the method further comprises administering to the subject a chemotherapeutic agent.

[0349] Embodiment 15C. The use of embodiment 14C, wherein the chemotherapeutic agent is a platinum-based agent.

[0350] The use of embodiment 15C, wherein the platinum-based drug is administered at a dose of AUC=about 4 to AUC=about 6.

[0351] The use of embodiment 15C or 16C, wherein the platinum-based agent is administered at a dose of AUC=about 5.

[0352] Embodiment 18C. The use of any one of Embodiments 15C to 17C, wherein the platinum-based agent is administered about once per week, about once every two weeks, about once every three weeks, or about once every four weeks.

[0353] Embodiment 19C. The use of any one of embodiments 15C to 18C, wherein the platinum-based agent is administered about once every three weeks.

[0354] Embodiment 20C. The use of any one of embodiments 15C to 18C, wherein the platinum-based agent is administered about once every four weeks.

[0355] Embodiment 21C. The use of any one of embodiments 1C to 20C, wherein the cancer is a solid tumor.

[0356] Embodiment 22C. The use of any one of embodiments 1C to 21C, wherein the cancer is head and neck squamous cell carcinoma.

[0357] Embodiment 23C. The use of any one of embodiments 1C to 21C, wherein the cancer is a gynecological cancer.

[0358] Embodiment 24C. The use of any one of embodiments 1C to 21C, wherein said cancer is selected from the list consisting of ovarian cancer, endometrial cancer, cervical cancer, perineal tissue cancer, fallopian tube cancer, uterine cancer, vaginal cancer, vulvar cancer, and gestational trophoblastic disease cancer.

[0359] Embodiment 25C. The use of any one of embodiments 1C to 24C, wherein the cancer is associated with a tissue factor positive primary tumor.

[0360] Embodiment 26C. The use of any one of embodiments 1C to 25C, wherein the cancer is an early stage cancer.

[0361] Embodiment 27C. The use of embodiment 26C, wherein the cancer is stage I or stage II cancer.

[0362] Embodiment 28C. The use of embodiment 26C or 27C, wherein the cancer is not a recurrent cancer.

[0363] Embodiment 29C. The use of any one of embodiments 26C to 28C, wherein the cancer is not locally advanced.

[0364] Embodiment 30C. The use of any one of embodiments 26C to 29C, wherein the cancer is not metastatic.

[0365] Embodiment 31C. The use of any one of embodiments 26C to 28C, wherein the cancer is locally advanced.

[0366] Aspect 32C. The use of any one of Aspects 1C to 31C, wherein the method of treatment is a neoadjuvant treatment for the cancer.

[0367] Embodiment 33C. The use according to embodiment 32C, wherein the antibody-drug conjugate is administered and the radiation therapy is performed prior to surgical intervention against the cancer.

[0368] Embodiment 34C. The use of embodiment 32C or 33C, further comprising administering a platinum-based agent prior to surgical intervention for said cancer.

[0369] Embodiment 35C. The use of embodiment 33C or 34C, wherein the antibody-drug conjugate is administered and the radiation therapy is performed prior to surgical resection of one or more tumors associated with the cancer.

[0370] Embodiment 36C. The use of any one of embodiments 33C to 35C, further comprising administering a platinum-based agent prior to surgical resection of one or more tumors associated with said cancer.

[0371] Embodiment 37C. The use of any one of embodiments 1C to 36C, wherein the subject has not undergone prior treatment for the cancer.

[0372] Embodiment 38C. The use of any one of embodiments 1C to 31C, wherein the method of treatment is an adjuvant treatment for the cancer.

[0373] Embodiment 39C. The use according to embodiment 38C, wherein the antibody-drug conjugate is administered and the radiation therapy is performed after surgical intervention against the cancer.

[0374] Embodiment 40C. The use of embodiment 38C or 39C, further comprising administering a platinum-based agent following surgical intervention for said cancer.

[0375] Embodiment 41C. The use of any one of embodiments 38C to 40C, wherein the antibody-drug conjugate is administered and the radiation therapy is performed after surgical resection of one or more tumors associated with the cancer.

[0376] Embodiment 42C. The use of any one of embodiments 38C to 41C, further comprising administering a platinum-based agent following surgical resection of one or more tumors associated with said cancer.

[0377] Embodiment 43C. The use according to any one of embodiments 1C to 42C, wherein the anti-TF antibody or antigen-binding fragment thereof of the antibody-drug conjugate is a monoclonal antibody or a monoclonal antigen-binding fragment thereof.

[0378] Embodiment 44C. The use according to any one of embodiments 1C to 43C, wherein the anti-TF antibody or antigen-binding fragment thereof of the antibody-drug conjugate comprises 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 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, wherein the CDRs of the anti-TF antibody or antigen-binding fragment thereof are defined according to the IMGT numbering scheme.

[0379] Embodiment 45C. The use of any one of embodiments 1C to 44C, wherein the anti-TF 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.

[0380] Embodiment 46C. The use of any one of embodiments 1C to 45C, wherein the anti-TF 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.

[0381] Embodiment 47C. The use of any one of embodiments 1C to 46C, wherein the anti-TF antibody of the antibody-drug conjugate is tisotumab.

[0382] Embodiment 48C. The use of any one of embodiments 1C to 47C, wherein the antibody-drug conjugate further comprises a linker between the anti-TF antibody or antigen-binding fragment thereof and the auristatin.

[0383] Embodiment 49C. The use of embodiment 48C, wherein said linker is a cleavable peptide linker.

[0384] Embodiment 50C. The cleavable peptide linker has the formula: -MC-vc-PAB-, wherein a) MC is TIFF2025515166000027.tif28128, b) vc is the dipeptide valine-citrulline; c) PAB is Use of embodiment 49C, which is TIFF2025515166000028.tif27128.

[0385] Embodiment 51C. The use of any one of embodiments 48C to 50C, wherein the linker is attached to a sulfhydryl residue of the anti-TF antibody obtained by partial or complete reduction of the anti-TF antibody or antigen-binding fragment thereof.

[0386] Embodiment 52C. The linker is attached to MMAE and the antibody-drug conjugate has the following structure: TIFF2025515166000029.tif27142, wherein p represents a number from 1 to 8, S represents a sulfhydryl residue of said anti-TF antibody, and Ab represents said anti-TF antibody or an antigen-binding fragment thereof.

[0387] Embodiment 53C. The use of embodiment 52C, wherein the average value of p in the population of antibody-drug conjugates is about 4.

[0388] Embodiment 54C. The use of any one of embodiments 1C to 53C, wherein the antibody-drug conjugate is tisotumab vedotin.

[0389] Embodiment 55C. The use of any one of embodiments 1C to 54C, wherein the route of administration of the antibody-drug conjugate is intravenous.

[0390] Embodiment 56C. The use of any one of embodiments 15C to 55C, wherein said platinum-based agent is selected from the group consisting of carboplatin, cisplatin, oxaliplatin, and nedaplatin.

[0391] Embodiment 57C. The use of any one of embodiments 15C to 56C, wherein the platinum-based agent is carboplatin.

[0392] Embodiment 58C. The use of any one of embodiments 15C to 56C, wherein the platinum-based agent is cisplatin.

[0393] Embodiment 59C. The use of any one of embodiments 15C to 58C, wherein the route of administration of the platinum-based agent is intravenous.

[0394] Embodiment 60C. The use of any one of embodiments 15C to 59C, wherein the platinum-based drug and the antibody-drug conjugate are administered sequentially.

[0395] Embodiment 61C. The use of any one of embodiments 15C to 59C, wherein said platinum-based drug and said antibody-drug conjugate are administered simultaneously.

[0396] Embodiment 62C. The use of any one of embodiments 1C to 61C, wherein the subject is a human.

[0397] Embodiment 63C. The use of any one of embodiments 1C to 62C, wherein the antibody-drug conjugate is present as a pharmaceutical composition comprising the antibody-drug conjugate and a pharma- ceutically acceptable carrier.

[0398] Embodiment 64C. The use of any one of Embodiments 15C to 63C, wherein the platinum-based agent is present as a pharmaceutical composition comprising the platinum-based agent and a pharma- ceutically acceptable carrier.

[0399] D. Use of Antibody-Drug Conjugates Aspect 1D. Use of an antibody-drug conjugate that binds TF to treat cancer in a subject, the use being in combination with radiation therapy, the antibody-drug conjugate comprising an anti-TF antibody, or an antigen-binding fragment thereof, conjugated to an auristatin, or a functional analogue or derivative thereof.

[0400] Aspect 2D. The use of aspect 1D, wherein said auristatin is monomethylauristatin or a functional analog or derivative thereof.

[0401] Embodiment 3D. The use of embodiment 1D or 2D, wherein said auristatin is monomethylauristatin E (MMAE).

[0402] Aspect 4D. The use of any one of Aspects 1D to 3D, wherein the antibody-drug conjugate is administered at a dose ranging from about 0.9 mg / kg to about 2.1 mg / kg.

[0403] Aspect 5D. The use of any one of Aspects 1D to 4D, wherein the antibody-drug conjugate is administered at a dose ranging from about 0.9 mg / kg to about 1.7 mg / kg.

[0404] Embodiment 6D. The use of embodiment 4D or 5D, wherein said antibody-drug conjugate is administered at a dose of about 1.3 mg / kg.

[0405] Embodiment 7D. The use of embodiment 4D or 5D, wherein said antibody-drug conjugate is administered at a dose of about 1.7 mg / kg.

[0406] Embodiment 8D. The use of embodiment 4D, wherein said antibody-drug conjugate is administered at a dose of about 2.0 mg / kg.

[0407] Embodiment 9D. The use of any one of embodiments 1D-8D, wherein the antibody-drug conjugate is administered about once per week, about once per two weeks, about once per three weeks, or about once per four weeks.

[0408] Aspect 10D. The use of any one of aspects 1D to 9D, wherein the antibody-drug conjugate is administered about once every two weeks.

[0409] Aspect 11D. The use of any one of aspects 1D to 9D, wherein the antibody-drug conjugate is administered about once every three weeks.

[0410] Aspect 12D. The use according to any one of Aspects 1D to 11D, wherein the radiation therapy is administered at a dose of about 1 Gy to about 100 Gy, such as at a dose of about 10 Gy to about 70 Gy, such as at a dose of about 30 Gy to about 60 Gy, such as at a dose of about 40 Gy to about 50 Gy.

[0411] Aspect 13D. The use of any one of aspects 1D to 12D, wherein the radiation therapy is selected from the group consisting of intensity modulated radiation therapy (IMRT), image guided radiation therapy (IGRT), tomotherapy, stereotactic radiosurgery, stereotactic body radiation therapy, photon beam, electron beam, and proton beam therapy.

[0412] Embodiment 14D. The use of any one of embodiments 1D to 13D, wherein the method further comprises administering to the subject a chemotherapeutic agent.

[0413] The use of embodiment 14D, wherein the chemotherapeutic agent is a platinum-based agent.

[0414] The use of embodiment 15D, wherein the platinum-based drug is administered at a dose of AUC=about 4 to AUC=about 6.

[0415] The use of embodiment 15D or 16D, wherein the platinum-based agent is administered at a dose of AUC=about 5.

[0416] Embodiment 18D. The use of any one of embodiments 15D to 17D, wherein the platinum-based agent is administered about once per week, about once every two weeks, about once every three weeks, or about once every four weeks.

[0417] Embodiment 19D. The use of any one of embodiments 15D to 18D, wherein the platinum-based agent is administered about once every three weeks.

[0418] Embodiment 20D. The use of any one of embodiments 15D to 18D, wherein the platinum-based agent is administered about once every four weeks.

[0419] Embodiment 21D. The use of any one of embodiments 1D to 20D, wherein the cancer is a solid tumor.

[0420] Embodiment 22D. The use of any one of embodiments 1D to 21D, wherein the cancer is head and neck squamous cell carcinoma.

[0421] Embodiment 23D. The use of any one of embodiments 1D to 21D, wherein the cancer is a gynecological cancer.

[0422] Embodiment 24D. The use of any one of embodiments 1D to 21D, wherein said cancer is selected from the list consisting of ovarian cancer, endometrial cancer, cervical cancer, perineal tissue cancer, fallopian tube cancer, uterine cancer, vaginal cancer, vulvar cancer, and gestational trophoblastic disease cancer.

[0423] Embodiment 25D. The use of any one of embodiments 1D to 24D, wherein the cancer is associated with a tissue factor positive primary tumor.

[0424] Embodiment 26D. The use of any one of embodiments 1D to 25D, wherein the cancer is an early stage cancer.

[0425] Embodiment 27D. The use of embodiment 26D, wherein the cancer is stage I or stage II cancer.

[0426] Embodiment 28D. The use of embodiment 26D or 27D, wherein the cancer is not a recurrent cancer.

[0427] Embodiment 29D. The use of any one of embodiments 26D to 28D, wherein the cancer is not locally advanced.

[0428] Embodiment 30D. The use of any one of embodiments 26D to 29D, wherein the cancer is not metastatic.

[0429] Embodiment 31D. The use of any one of embodiments 26D to 28D, wherein the cancer is locally advanced.

[0430] Aspect 32D. The use of any one of Aspects 1D to 31D, wherein the method of treatment is a neoadjuvant treatment for the cancer.

[0431] Embodiment 33D. The use according to embodiment 32D, wherein the antibody-drug conjugate is administered and the radiation therapy is performed prior to surgical intervention against the cancer.

[0432] Embodiment 34D. The use of embodiment 32D or 33D, further comprising administering a platinum-based agent prior to surgical intervention for said cancer.

[0433] Embodiment 35D. The use of embodiment 33D or 34D, wherein the antibody-drug conjugate is administered and the radiation therapy is performed prior to surgical resection of one or more tumors associated with the cancer.

[0434] Embodiment 36D. The use of any one of embodiments 33D to 35D, further comprising administering a platinum-based agent prior to surgical resection of one or more tumors associated with said cancer.

[0435] Embodiment 37D. The use of any one of embodiments 1D to 36D, wherein the subject has not undergone prior treatment for the cancer.

[0436] Embodiment 38D. The use of any one of embodiments 1D to 31D, wherein the method of treatment is an adjuvant treatment for the cancer.

[0437] Embodiment 39D. The use according to embodiment 38D, wherein the antibody-drug conjugate is administered and the radiation therapy is performed after a surgical intervention against the cancer.

[0438] Embodiment 40D. The use of embodiment 38D or 39D, further comprising administering a platinum-based agent following surgical intervention for said cancer.

[0439] Embodiment 41D. The use of any one of embodiments 38D to 40D, wherein the antibody-drug conjugate is administered and the radiation therapy is performed after surgical resection of one or more tumors associated with the cancer.

[0440] Embodiment 42D. The use of any one of embodiments 38D to 41D, further comprising administering a platinum-based agent following surgical resection of one or more tumors associated with said cancer.

[0441] Embodiment 43D. The use of any one of embodiments 1D to 42D, wherein the anti-TF antibody or antigen-binding fragment thereof of the antibody-drug conjugate is a monoclonal antibody or a monoclonal antigen-binding fragment thereof.

[0442] Embodiment 44D. The use according to any one of embodiments 1D to 43D, wherein the anti-TF antibody or antigen-binding fragment thereof of the antibody-drug conjugate comprises 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 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, wherein the CDRs of the anti-TF antibody or antigen-binding fragment thereof are defined according to the IMGT numbering scheme.

[0443] Embodiment 45D. The use of any one of embodiments 1D to 44D, wherein the anti-TF antibody or antigen-binding fragment thereof of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is 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 that is at least 85% identical to the amino acid sequence of SEQ ID NO:8.

[0444] Embodiment 46D. The use of any one of embodiments 1D to 45D, wherein the anti-TF 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.

[0445] Embodiment 47D. The use of any one of embodiments 1D to 46D, wherein the anti-TF antibody of the antibody-drug conjugate is tisotumab.

[0446] Embodiment 48D. The use of any one of embodiments 1D to 47D, wherein the antibody-drug conjugate further comprises a linker between the anti-TF antibody or antigen-binding fragment thereof and the auristatin.

[0447] Embodiment 49D. The use according to embodiment 48D, wherein the linker is a cleavable peptide linker.

[0448] Embodiment 50D. The cleavable peptide linker has the formula: -MC-vc-PAB-, wherein a) MC is TIFF2025515166000030.tif28128, b) vc is the dipeptide valine-citrulline; c) PAB is The use according to embodiment 49D, wherein the image is TIFF2025515166000031.tif27128.

[0449] Embodiment 51D. The use according to any one of embodiments 48D to 50D, wherein the linker is attached to a sulfhydryl residue of the anti-TF antibody obtained by partial or complete reduction of the anti-TF antibody or antigen-binding fragment thereof.

[0450] Embodiment 52D. The linker is attached to MMAE and the antibody-drug conjugate has the structure: TIFF2025515166000032.tif27142, wherein p represents a number from 1 to 8, S represents a sulfhydryl residue of said anti-TF antibody, and Ab represents said anti-TF antibody or an antigen-binding fragment thereof.

[0451] Embodiment 53D. The use according to embodiment 52D, wherein the average value of p in the population of antibody-drug conjugates is about 4.

[0452] Embodiment 54D. The use of any one of embodiments 1D to 53D, wherein the antibody-drug conjugate is tisotumab vedotin.

[0453] Embodiment 55D. The use according to any one of embodiments 1D to 54D, wherein the route of administration of the antibody-drug conjugate is intravenous.

[0454] Embodiment 56D. The use of any one of embodiments 15D to 55D, wherein the platinum-based agent is selected from the group consisting of carboplatin, cisplatin, oxaliplatin, and nedaplatin.

[0455] Embodiment 57D. The use of any one of embodiments 15D to 56D, wherein the platinum-based agent is carboplatin.

[0456] Embodiment 58D. The use of any one of embodiments 15D to 56D, wherein the platinum-based agent is cisplatin.

[0457] Embodiment 59D. The use of any one of embodiments 15D to 58D, wherein the route of administration of the platinum-based agent is intravenous.

[0458] Embodiment 60D. The use of any one of embodiments 15D to 59D, wherein the platinum-based drug and the antibody-drug conjugate are administered sequentially.

[0459] Embodiment 61D. The use of any one of embodiments 15D to 59D, wherein the platinum-based drug and the antibody-drug conjugate are administered simultaneously.

[0460] Embodiment 62D. The use according to any one of embodiments 1D to 61D, wherein the subject is a human.

[0461] Embodiment 63D. The use of any one of embodiments 1D to 62D, wherein the antibody-drug conjugate is in a pharmaceutical composition comprising the antibody-drug conjugate and a pharma- ceutically acceptable carrier.

[0462] Embodiment 64D. The use of any one of embodiments 15D to 63D, wherein the platinum-based agent is in a pharmaceutical composition comprising the platinum-based agent and a pharma- ceutically acceptable carrier. EXAMPLES

[0463] The present application can be better understood by reference to the following non-limiting examples, which are provided as exemplary embodiments of the present application. The following examples are presented to more fully explain the embodiments and should not be construed as limiting the broad scope of the present application. Although specific embodiments of the present application have been shown and described herein, it will be apparent that such embodiments are provided by way of example only. Numerous variations, modifications, and substitutions will occur to those skilled in the art without departing from the spirit and scope of the present invention. It should be understood that various alternatives to the embodiments described herein may be employed when carrying out the methods described herein.

[0464] Example 1A: Increased expression of CD142 / tissue factor is associated with samples from head and neck squamous cell carcinoma. CD142, also known as tissue factor (TF), is a protein expressed in solid tumors. The tumors found in patients with HNSCC are a type of solid tumor arising from squamous epithelial cells lining the upper aerodigestive tract. In this example, experiments were performed to demonstrate that many solid tumor samples from patients with HNSCC show TF expression when analyzed by immunohistochemistry (IHC).

[0465] method: Formalin-fixed paraffin-embedded (FFPE) tumor blocks from head and neck squamous cell carcinoma (HNSCC) specimens (n=62) were cut into 3 μm thick sections, deparaffinized by incubation in xylene and graded concentrations of ethanol, and rehydrated. Antigen retrieval was performed by heat-induced epitope retrieval in sodium citrate buffer (pH 6.0) by microwave heating at 900 watts for 5 min, followed by heating at 450 watts for an additional 10 min. Endogenous peroxidase was blocked by immersion in 0.3% hydrogen peroxide in methanol for 30 min, after which samples were blocked with 10% normal goat serum (Dako, X0907) for 30 min at room temperature. Slides were incubated with CD142-FITC clone HTF-1 (MACS Miltenyi Biotec, 130-098-853) or isotype control (IgG1-FITC, Biolegend, 400107) at 5 μg / ml in antibody diluent (phosphate buffered saline (PBS) + 0.1% and 2% normal goat serum (NGS)) for 1 h at room temperature, followed by incubation with rabbit anti-FITC (Thermo Fisher, 71-1900) at 2.5 μg / ml in antibody diluent for 30 min at room temperature. Staining was performed using a ready to use poly-HRP anti-rabbit / mouse IgG solution (Immunologic DPVB55HRP, bright vision) for 30 min at room temperature and visualized with 3,3'-diaminobenzidine (DAB, Sigma, D5637). All tissue sections were briefly rinsed with water and counterstained with Mayer's hematoxylin (Merck, 092490500) for 1 min, after which the slides were rinsed again with water and mounted in Kaiser Glycerol gelatin (Merck, 1092420100).

[0466] The percentage of tumor cells within the tumor area (containing at least 100 tumor cells) of HNSCC patient tumors was estimated by an HNSCC pathologist on slides stained with hematoxylin and TF-DAB. Photographs of immunostained slides were taken using a LEICA 6000 DM microscope (LEICA, SOLMs, Germany) and Leica software. Details regarding patient samples are summarized in Table 1 below.

[0467] Table 1. Origin of tumor cells in HNSCC patients TIFF2025515166000033.tif102137

[0468] result : TF expression was observed to be variable among tissue samples (Figure 1A). The level of TF expression could be classified into five different categories (buckets), with I being negative for TF expression and II–V representing progressively increasing amounts of TF molecules (II: >0–25%, III: >25–50%, IV: >50–75%, V: >75%). Of the samples analyzed, approximately 67% of tumor specimens showed expression of TF (Figure 1B). The majority of TF-positive tumors showed up to 25% positive tumor cells (II) within the tumor area. TF, when present, was mainly localized on the membrane, sometimes coexisting with cytoplasmic localization.

[0469] Example 1B: Tissue factor (TF) is expressed in HNSCC cell culture models. HNSCC arises from human papillomavirus (HPV) infection or exposure to exogenous carcinogens. HNSCC caused by HPV is now considered a separate disease entity. In this example, experiments were performed to show that HNSCC human mucosal cell lines that are either HPV+ or HPV- have elevated TF expression compared to noncancerous primary cells.

[0470] methodPrimary human mucosal cells were isolated from resected tumor specimens of patients treated with uvulopalatopharyngeoplasty as previously described and cultured in Dulbecco's modified Eagle's medium (DMEM) containing 5% fetal bovine serum (FBS) and 2 mM L-glutamine.

[0471] Keratinocytes were cultured in serum-free keratinocyte medium (KSFM, Gibco, 17005-034) supplemented with 0.1% bovine serum albumin (BSA, Biovision), recombinant epidermal growth factor (EGF) (Gibco, 10450-013), and bovine pituitary extract (Gibco, 13028-014). HNSCC cell lines were cultured in Dulbecco's modified Eagle's medium (DMEM) containing 5% fetal bovine serum (FBS, Gibco, 10270-106) and 2 mM L-glutamine (Lonza, BE-17-605E). FaDu cell line was purchased from ATCC. The cell lines UM-SCC-14A, UM-SCC-14B, UM-SCC-22A, UM-SCC-22B, UM-SCC-47(HPV+) and UM-SCC-104(HPV+) have been described previously (Lin et al., "Head and neck squamous cell carcinoma cell lines: established models and rationale for selection", Head Neck 2007; 29:163-88). VU-SCC-017, VU-SCC-078, VU-SCC-080, VU-SCC-094, VU-SCC-096, VU-SCC-120, VU-SCC-1365, VU-SCC-OE and VU-SCC-RO cell lines have also been previously described (Hermsen et al., "Centromeric breakage as a major cause of cytogenetic abnormalities in oral squamous cell carcinoma", Genes Chromosomes Cancer 1996;15:1-9; and van Zeeburg et al., "Generation and molecular characterization of head and neck squamous cell lines of fanconi anemia patients", Cancer Res. 2005;65:1271-6). Details of the cell lines are listed in Table 2 below.

[0472] Table 2. Characteristics of HNSCC cell lines TIFF2025515166000034.tif117150+=HPV positive tumor F=Fanconi anemia HNSCC

[0473] Cell lines were verified to be authentic by microsatellite PCR profiling and TP53 sequencing. HPV status was confirmed by GP5+ / 6+ DNA PCR (Smeets et al., "A novel algorithm for reliable detection of human papillomavirus in paraffin embedded head and neck cancer specimen", Int. J. Cancer 2007;121:2465-72). All cells were maintained at 37°C with 5% CO2.

[0474] TF expression was detected on the cell surface using a mouse anti-human TF antibody (R&D systems, clone 323514, MAB2339) and mouse IgG 2a (BD Pharmingen, 555571) was used as a negative control. Expression was quantified using QIFIKIT analysis (DAKO K0078) and measured on an LSR-Fortessa™ cell analyzer (BD Biosciences, San Diego, CA) and analyzed with DIVA software version 8.0 or FCS Express 6.0.

[0475] result Except for VU-SCC-OE and VU-SCC-096, most of the HNSCC cell lines tested showed higher numbers of TF molecules compared to primary keratinocytes and fibroblasts used as normal cell references (Figure 2). TF expression was found to be highest in UM-SCC-22B and UM-SCC-104 (Figure 2).

[0476] Example 1C: Tisotumab binds to HNSCC cells expressing TF. methodThree VU-SCC cell lines with different TF expression levels were selected for further analysis. VU-SCC-OE had a TF expression level similar to non-cancerous fibroblasts, VU-SCC-078 had a slightly higher TF expression level compared to VU-SCC-OE, and VU-SCC-120 was found to be a cell line with a higher TF expression level (Figure 2). These three cell lines were cultured and subsequently assayed for binding to tisotumab. Cells were incubated with anti-human TF monoclonal antibody (tisotumab, 2 μg / ml, IgG1-1015-011, Genmab) or isotype control IgG (Genmab IgG1-b12). PE-conjugated goat (Fab')2 anti-human IgG secondary antibody (1:50, Jackson, 109-116-098) was added and cells were analyzed by flow cytometry.

[0477] result : Binding of tisotumab, the antibody moiety of tisotumab vedotin, was verified by flow cytometry on selected HNSCC cell lines that have different levels of TF molecules on the cell surface (Figure 3). Tisotumab bound tightly to the HNSCC tumor cell lines VU-SCC-078 (intermediate TF expression) and VU-SCC-120 (high levels of TF) (Figure 3). Tisotumab was still capable of binding to VU-SCC-OE, which represents HNSCC cells with low levels of TF expression (Figure 3). Staining with an IgG isotype control served as background control.

[0478] Example 2: TV induces dose-dependent tumor cell killing in HNSCC cells. In the previous example, it was shown that tisotumab can bind to TF-expressing cells derived from HNSCC. In this example, the cytotoxic effect of the antibody-drug conjugate tisotumab vedotin (TV) on HNSCC cells in culture is shown.

[0479] method: Cells were seeded on day 0 in 96-well plates (1000-6000 cells / well depending on the cell line). After overnight culture, increasing concentrations of tisotumab vedotin or the negative control isotype IgG1-vedotin (IgG1-c-b12-vc monomethyl auristatin E (MMAE)) were added to each well. On day 5, the relative number of live cells was assessed using the Cell Titer-Blue assay (Promega, Leiden, The Netherlands, G8080) according to the manufacturer's protocol and fluorescence was measured using the GloMax® Multidetection System (Promega). Staurosporine (5 μM, Sigma, UCN-01 or 56942) was used as a positive control to induce maximal cell death, and untreated cells were also used as a negative control. After subtracting background (medium only), the percentage of viable cells was calculated by the following formula: Viable Cell % = ((Mean Fluorescence Test Sample - Mean Fluorescence Staurosporine Sample) / (Mean Fluorescence Untreated Sample - Mean Fluorescence Staurosporine Sample)) * 100. Graphs represent nonlinear regression curves of log-transformed antibody concentrations using Graphpad Prism version 9.1.0 (GraphPad Software, San Diego, CA).

[0480] result Tisotumab vedotin (TV) demonstrated effective and dose-dependent killing of HNSCC cell lines (Figures 4A-4B). Effective cell killing was observed at low concentrations of TV (Figures 4A-C). Cells with low TF expression, such as primary keratinocytes and the HNSCC cell line VU-SCC-OE, showed average IC50 doses above 0.025 μg / ml, whereas HNSCC cell lines with intermediate and high levels of TF expression showed average IC50 values ​​ranging from 0.0025 to 0.007 μg / ml (Figures 4A-4C). A non-targeting isotype IgG1-vedotin control antibody did not demonstrate cell killing in HNSCC cell lines until a 100-fold increased dose was used, compared to TV (Figures 4A-4B). This indicated that binding of tisotumab vedotin to TF is essential for effective killing of HNSCC tumor cells.

[0481] Example 3A: HNSCC cells injected into mice give rise to solid tumors that express TF. In this example, it is shown that different HNSCC cell lines could be used to establish xenografts with distinct TF expression profiles.

[0482] method : Three HNSCC cell lines used to induce human xenograft tumors in mice were assessed for TF expression by flow cytometry. Cells were stained with either 7.5 μg / ml of human anti-TF antibody (CD142-FITC, Macs Miltenyi Biotec, 130-098-853) or the isotype control mouse IgG1-FITC (Biolegend, 400170). All three selected cell lines were shown to express TF (Figure 5).

[0483] Nude mice (female, athymic nu / nu, 6–8 weeks old, obtained from Envigo, Horst, The Netherlands) were housed in sterile filter-top cages under standardized environmental conditions. HNSCC cell lines FaDu, VU-SCC-OE or VU-SCC-040 were injected subcutaneously into both flanks (2 × 10 per flank). 6 The tumor cells were transplanted at an average of 100 mm 3 (40~180mm 3 Mice were treated intraperitoneally (ip) with tisotumab vedotin or isotype control (IgG1-b12-c-vcMMAE) (Figure 6). Mice were sacrificed when tumor volume reached 5 times the initial volume in one of the two flanks and / or tumor ulceration was observed, or when mice showed ≥20% weight loss or appeared moribund. Tumor volume was measured with electronic calipers (V=(L×W×H)×0.5, where V=volume, L=length, W=width, H=height) and calculated as the mean tumor(s) per mouse. Tumors with an initial volume of 40 mm were sacrificed when tumor volume reached 5 times the initial volume in one of the two flanks and / or tumor ulceration was observed, or when mice showed ≥20% weight loss or appeared moribund. Tumor volume was measured with electronic calipers (V=(L×W×H)×0.5, where V=volume, L=length, W=width, H=height) and calculated as the mean tumor(s) per mouse. 3Tumors less than 100% complete and showing no signs of growth were excluded from the analysis. Tumors from untreated tumor-bearing mice were harvested, embedded in paraffin, and analyzed for TF expression using IHC analysis as described in the previous examples. TF expression was detected with rabbit anti-FITC (Zymed) and BrightVision immunohistochemistry (IHC) detection kits using anti-CD142-FITC or isotype control (IgG1-FITC), and visualized by DAB counterstained with hematoxylin.

[0484] result : All tumors excised from xenografted mice showed expression of TF (Figure 7). FaDu and VU-SCC-040 showed abundant TF expression in culture, consistent with the high expression of TF seen in in vivo grown tumors. FaDu and VU-SCC-040 xenografts showed V>75% TF expression (Figure 7). VU-SCC-OE cell lines, which had consistently low TF expression (Figures 2 and 5), also showed fewer TF-positive tumor cells in xenograft tumors [TF expression bucket II>0-25%] (Figure 7).

[0485] Example 3B: TV monotherapy reduces tumor volume in xenografted mice by day 7. This example shows that tisotumab vedotin (TV) monotherapy inhibited tumor growth in xenograft mice.

[0486] Nude mice were injected with HNSCC cells and xenografts were established as described above in Example 3A. Xenografted mice (5 mice with 8-10 tumors per group) were treated with PBS, 2 mg / kg and 4 mg / kg tisotumab vedotin, or 4 mg / kg isotype IgG1-vedotin on days 0, 7, and 13 (FaDu) or 0, 7, and 14 (VU-SCC-OE and VU-SCC-040) (Figure 6). Tumor volumes were measured as described in previous examples. Data analysis was performed using Graph Pad Prism version 9.1.0 (GraphPad Software, San Diego, CA). Data were expressed as mean ± SD or mean ± SEM. Statistical differences were determined using the Kruskal-Wallis test and multiple comparison test (>2 groups). Improvement in overall survival (OS) was assessed using the Kaplan-Meier method and differences between groups were assessed by the Log-rank test (Mantel-Cox). A p-value <0.05 was considered significant (* p<0.05, ** p<0.01, *** p<0.001, **** p<0.0001, ns = not significant).

[0487] result : FaDu mice treated with PBS or IgG1-vedotin showed rapid tumor growth and most of the mice had to be sacrificed on day 7 (Figures 8A and 8B). Mice treated with 2 mg / kg TV showed a marked inhibition of tumor growth compared to mice in the control group, with tumor regression observed after three treatments (Figure 8A). After cessation of treatment (last treatment on day 13), tumor regrowth began, which was visible from 30 days after the start of the first treatment. Mice treated with 4 mg / kg TV showed a significant and sustained tumor regression after the first treatment (Figure 8A). Moreover, in this group, complete tumor regression was observed in all mice within 30 days, and no recurrence of tumor growth occurred until the end of the experiment (day 76) (Figure 8A). Comparison of tumor volumes between treatment groups on day 7 (the final day after all treatment groups were completed) confirmed that tumor size was significantly smaller in mice treated with tisotumab vedotin compared to isotype control or PBS (Figure 8B).

[0488] Treatment (days 0, 7, and 14) of mice bearing tumors induced by injection of the VU-SCC-OE cell line, which has low TF expression, not only showed rapid tumor growth in both control groups (mice treated with PBS or IgG1-V), but also when mice were treated with a low dose of TV (1 mg / kg) (Figures 8C and 8D). Higher treatment doses of 2 mg / kg and 4 mg / kg led to inhibition of tumor growth.

[0489] VU-SCC-040 tumor-bearing mice treated with 4 mg / kg TV showed reduced tumor growth on day 7 after a single treatment compared to mice treated with isotype control (Figures 8E and 8F). While 1 mg / kg TV monotherapy did not suppress tumor growth compared to the control group, suppression of tumor growth was observed at 2 mg / kg and especially at 4 mg / kg TV doses (Figures 8E and 8F).

[0490] Example 4: TV improves the antitumor activity of chemoradiotherapy (CRT) in vivo in HNSCC xenograft models. Concurrent chemoradiotherapy (CRT) is the current standard of care for patients with locally advanced HNSCC outside the oral cavity. However, despite this highly invasive treatment, 30-40% of patients experience tumor recurrence. In this example, TV was evaluated for its ability to preclinically inhibit tumor growth and extend survival when combined with standard chemoradiotherapy in an HNSCC xenograft model.

[0491] method :FaDu xenografts were established in nude mice (5-6 / group) as described above in Example 3. For combination therapy, mice were sacrificed when tumor volume reached 10 times the starting volume in one of the two flanks and / or tumor ulceration was observed, or when mice showed ≥20% weight loss or appeared moribund.

[0492] FaDu xenografted mice were treated with TV or isotype control (administered on days 0 and 10) 24 hours prior to CRT (CRT was performed on days 1 and 11). VU-SCC-OE xenografted mice were treated with TV or isotype (IgG1-vedotin) control (administered on days 0 and 7) 24 hours prior to CRT (CRT was performed on days 1 and 8). Mice receiving CRT were administered cisplatin (CDDP, 3 mg / kg) followed by total body irradiation (2 Gy; Varian TrueBeam™ linear accelerator) approximately 4 hours later. Tumor volumes were measured as described above, and statistical analysis was performed on collected data as described above.

[0493] result : FaDu xenografted mice from the negative control group (treated with PBS or IgG1-vedotin (IgG1-V)) showed rapid tumor growth, and treatment with CRT or IgG1-V+CRT did not significantly affect tumor growth (Figures 9A and 9B). In contrast, mice treated with a dose of 2 mg / kg TV showed reduced tumor growth compared to the IgG1-vedotin control group, although variability within treated animals was observed (Figure 9A). In this model, CRT by itself did not suppress tumor growth, but when combined with TV, a significant reduction in tumor size was observed 9 days after the first treatment compared to the control group administered IgG1-vedotin and CRT (Figures 9A and 9B).

[0494] In the VU-SCC-OE xenograft tumor model, which has low TF expression, there was no difference in tumor growth between PBS- and IgG1-vedotin-treated mice. Treatment with CRT (+ / - IgG1-V) or 2 mg / kg TV showed some inhibition of tumor growth compared to the control treatment groups (PBS and IgG1-vedotin). In contrast, the combination of CRT with 2 mg / kg TV (Figures 9C and 9D) induced tumor regression.

[0495] In FaDu xenograft mice, the combination of CRT and TV resulted in a significant increase in the overall survival rate of mice compared with the control group or CRT or TV alone, as shown by Kaplan-Meir analysis (Figure 9E).Also, in the VU-SCC-OE xenograft tumor model with low TF expression, the combination treatment significantly extended survival compared with the control group or CRT or TV alone (Figure 9F).

[0496] These data indicate that in a xenograft HNSCC model, treatment with TV exerted synergy with standard chemoradiotherapy, significantly inhibiting tumor growth and prolonging survival of tumor-bearing mice compared with chemoradiotherapy or tisotumab vedotin alone.

[0497] Example 5A: Xenografted mice show reduced tumor size and improved survival outcomes when treated with tisotumab vedotin in combination with radiation therapy compared to radiation therapy alone. In this example, TV was evaluated for its ability to preclinically inhibit tumor growth and extend survival when combined with radiation therapy in an HNSCC xenograft model.

[0498] method : The combined effect of tisotumab vedotin (TV) and radiation therapy (RT) was evaluated by administering TV doses of 1 mg / kg and 2 mg / kg as monotherapy or in combination with RT and comparing with RT alone. FaDu xenografts were established in nude mice as described in Example 3. Tisotumab vedotin (TV) or control IgG1-vedotin (IgG1-V) was administered on day 0. Mice receiving RT were administered 2 Gy total body radiation therapy on day 1. A minimum of 8 tumors were included per group.

[0499] result Mice treated with TV 2 mg / kg and TV 2 mg / kg + RT showed the lowest tumor burden on day 7 compared to RT alone or TV administered at 1 mg / kg (alone or in combination with RT) (Figure 10A).

[0500] Treatment with RT alone, IgG-V+RT or 1mg / kg TV alone did not extend the survival of tumor-bearing mice compared to treatment with controls (PBS or IgG-V). At day 7, none of the treatments with the IgG1-vedotin control reduced the tumor volume of the mice. A reduction in tumor volume was observed with 1mg / kg TV and 2mg / kg TV when combined with radiotherapy (Figure 10A). Notably, a significantly better survival time was observed in animals treated with 2mg / kg TV+RT compared to animals treated with RT alone (p<0.001) (Figure 10B). The median and range of survival rates for each treatment are shown in Table 3 below. Mice receiving 2mg / kg TV+RT were more likely to survive compared to 2mg / kg TV alone. The median survival time for the 2mg / kg TV+RT combination treatment could not be calculated because the median had not been reached by the end of the experiment (day 112).

[0501] Although the median survival time differed between 2 mg / kg TV monotherapy (69.5 days) and 2 mg / kg TV + RT (median not reached at the end of the study, day 112), there was no significant difference in survival time between these groups (Figure 10B, Table 3 below). Data from these in vivo experiments suggest that tisotumab vedotin can improve the clinical efficacy of RT in the treatment of HNSCC.

[0502] (Table 3) Median survival time for combined TV and radiotherapy TIFF2025515166000035.tif43148* The experiment ended on the 112th day.

[0503] Example 5B: Xenografted mice show reduced tumor size and improved survival outcomes when treated with tisotumab vedotin in combination with chemotherapy compared to chemotherapy alone. In this example, TV was evaluated for its ability to preclinically inhibit tumor growth and extend survival when combined with chemotherapy in an HNSCC xenograft model.

[0504] method : The combined effect of tisotumab vedotin (TV) and cisplatin therapy (CDDP, a type of platinum-based chemotherapy) was evaluated by administering TV doses of 1 mg / kg and 2 mg / kg, either as monotherapy or in combination with cisplatin therapy, and comparing them to cisplatin therapy alone. FaDu xenografts were established in nude mice (6-7 mice / group) as described above in Example 4. Mice were treated with antibody on days 0 and 7 and / or with 3 mg / kg intraperitoneal cisplatin (CDDP) chemotherapy (CT) on days 1 and 8 (Figure 6). TV or control IgG-vedotin (IgG1-V) was administered on day 0. Mice receiving chemotherapy were administered cisplatin on day 1. A minimum of 8 tumors were included per group.

[0505] result Furthermore, we evaluated the effect of adding TV to cisplatin treatment and observed that the addition of 2 mg / kg TV to cisplatin therapy significantly reduced tumor load at day 7 and improved survival compared to either treatment alone (Figures 10C and 10D).

Claims

1. A pharmaceutical composition for treating cancer in a subject, comprising an antibody-drug conjugate bound to tissue factor (TF), to be used in combination with radiotherapy, wherein the antibody-drug conjugate comprises an anti-TF antibody or its antigen-binding fragment conjugated to auristatin or a functional analog or functional derivative thereof.

2. The pharmaceutical composition according to claim 1, wherein the auristatin is monomethyl auristatin or a functional analog thereof or a functional derivative thereof.

3. The pharmaceutical composition according to claim 1, wherein the auristatin is monomethyl auristatin E (MMAE).

4. The pharmaceutical composition according to claim 1, wherein the antibody-drug conjugate is used to be administered in a dose in the range of about 0.9 mg / kg to about 2.1 mg / kg.

5. The pharmaceutical composition according to claim 1, wherein the antibody-drug conjugate is used to be administered in a dose in the range of about 0.9 mg / kg to about 1.7 mg / kg.

6. The pharmaceutical composition according to claim 1, wherein the antibody-drug conjugate is used to be administered at a dose of approximately 1.3 mg / kg.

7. The pharmaceutical composition according to claim 1, wherein the antibody-drug conjugate is used to be administered at a dose of about 1.7 mg / kg.

8. The pharmaceutical composition according to claim 1, wherein the antibody-drug conjugate is used to be administered at a dose of approximately 2.0 mg / kg.

9. The pharmaceutical composition according to claim 1, administered approximately once a week, approximately once every two weeks, approximately once every three weeks, or approximately once every four weeks.

10. The pharmaceutical composition according to claim 1, administered approximately once every two weeks.

11. The pharmaceutical composition according to claim 1, administered approximately once every three weeks.

12. The pharmaceutical composition according to claim 1, wherein the radiotherapy is performed at a dose of approximately 1 Gy to approximately 100 Gy, for example, a dose of approximately 10 Gy to approximately 70 Gy, for example, a dose of approximately 30 Gy to approximately 60 Gy, for example, a dose of approximately 40 Gy to approximately 50 Gy.

13. The pharmaceutical composition according to claim 1, wherein the radiotherapy is selected from the group consisting of intensity-modulated radiation therapy (IMRT), image-guided radiation therapy (IGRT), tomotherapy, stereotactic radiosurgery, stereotactic body radiotherapy, photon beam therapy, electron beam therapy, and proton beam therapy.

14. The pharmaceutical composition according to claim 1, further used in combination with a chemotherapeutic agent.

15. The pharmaceutical composition according to claim 14, wherein the chemotherapeutic agent is a platinum-based agent.

16. The pharmaceutical composition according to claim 15, wherein the platinum-based agent is administered in a dose with an AUC of approximately 4 to approximately 6.

17. The pharmaceutical composition according to claim 15, wherein the platinum-based agent is administered in a dose with an AUC of approximately 5.

18. The pharmaceutical composition according to claim 15, wherein the platinum-based agent is administered approximately once a week, approximately once every two weeks, approximately once every three weeks, or approximately once every four weeks.

19. The pharmaceutical composition according to claim 15, wherein the platinum-based agent is administered approximately once every three weeks.

20. The pharmaceutical composition according to claim 15, wherein the platinum-based agent is administered approximately once every four weeks.

21. The pharmaceutical composition according to claim 1, wherein the cancer is a solid tumor.

22. The pharmaceutical composition according to claim 1, wherein the cancer is squamous cell carcinoma of the head and neck.

23. The pharmaceutical composition according to claim 1, wherein the cancer is gynecological cancer.

24. The pharmaceutical composition according to claim 1, wherein the cancer is selected from the list consisting of ovarian cancer, endometrial cancer, cervical cancer, perineal tissue cancer, fallopian tube cancer, uterine cancer, vaginal cancer, vulvar cancer, and gestational trophoblastic disease cancer.

25. The pharmaceutical composition according to claim 1, wherein the cancer is associated with a tissue factor-positive primary tumor.

26. The pharmaceutical composition according to claim 1, wherein the cancer is an early-stage cancer.

27. The pharmaceutical composition according to claim 26, wherein the cancer is a stage I or stage II cancer.

28. The pharmaceutical composition according to claim 26, wherein the cancer is not a recurrent cancer.

29. The pharmaceutical composition according to claim 26, wherein the cancer is not locally progressive.

30. The pharmaceutical composition according to claim 26, wherein the cancer is not metastatic.

31. The pharmaceutical composition according to claim 26, wherein the cancer is locally progressive.

32. The pharmaceutical composition according to claim 1, used in neoadjuvant therapy for the aforementioned cancer.

33. The pharmaceutical composition according to claim 32, wherein the pharmaceutical composition is administered and the radiotherapy is performed prior to the surgical intervention for the cancer.

34. The pharmaceutical composition according to claim 32, wherein a platinum-based agent is further administered prior to surgical intervention for the cancer.

35. The pharmaceutical composition according to claim 33, wherein the pharmaceutical composition is administered and the radiotherapy is performed prior to the surgical resection of one or more tumors related to the cancer.

36. The pharmaceutical composition according to claim 33, wherein a platinum-based agent is further administered before the surgical removal of one or more tumors associated with the aforementioned cancer.

37. The pharmaceutical composition according to claim 1, wherein the subject has not received prior treatment for the cancer.

38. The pharmaceutical composition according to claim 1, used in adjuvant therapy for the aforementioned cancer.

39. The pharmaceutical composition according to claim 38, wherein the pharmaceutical composition is administered and the radiotherapy is performed after a surgical intervention for the cancer.

40. The pharmaceutical composition according to claim 38, wherein a platinum-based agent is further administered after surgical intervention for the cancer.

41. The pharmaceutical composition according to claim 38, wherein the pharmaceutical composition is administered and the radiotherapy is performed after surgical resection of one or more tumors related to the cancer.

42. The pharmaceutical composition according to claim 38, wherein a platinum-based agent is further administered after surgical resection of one or more tumors associated with the cancer.

43. The pharmaceutical composition according to claim 1, wherein the anti-TF antibody or its antigen-binding fragment in the antibody-drug conjugate is a monoclonal antibody or its monoclonal antigen-binding fragment.

44. The anti-TF antibody or its antigen-binding fragment in the antibody-drug conjugate includes a heavy chain variable region and a light chain variable region, and the heavy chain variable region is (i) CDR-H1 containing the amino acid sequence of SEQ ID NO:1; (ii) CDR-H2 containing the amino acid sequence of SEQ ID NO:2; and (iii) CDR-H3 containing the amino acid sequence of SEQ ID NO:3 It includes and the light chain variable region is (i) CDR-L1 containing the amino acid sequence of SEQ ID NO:4; (ii) CDR-L2 containing the amino acid sequence of SEQ ID NO:5; and (iii) CDR-L3 containing the amino acid sequence of SEQ ID NO:6 The pharmaceutical composition according to claim 1, comprising, wherein the CDR of the anti-TF antibody or its antigen-binding fragment is defined by the IMGT numbering scheme.

45. The pharmaceutical composition according to claim 1, wherein the anti-TF antibody or its antigen-binding fragment of the antibody-drug conjugate comprises a heavy chain variable region having an amino acid sequence identical to at least 85% of the amino acid sequence of SEQ ID NO:7, and a light chain variable region having an amino acid sequence identical to at least 85% of the amino acid sequence of SEQ ID NO:

8.

46. The pharmaceutical composition according to claim 1, wherein the anti-TF antibody or its antigen-binding fragment of the antibody-drug conjugate comprises a heavy chain variable region containing the amino acid sequence of SEQ ID NO:7 and a light chain variable region containing the amino acid sequence of SEQ ID NO:

8.

47. The pharmaceutical composition according to claim 1, wherein the anti-TF antibody of the antibody-drug conjugate is tisotumab.

48. The pharmaceutical composition according to claim 1, wherein the antibody-drug conjugate further comprises a linker between the anti-TF antibody or its antigen-binding fragment and the auristatin.

49. The pharmaceutical composition according to claim 48, wherein the linker is a cleavable peptide linker.

50. The cleavable peptide linker has the formula: -MC-vc-PAB-, wherein, a) MC is, And, b) vc is a dipeptide called valine-citrulline, c) PAB is The pharmaceutical composition according to claim 49.

51. The pharmaceutical composition according to claim 48, wherein the linker is bound to a sulfhydryl residue of the anti-TF antibody obtained by partial or complete reduction of the anti-TF antibody or its antigen-binding fragment.

52. The linker is bound to MMAE, and the antibody-drug conjugate has the following structure: The pharmaceutical composition according to claim 51, wherein p represents a number from 1 to 8, S represents a sulfhydryl residue of the anti-TF antibody, and Ab represents the anti-TF antibody or its antigen-binding fragment.

53. The pharmaceutical composition according to claim 52, wherein the mean value of p in the population of the antibody-drug conjugate is approximately 4.

54. The pharmaceutical composition according to claim 1, wherein the antibody-drug conjugate is tisotumab vedotin.

55. The pharmaceutical composition according to claim 1, wherein the route of administration of the pharmaceutical composition is intravenous.

56. The pharmaceutical composition according to claim 15, wherein the platinum-based agent is selected from the group consisting of carboplatin, cisplatin, oxaliplatin, and nedaplatin.

57. The pharmaceutical composition according to claim 15, wherein the platinum-based agent is carboplatin.

58. The pharmaceutical composition according to claim 15, wherein the platinum-based agent is cisplatin.

59. The pharmaceutical composition according to claim 15, wherein the route of administration of the platinum-based agent is intravenous.

60. The pharmaceutical composition according to claim 15, wherein the platinum-based agent and the pharmaceutical composition are administered sequentially.

61. The pharmaceutical composition according to claim 15, wherein the platinum-based agent and the pharmaceutical composition are administered simultaneously.

62. The pharmaceutical composition according to claim 1, wherein the subject is a human.

63. The pharmaceutical composition according to claim 1, further comprising a pharmaceutically acceptable carrier.

64. The pharmaceutical composition according to claim 15, wherein the platinum-based agent is present in a pharmaceutical composition comprising the platinum-based agent and a pharmaceutically acceptable carrier.

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