Anti-tissue factor antibody-drug conjugates and their use in cancer treatment

Abstract

This invention provides a method for treating cervical cancer in the target population. [Solution] A method is provided for treating cervical cancer in a subject, comprising the step of administering an antibody-drug conjugate bound to tissue factor (TF) to the subject, wherein the antibody-drug conjugate is tisotumab vedotin or a biosimilar thereof, and the antibody-drug conjugate is administered at a dose of 2.0 mg / kg once every three weeks, wherein the subject has been previously treated with bevacizumab.

Description

Technical Field

[0001] Field of the Invention The present invention relates to anti-tissue factor (TF) antibody-drug conjugates and methods of using them for treating cancers such as advanced cervical cancer.

[0002] Submission of Sequence Listing in ASCII Text File The following content of the submission in ASCII text file is hereby incorporated by reference in its entirety: computer-readable format (CRF) of the sequence listing.

Background Art

[0003] Background Tissue factor (TF), also known as thromboplastin, factor III, or CD142, is a transmembrane glycoprotein that functions in the coagulation pathway under normal physiological conditions. See Lwaleed et al., 2007, Biol. Res. Nurs., 9:97-107 (Non-Patent Document 1). TF is required to initiate the generation of thrombin from the zymogen prothrombin. The generation of thrombin ultimately leads to blood coagulation. TF enables cells to initiate the blood coagulation cascade and functions as a high-affinity receptor for blood coagulation factor VII (FVII), a serine protease. The resulting complex provides the catalytic activity involved in initiating the blood coagulation protease cascade by specific limited proteolysis. Unlike other cofactors of these protease cascades (circulating as inactive precursors), TF is a potent initiator that is fully functional when expressed on the cell surface. In carcinogenesis, TF is involved in tumor-associated angiogenesis, progression, and metastasis. See Anand et al., 2012, Thromb. Res., 129 Suppl 1:S46-9 (Non-Patent Document 2) and Foster et al., 2006, Clin. Chim. Acta., 364:12-21 (Non-Patent Document 3). The expression of TF is associated with poor clinical outcomes in solid tumors, and TF is highly expressed in cervical cancer (see Zhao et al., 2018, Exp. Ther. Med., 16:4075-81 (Non-Patent Document 4)).

[0004] Cervical cancer is the fourth leading cause of cancer-related death in women worldwide and is a very common cancer. Patients with recurrent or metastatic cervical cancer (r / mCC) have a poor prognosis, with a 5-year survival rate of only 17% for women diagnosed with metastatic disease. Doublet chemotherapy in combination with bevacizumab (paclitaxel-platinum or paclitaxel-topotecan) is currently the standard-of-care (SOC) first-line (1L) treatment for r / mCC patients, if eligible. See Tewari et al., 2014, N. Engl. J. Med., 370:734-43 (Non-patent Literature 5). However, the majority of patients experience relapse after 1L treatment, and there is currently no established SOC for second-line or later (2L+) treatment. Prior to the adoption of doublet chemotherapy plus bevacizumab in 1L situations (see Miller et al., 2008, Gynecol. Oncol., 110:65-70 (Non-Patent Literature 6)), existing 2L+ treatment options (i.e., monotherapy, bevacizumab) demonstrated response rates of 4.5% to 15% and median survival of less than 8 months. Data on the outcomes of 2L+ treatment following current 1L SOC are limited. Single-center studies have shown low response rates of less than 6% with 2L treatment and approximately 3% with third-line (3L) treatment. See McLachlan et al., 2017, Clin Oncol (R. Coll. Radiol.), 28:153-60 (Non-Patent Literature 7). In 2018, pembrolizumab (an anti-programmed cell death 1 antibody) received accelerated approval in the United States as a 2L+ treatment for patients with programmed cell death ligand 1 (PD-L1) positive (combined positive score ≥ 1%) r / mCC. In this setting, where 42% of patients had previously been treated with bevacizumab, the objective response rate (ORR) for pembrolizumab was 14%. See Keytruda (pembrolizumab), MSD; Whitehouse Station, NJ: Merck & Co., Inc.; 06 / 2018.Most of the patients enrolled in this trial had the squamous cell histology type (92%) (see reference), and therefore little is known about the efficacy of pembrolizumab in patients with non-squamous cell histology type. The majority of second-line (and later) patients with recurrent or metastatic cervical cancer have not benefited from pembrolizumab treatment. These data highlight the urgent need for a more effective treatment that provides clinical benefit to the broad r / mCC patient population previously treated with doublet chemotherapy, with or without bevacizumab, and that is not limited by biomarker expression.

[0005] This invention satisfies this need by providing a highly specific and effective anti-TF antibody-drug conjugate, particularly for use in the treatment of cervical cancer.

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

[0007] [Non-Patent Document 1] Lwaleed et al., 2007, Biol. Res. Nurs., 9:97-107 [Non-Patent Document 2] Anand et al., 2012, Thromb. Res., 129 Suppl 1:S46-9 [Non-Patent Document 3] Foster et al., 2006, Clin. Chim. Acta., 364:12-21 [Non-Patent Document 4] Zhao et al., 2018, Exp. Ther. Med., 16:4075-81 [Non-Patent Document 5] Tewari et al., 2014, N. Engl. J. Med., 370:734-43 [Non-Patent Document 6] Miller et al., 2008, Gynecol. Oncol., 110:65-70 [Non-Patent Document 7] McLachlan et al., 2017, Clin Oncol (R. Coll. Radiol.), 28:153-60 [Overview of the project]

[0008] overview This specification provides a method for treating cervical cancer in a subject, comprising the step of administering to the subject an antibody-drug conjugate bound to tissue factor (TF), wherein the antibody-drug conjugate is tisotumab vedotin or a biosimilar thereof, the antibody-drug conjugate is administered at a dose of 2.0 mg / kg once every three weeks, and the subject has been previously treated with bevacizumab. In some embodiments, the subject has an ECOG score of 0. In some embodiments, the subject has an ECOG score of 1. In some embodiments, the subject is under 65 years of age. In some embodiments, the subject is a) Paclitaxel and cisplatin; b) Paclitaxel and carboplatin; or c) Paclitaxel and Topotecan I have been treated there before.

[0009] Furthermore, this specification provides a method for treating cervical cancer in a subject, comprising the step of administering to the subject an antibody-drug conjugate bound to tissue factor (TF), wherein the antibody-drug conjugate is tisotumab vedotin or a biosimilar thereof, the antibody-drug conjugate is administered at a dose of 2.0 mg / kg once every three weeks, and the subject has not been previously treated with bevacizumab. In some embodiments, the subject has an ECOG score of 0. In some embodiments, the subject has an ECOG score of 1. In some embodiments, the subject is under 65 years of age. In some embodiments, the subject is a) Paclitaxel and cisplatin; b) Paclitaxel and carboplatin; or c) Paclitaxel and Topotecan I have been treated there before.

[0010] Furthermore, this specification provides a method for treating cervical cancer in a subject, comprising the step of administering to the subject an antibody-drug conjugate bound to tissue factor (TF), wherein the antibody-drug conjugate is tisotumab vedotin or a biosimilar thereof, the antibody-drug conjugate is administered at a dose of 2.0 mg / kg once every three weeks, and the subject has an Eastern Cooperative Oncology Group (ECOG) score of 0. In some embodiments, the subject is under 65 years of age. In some embodiments, the subject is a) Paclitaxel and cisplatin; b) Paclitaxel and carboplatin; or c) Paclitaxel and Topotecan I have been treated there before.

[0011] Furthermore, this specification provides a method for treating cervical cancer in a subject, comprising the step of administering to the subject an antibody-drug conjugate bound to tissue factor (TF), wherein the antibody-drug conjugate is tisotumab vedotin or a biosimilar thereof, the antibody-drug conjugate is administered at a dose of 2.0 mg / kg once every three weeks, and the subject has an East Coast Clinical Oncology Group (ECOG) score of 1. In some embodiments, the subject is under 65 years of age. In some embodiments, the subject is a) Paclitaxel and cisplatin; b) Paclitaxel and carboplatin; or c) Paclitaxel and Topotecan I have been treated there before.

[0012] Furthermore, this specification provides a method for treating cervical cancer in a subject, comprising the step of administering to the subject an antibody-drug conjugate bound to tissue factor (TF), wherein the antibody-drug conjugate is tisotumab vedotin or a biosimilar thereof, the antibody-drug conjugate is administered at a dose of 2.0 mg / kg once every three weeks, and the subject is under 65 years of age. In some embodiments, the subject has an ECOG score of 0. In some embodiments, the subject has an ECOG score of 1. In some embodiments, the subject is under 65 years of age. In some embodiments, the subject is a) Paclitaxel and cisplatin; b) Paclitaxel and carboplatin; or c) Paclitaxel and Topotecan I have been treated there before.

[0013] In some aspects of any of the above methods or embodiments, the objective response rate is approximately 13% to approximately 35%, and in some cases, the objective response rate is at least approximately 14%, approximately 19%, approximately 21%, 23.8%, approximately 24%, approximately 25%, approximately 26%, approximately 28%, approximately 30%, or approximately 33%. In some aspects, the subjects show progression-free survival of at least approximately 3 months after administration of the antibody-drug conjugate, and in some cases, the subjects show progression-free survival of at least approximately 4 months, approximately 5 months, or approximately 6 months after administration of the antibody-drug conjugate. In some aspects, the subjects show overall survival of at least approximately 10 months after administration of the antibody-drug conjugate, and in some cases, the subjects show overall survival of at least approximately 11 months, approximately 12 months, approximately 13 months, or 14 months after administration of the antibody-drug conjugate. In some embodiments, the duration of response to antibody-drug conjugates is at least about 6 months after administration of the antibody-drug conjugate, and in some cases, the duration of response to antibody-drug conjugates is at least about 7 months, about 8 months, or about 10 months after administration of the antibody-drug conjugate. In some embodiments, the time to response is less than about 6 months after administration of the antibody-drug conjugate, and in some cases, the time to response is shorter than about 4 months, about 2 months, 1.4 months, or about 1.2 months after administration of the antibody-drug conjugate.

[0014] Furthermore, this specification provides a method for treating cervical cancer in a subject, comprising the step of administering to the subject an antibody-drug conjugate bound to tissue factor (TF), wherein the antibody-drug conjugate is tisotumab vedotin or a biosimilar thereof, and the antibody-drug conjugate is administered at a dose of 2.0 mg / kg once every three weeks, with an objective response rate of approximately 13% to approximately 35%, and in some cases, an objective response rate of at least approximately 14%, approximately 19%, approximately 21%, 23.8%, approximately 24%, approximately 25%, approximately 26%, approximately 28%, approximately 30%, or approximately 33%. In some embodiments, the subject exhibits a progression-free survival of at least approximately three months after administration of the antibody-drug conjugate, and in some cases, the subject exhibits a progression-free survival of at least approximately four months, approximately five months, or approximately six months after administration of the antibody-drug conjugate. In some embodiments, the subjects exhibit an overall survival of at least approximately 10 months after administration of the antibody-drug conjugate, and in some cases, an overall survival of at least approximately 11 months, approximately 12 months, approximately 13 months, or 14 months after administration of the antibody-drug conjugate. In some embodiments, the duration of response to the antibody-drug conjugate is at least approximately 6 months after administration of the antibody-drug conjugate, and in some cases, the duration of response to the antibody-drug conjugate is at least approximately 7 months, approximately 8 months, or approximately 10 months after administration of the antibody-drug conjugate. In some embodiments, the time to response is less than approximately 6 months after administration of the antibody-drug conjugate, and in some cases, the time to response is shorter than approximately 4 months, approximately 2 months, 1.4 months, or approximately 1.2 months after administration of the antibody-drug conjugate.

[0015] Furthermore, this specification provides a method for treating cervical cancer in a subject, comprising the step of administering to the subject an antibody-drug conjugate bound to tissue factor (TF), wherein the antibody-drug conjugate is tisotumab vedotin or a biosimilar thereof, and the antibody-drug conjugate is administered at a dose of 2.0 mg / kg once every three weeks, wherein the subject exhibits a progression-free survival of at least about three months after administration of the antibody-drug conjugate, and optionally, the subject exhibits a progression-free survival of at least about four months, about five months, or about six months after administration of the antibody-drug conjugate. In some embodiments, the objective response rate is about 13% to about 35%, and optionally, the objective response rate is at least about 14%, about 19%, about 21%, 23.8%, about 24%, about 25%, about 26%, about 28%, about 30%, or about 33%. In some embodiments, the subjects exhibit an overall survival of at least approximately 10 months after administration of the antibody-drug conjugate, and in some cases, an overall survival of at least approximately 11 months, approximately 12 months, approximately 13 months, or 14 months after administration of the antibody-drug conjugate. In some embodiments, the duration of response to the antibody-drug conjugate is at least approximately 6 months after administration of the antibody-drug conjugate, and in some cases, the duration of response to the antibody-drug conjugate is at least approximately 7 months, approximately 8 months, or approximately 10 months after administration of the antibody-drug conjugate. In some embodiments, the time to response is less than approximately 6 months after administration of the antibody-drug conjugate, and in some cases, the time to response is shorter than approximately 4 months, approximately 2 months, 1.4 months, or approximately 1.2 months after administration of the antibody-drug conjugate.

[0016] Furthermore, this specification provides a method for treating cervical cancer in a subject, comprising the step of administering to the subject an antibody-drug conjugate bound to tissue factor (TF), wherein the antibody-drug conjugate is tisotumab vedotin or a biosimilar thereof, and the antibody-drug conjugate is administered at a dose of 2.0 mg / kg once every three weeks, wherein the subject exhibits an overall survival of at least about 10 months after administration of the antibody-drug conjugate, and optionally, an overall survival of at least about 11 months, about 12 months, about 13 months, or 14 months after administration of the antibody-drug conjugate. In some embodiments, the subject exhibits a progression-free survival of at least about 3 months after administration of the antibody-drug conjugate, and optionally, the subject exhibits a progression-free survival of at least about 4 months, about 5 months, or about 6 months after administration of the antibody-drug conjugate. In some embodiments, the objective response rate is approximately 13% to 35%, and in some cases, the objective response rate is at least approximately 14%, 19%, 21%, 23.8%, 24%, 25%, 26%, 28%, 30%, or 33%. In some embodiments, the subjects show an overall survival of at least approximately 10 months after administration of the antibody-drug conjugate, and in some cases, the subjects show an overall survival of at least approximately 11 months, 12 months, 13 months, or 14 months after administration of the antibody-drug conjugate. In some embodiments, the duration of response to the antibody-drug conjugate is at least approximately 6 months after administration of the antibody-drug conjugate, and in some cases, the duration of response to the antibody-drug conjugate is at least approximately 7 months, 8 months, or 10 months after administration of the antibody-drug conjugate. In some embodiments, the time to response is less than approximately 6 months after administration of the antibody-drug conjugate, and in some cases, the time to response is shorter than approximately 4 months, 2 months, 1.4 months, or 1.2 months after administration of the antibody-drug conjugate.

[0017] Furthermore, this specification provides a method for treating cervical cancer in a subject, comprising the step of administering to the subject an antibody-drug conjugate bound to tissue factor (TF), wherein the antibody-drug conjugate is tisotumab vedotin or a biosimilar thereof, the antibody-drug conjugate is administered at a dose of 2.0 mg / kg once every three weeks, and the duration of response to the antibody-drug conjugate is at least about six months after administration of the antibody-drug conjugate, and optionally, the duration of response to the antibody-drug conjugate is at least about seven months, about eight months, or about ten months after administration of the antibody-drug conjugate. In some embodiments, the subject exhibits a progression-free survival of at least about three months after administration of the antibody-drug conjugate, and optionally, the subject exhibits a progression-free survival of at least four months, about five months, or about six months after administration of the antibody-drug conjugate. In some embodiments, the subjects exhibit an overall survival of at least approximately 10 months after administration of the antibody-drug conjugate, and in some cases, an overall survival of at least approximately 11 months, approximately 12 months, approximately 13 months, or 14 months after administration of the antibody-drug conjugate. In some embodiments, the objective response rate is approximately 13% to approximately 35%, and in some cases, the objective response rate is at least approximately 14%, approximately 19%, approximately 21%, 23.8%, approximately 24%, approximately 25%, approximately 26%, approximately 28%, approximately 30%, or approximately 33%. In some embodiments, the time to response is less than approximately 6 months after administration of the antibody-drug conjugate, and in some cases, the time to response is shorter than approximately 4 months, approximately 2 months, 1.4 months, or approximately 1.2 months after administration of the antibody-drug conjugate.

[0018] Furthermore, this specification provides a method for treating cervical cancer in a subject, comprising the step of administering to the subject an antibody-drug conjugate bound to tissue factor (TF), wherein the antibody-drug conjugate is tisotumab vedotin or a biosimilar thereof, the antibody-drug conjugate is administered at a dose of 2.0 mg / kg once every three weeks, and the time to response is less than approximately six months after administration of the antibody-drug conjugate, and in some cases, the time to response is shorter than approximately four months, approximately two months, 1.4 months, or approximately 1.2 months after administration of the antibody-drug conjugate. In some embodiments, the subject exhibits a progression-free survival of at least approximately three months after administration of the antibody-drug conjugate, and in some cases, the subject exhibits a progression-free survival of at least approximately four months, approximately five months, or approximately six months after administration of the antibody-drug conjugate. In some embodiments, the subjects exhibit an overall survival of at least approximately 10 months after administration of the antibody-drug conjugate, and in some cases, an overall survival of at least approximately 11 months, approximately 12 months, approximately 13 months, or 14 months after administration of the antibody-drug conjugate. In some embodiments, the duration of response to the antibody-drug conjugate is at least approximately 6 months after administration of the antibody-drug conjugate, and in some cases, the duration of response to the antibody-drug conjugate is at least approximately 7 months, approximately 8 months, or approximately 10 months after administration of the antibody-drug conjugate. In some embodiments, the objective response rate is approximately 13% to approximately 35%, and in some cases, the objective response rate is at least approximately 14%, approximately 19%, approximately 21%, 23.8%, approximately 24%, approximately 25%, approximately 26%, approximately 28%, approximately 30%, or approximately 33%.

[0019] In some aspects of any of the above methods or embodiments, the subject has been previously treated with bevacizumab. In some aspects, the subject has not been previously treated with bevacizumab. In some aspects, the subject is a) Paclitaxel and cisplatin; b) Paclitaxel and carboplatin; c) Paclitaxel and topotecan; d) Bevacizumab, paclitaxel, and cisplatin; e) Bevacizumab, paclitaxel, and carboplatin; or f) Bevacizumab, paclitaxel, and topotecan The patient has experienced disease progression during or after treatment with [agent]. In some embodiments, the patient is under 65 years of age. In some embodiments, the patient has an ECOG score of 0. In some embodiments, the patient has an ECOG score of 1. In some embodiments, the cervical cancer is adenocarcinoma. In some embodiments, the cervical cancer is adenosquamous carcinoma. In some embodiments, the cervical cancer is squamous cell carcinoma. In some embodiments, the cervical cancer is non-squamous cell carcinoma. In some embodiments, the cervical cancer is recurrent or metastatic cervical cancer. In some embodiments, the patient has been previously treated with one or more therapeutic agents and did not respond to that treatment; where the one or more therapeutic agents are not antibody-drug conjugates. In some embodiments, the patient has been previously treated with one or more therapeutic agents and experienced a relapse after that treatment; where the one or more therapeutic agents are not antibody-drug conjugates. In some embodiments, the subject has been previously treated with one or more therapeutic agents and has experienced disease progression during that treatment; where the one or more therapeutic agents are not an antibody-drug conjugate. In some embodiments, the one or more therapeutic agents are platinum-based therapeutic agents. In some embodiments, the one or more therapeutic agents are selected from the group consisting of paclitaxel, cisplatin, carboplatin, topotecan, gemcitabine, fluorouracil, ixabepilone, imatinib mesylate, docetaxel, gefitinib, nab-paclitaxel, pemetrexed, vinorelbine, doxil, cetuximab, pembrolizumab, nivolumab, and bevacizumab. In some embodiments, the subject is not a candidate for curative treatment. In some embodiments, curative treatment includes radiotherapy and / or exenterative surgery. In some embodiments, the subject has previously received radiation therapy to the pelvis. In some embodiments, the subject has not previously received radiation therapy to the pelvis. In some embodiments, the subject has previously received one line of systemic therapy for relapsed, recurrent, or metastatic cancer.In some embodiments, the subject has previously received two (two lines) of systemic therapy for relapsing, recurrent, or metastatic cancer. In some embodiments, the subject did not respond to prior systemic therapy. In some embodiments, the subject experienced a relapse after prior systemic therapy. In some embodiments, the cervical cancer is advanced-stage cervical cancer, e.g., stage 3 or stage 4 cervical cancer, e.g., metastatic cervical cancer. In some embodiments, the cervical cancer is recurrent cervical cancer. In some embodiments, the route of administration of the antibody-drug conjugate is intravenous. In some embodiments, at least about 0.1%, at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, or at least about 80% of cervical cancer cells express TF. In some embodiments, the subject has at least one TF histological score (H score). In some embodiments, the subject has one or more adverse events and is further administered additional therapeutic agents to eliminate or reduce the severity of one or more adverse events. In some embodiments, the subject is at risk of developing one or more adverse events and is further administered additional therapeutic agents to prevent or reduce the severity of one or more adverse events. In some embodiments, the subject experiences one or more adverse events, and the dose of the antibody-drug conjugate is reduced after the one or more adverse events. In some embodiments, the dose is reduced from 2.0 mg / kg to 1.3 mg / kg. In some embodiments, the dose is reduced from 1.3 mg / kg to 0.9 mg / kg. In some embodiments, the one or more adverse events are anemia, abdominal pain, hypokalemia, hyponatremia, epistaxis, fatigue, nausea, alopecia, conjunctivitis, constipation, loss of appetite, diarrhea, vomiting, peripheral neuropathy, or deterioration of general health. In some embodiments, the one or more adverse events are grade 3 or higher.In some embodiments, one or more adverse events are serious adverse events. In some embodiments, one or more adverse events are conjunctivitis and / or keratitis, and additional therapeutic agents are preservative-free lubricating eye drops, ocular vasoconstrictors and / or steroid eye drops. In some embodiments, the antibody-drug conjugate is administered as monotherapy. In some embodiments, the subject is human. In some embodiments, the antibody-drug conjugate is in a pharmaceutical composition comprising the antibody-drug conjugate and a pharmaceutically acceptable carrier.

[0020] Furthermore, this specification also provides antibody-drug conjugates that bind to TF for use in any of the methods or embodiments provided herein.

[0021] Furthermore, this specification also provides the use of antibody-drug conjugates that bind to TF for the manufacture of pharmaceuticals used in any of the methods or embodiments provided herein. [Brief explanation of the drawing]

[0022] [Figure 1] This figure shows the mechanism of action (MOA) of tisotumab vedotin, an antibody-drug conjugate. [Figure 2] This figure shows the Phase II trial design for treatment with tisotumab vedotin in patients with a history of prior treatment for recurrent or metastatic cancer who have received at least one prior systemic therapy. 'a' indicates that tisotumab vedotin 2.0 mg / kg was administered by intravenous infusion on day 1 of each cycle until disease progression. Each treatment cycle was 3 weeks (Q3W). 'b' indicates that CT or MRI scans were performed every 6 weeks (±7 days) for the first 30 weeks of treatment, and then every 12 weeks (±7 days) thereafter, regardless of any treatment delays. [Figure 3] This is the patient flowchart and layout for the Phase II trial. [Figure 4] This figure shows the target lesion response in each subject. The bar graph shows the best percentage change in lesion size relative to baseline for each subject. [Figure 5] This graph shows the percentage of subjects who have maintained a positive response over time. [Figure 6] This graph shows the percentage of patients who show progression-free survival over time. [Figure 7] This graph shows the percentage of subjects who survived over time. [Modes for carrying out the invention]

[0023] Detailed explanation I. Definition To facilitate understanding of this disclosure, certain terms are defined first. As used in this application, unless otherwise defined herein, the following terms shall have the meanings set forth below. Additional definitions are provided throughout this application.

[0024] As used herein, the term "and / or" should be interpreted as the specific disclosure of each of the two designated features or components, with or without the other. Accordingly, as used herein in expressions such as "A and / or B," the term "and / or" includes "A and B," "A or B," "A" (alone), and "B" (alone). Similarly, as used in expressions such as "A, B, and / or C," the term "and / or" includes 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 (alone); B (alone); C (alone).

[0025] The aspects and embodiments of the present invention described herein will be understood to include the terms "including," "consisting of," and "essentially consisting of."

[0026] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art in the field relating to this disclosure. For example, the following provides a general dictionary of many of the terms used herein: 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.

[0027] Units, prefixes, and symbols are presented in the format approved by the International System of Units (SI). Numerical ranges include the numerical values ​​that define that range. The headings provided herein are not limitations on the various aspects of this disclosure, which are obtained by referring to this specification as a whole. Thus, the terms defined immediately below are more fully defined by referring to this specification as a whole.

[0028] 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 expressed naturally by cells or in cells transfected with the tissue factor gene. Tissue factor may be the sequence of Genbank accession NP_001984.

[0029] The term "immunoglobulin" refers to a class of structurally related glycoproteins consisting 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 is well characterized. See, for example, Chapter 7 of Fundamental Immunology (edited by Paul, W., 2nd edition, Raven Press, N.Y. (1989)). Briefly, each heavy chain typically consists of a heavy chain variable region (abbreviated herein as V H or VH) and a heavy chain constant region (C H or CH). The heavy chain constant region generally consists of three domains, C H 1, C H 2, and C H 3. Heavy chains are generally interconnected via disulfide bonds in the so-called "hinge region". Each light chain typically consists of a light chain variable region (abbreviated herein as V L or VL) and a light chain constant region (C L or CL). The light chain constant region generally consists of one domain C L 1. CL can be of the κ (kappa) or λ (lambda) isotype. The terms "constant domain" and "constant region" are used interchangeably herein. Immunoglobulins can be derived from any of the generally 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 an antibody class or subclass (e.g., IgM or IgG1) encoded by a heavy chain constant region gene.

[0030] The term "variable region" or "variable domain" refers to the domain of an antibody heavy or light chain that is involved in binding to an antigen. The variable regions of the heavy and light chains of a native antibody (V H and V LThe heavy chain variable region can be further divided into hypervariable regions, also called complementarity-determining regions (CDRs), which are hypervariable regions (i.e., regions whose sequences are hypervariable and / or can be in the form of structurally defined loops), and these hypervariable regions are interposed by more conserved regions called framework regions (FRs). The terms "complementarity-determining regions" and "CDRs" are known in the art to be synonymous with "hypervariable regions" or "HVRs," and refer to discontinuous sequences of amino acids within the antibody variable region that give antigen specificity and / or binding affinity. Generally, each heavy chain variable region has three CDRs (CDR-H1, CDR-H2, CDR-H3), and each light chain variable region has three CDRs (CDR-L1, CDR-L2, CDR-L3). The terms "framework regions" and "FRs" are known in the art to refer to the non-CDR portions of the heavy chain 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 the molecule, the three CDRs and four FRs are typically arranged in the following order from the amino terminus to the carboxyl terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4 (see also Chothia and Lesk J. Mot. Biol., 195, 901-917 (1987)).

[0031] In relation to the present invention, the term “antibody” (Ab) means an immunoglobulin molecule, a fragment of an immunoglobulin molecule, or a derivative thereof; these have the ability to specifically bind to an antigen under normal physiological conditions, and their half-lives are fairly long, for example, 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, at least about 24 hours or more, at least about 48 hours or more, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, or more, or other relevant functionally defined periods (e.g., a period sufficient to induce, promote, enhance and / or modulate the physiological response associated with the binding of an antibody to an antigen, and / or a period sufficient for the antibody to recruit effector activity). The variable regions of the heavy and light chains of the immunoglobulin molecule contain binding domains that interact with the antigen. The constant region of an antibody (Ab) can mediate the binding of immunoglobulins 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.

[0032] As used herein, the term "monoclonal antibody" refers to a recombinant antibody molecule preparation having a single primary amino acid sequence. Monoclonal antibody compositions exhibit a single binding specificity and affinity for a specific epitope. Therefore, the term "human monoclonal antibody" refers to an antibody exhibiting a single binding specificity, having a variable region and a constant region derived from a human germline immunoglobulin sequence. Human monoclonal antibodies can be prepared by hybridomas, including B cells obtained from transgenic or transchromosomal non-human animals, such as transgenic mice, which have a genome containing human heavy-chain and light-chain transgenes fused to immortalized cells.

[0033] "Isolated antibody" refers to an antibody that substantially does not contain other antibodies with different antigen specificities (for example, an isolated antibody that specifically binds to TF substantially does not contain 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 substantially does not contain other cellular material and / or chemical substances. In one embodiment, the isolated antibody includes a conjugate conjugated to another drug (e.g., a small molecule drug). In several embodiments, the isolated anti-TF antibody includes a conjugate of an anti-TF antibody and a small molecule drug (e.g., MMAE or MMAF).

[0034] A “human antibody” (HuMAb) refers to an antibody having variable regions in which both the FR and CDR are derived from human germline immunoglobulin sequences. Furthermore, if the antibody includes a constant region, that constant region is also derived from a human germline immunoglobulin sequence. The human antibodies of this disclosure may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-directed mutagenesis in vitro, or by somatic mutation in vivo). However, as used herein, the term “human antibody” is not intended to include antibodies in which a CDR sequence derived from the germline of another mammalian species, such as mouse, is grafted onto a human framework sequence. The terms “human antibody” and “full human antibody” are used synonymously.

[0035] As used herein, the term “humanized antibody” refers to a genetically engineered non-human antibody comprising a human antibody constant domain and a non-human variable domain modified to contain a high level of sequence homology to the human variable domain. This can be achieved by grafting six non-human antibody complementarity-determining regions (CDRs) that together form an antigen-binding site onto a homologous human acceptor framework region (FR) (see WO92 / 22653 and EP0629240). To fully reconstitute the binding affinity and specificity of the parent antibody, substitution of framework residues from the parent antibody (i.e., the non-human antibody) into the human framework region (back-mutation) may be necessary. Structural homology modeling can help identify amino acid residues in the framework region that are important for the antibody’s binding properties. Thus, a humanized antibody may contain a non-human CDR sequence, a predominantly human framework region that optionally includes one or more amino acid back-mutations into the non-human amino acid sequence, and a complete human constant domain. If necessary, additional amino acid modifications, not necessarily back-mutations, may also be applied to obtain a humanized antibody with desirable properties, such as affinity and biochemical characteristics.

[0036] As used herein, the term "chimeric antibody" refers to an antibody in which the variable region originates from a non-human species (e.g., rodents) and the constant region originates from a different species (e.g., humans). Chimeric antibodies can be created by antibody engineering. "Antibody engineering" is a commonly used term 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 may 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 carried out by methods other than those described herein. Chimeric monoclonal antibodies for therapeutic purposes have been developed to reduce the immunogenicity of antibodies. They typically may contain a non-human (e.g., mouse) variable region specific to the target antigen and constant domains of the human antibody heavy and light chains. The term "variable region" or "variable domain," as used in relation to chimeric antibodies, refers to the region containing the CDR and framework regions of both the heavy and light chains of immunoglobulins.

[0037] An "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. In another aspect, an anti-VEGF antibody is an antibody that binds to the antigen VEGF.

[0038] An antibody's "antigen-binding site" or "antigen-binding fragment" refers to one or more fragments of an antibody that retain the ability to specifically bind to the antigen to which the whole antibody binds. 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 yields two identical antigen-binding fragments called "Fab" fragments (each having a single antigen-binding site) and the remaining "Fc" fragment (its name reflects its ability to easily crystallize). Pepsin treatment produces an F(ab')2 fragment, which has two antigen-binding sites and can still crosslink antigens.

[0039] The "sequence identity percentage (%)" relative to a reference polypeptide sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical to the amino acid residues of the reference polypeptide sequence, after introducing gaps as necessary to align the sequences and achieve maximum sequence identity (without considering any conservative substitutions as part of sequence identity). Alignment for determining amino acid sequence identity percentage can be achieved in various ways within the scope of the art using publicly available computer software, such as BLAST, BLAST-2, ALIGN, or Megalign (DNASTAR) software. A person skilled in the art can determine appropriate parameters for aligning sequences, including the algorithm required to achieve maximum alignment over the entire length of the sequences being compared. For example, the sequence identity percentage of a given amino acid sequence A to a given amino acid sequence B (which can also be rephrased as a specific amino acid sequence A having a certain sequence identity percentage to a particular amino acid sequence B) is calculated as follows: 100 x fraction X / Y Here, X is the number of amino acid residues recorded as a perfect sequence match in the alignment of A and B in the program, 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 is not equal to the sequence identity % of B to A.

[0040] As used herein, the terms “binding,” “binding,” or “specifically binding” in relation to the binding of an antibody to a given antigen typically mean, for example, approximately 10 when measured by BioLayer Interferometry (BLI) using an Octet HTX instrument with the antibody as a ligand and the antigen as an 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 The antibody binds with an affinity corresponding to the antigen, and the antibody binds to nonspecific antigens other than the given antigen or closely related antigens (e.g., BSA, casein). D K is at least 10 times lower than D For example, K that is at least 100 times lower, at least 1,000 times lower, at least 10,000 times lower, or at least 100,000 times lower. D It binds to a predetermined antigen with the corresponding affinity. D The amount at which the K of the antibody decreases is D It depends on the K of the antibody; therefore, the K D If the K of antigen binding is very low, D K is the binding of nonspecific antigens D The amount that is lower than that can be at least 10,000 times (i.e., the antibody is highly specific).

[0041] The term "K" as used in this specification D (M) refers to the dissociation equilibrium constant of a specific antibody-antigen interaction. Affinity and K as used hereinD The opposite relationship exists, meaning that higher affinity corresponds to lower K D It is intended to refer to a lower affinity with a higher K D This is intended to refer to...

[0042] The term "k" as used herein d (sec -1 ) refers to the dissociation rate constant of a specific antibody-antigen interaction. This value is k off Also called a value.

[0043] The term "k" as used herein a (M -1 ×sec -1 ) refers to the association rate constant of a specific antibody-antigen interaction.

[0044] The term "K" as used in this specification A (M -1 ) refers to the association equilibrium constant of a specific antibody-antigen interaction, k a to k d It is obtained by dividing by [a certain factor].

[0045] The term "ADC" refers to an antibody-drug conjugate, and in the context of this invention, it refers to an anti-TF antibody conjugated to another portion (e.g., MMAE or MMAF) as described in this application.

[0046] The abbreviations "vc" and "val-cit" refer to the dipeptide valine-citrulline.

[0047] The abbreviation "PAB" stands for self-immolative spacer: This refers to TIFF2026082887000001.tif28128.

[0048] The abbreviation "MC" stands for maleimidocaproyl, a type of stretcher. This refers to TIFF2026082887000002.tif27128.

[0049] The term "Ab-MC-vc-PAB-MMAE" refers to an antibody conjugated to a drug MMAE via an MC-vc-PAB linker.

[0050] "Cancer" refers to a broad group of diseases characterized by the uncontrolled proliferation of abnormal cells in the body. "Cancer" or "cancer tissue" can include tumors. Uncontrolled cell division and proliferation lead to the formation of malignant tumors, which can invade neighboring tissues and metastasize to distant parts of the body through the lymphatic system or bloodstream. After metastasis, the distal 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 metastatic cervical cancer.

[0051] The term "treatment" or "treatment" for a subject means any type of intervention or process performed on the subject, or the administration of an active agent to the subject, with the aim of reversing, alleviating, improving, suppressing, slowing, or preventing the onset, progression, development, severity, or recurrence of symptoms, complications, conditions, or biochemical signs associated with the disease. In some embodiments, the disease is cancer.

[0052] The term "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 human. The terms "subject," "patient," and "individual" are used interchangeably herein.

[0053] "Effective dose," "therapeutic effective dose," or "therapeutic effective dose" refers to the effective amount in the required dosage and duration to obtain the desired therapeutic outcome. Such desirable therapeutic outcomes include protecting the subject from the onset of the disease, promoting disease regression as demonstrated by a reduction in the severity of symptoms, increasing the frequency and duration of asymptomatic periods, or preventing functional or physical disability due to the disease. The ability of a therapeutic agent to promote disease regression can be evaluated using various methods known to those skilled in the art, for example, in human subjects during clinical trials, in animal model systems to predict efficacy in humans, or by measuring the activity of the therapeutic agent in in vitro assays. The therapeutic effective dose of an anti-TF antibody-drug conjugate may vary depending on factors such as the individual's disease state, age, sex, and weight, and the ability of the anti-TF antibody-drug conjugate to elicit the desired response in the individual. The therapeutic effective dose is also the amount in which the therapeutically beneficial effects of the anti-TF antibody-drug conjugate outweigh its toxic or adverse effects.

[0054] The therapeutically effective dose of a drug (e.g., an anti-TF antibody-drug conjugate) includes a “prophylactically effective dose,” which is the amount of the drug administered, either alone or in combination with an anticancer agent, to a subject at risk of developing cancer (e.g., a subject with a precancerous condition) or a subject at risk of cancer recurrence, that prevents the development or recurrence of cancer. In some embodiments, a prophylactically effective dose completely prevents the development or recurrence of cancer. To “prevent” the development or recurrence of cancer means to reduce the likelihood of cancer development or recurrence, or to completely prevent the development or recurrence of cancer.

[0055] As used herein, “subtherapeutic dose” means a dose of a therapeutic compound (e.g., an antibody-drug conjugate) lower than the usual or typical dose when administered alone for the treatment of hyperproliferative diseases (e.g., cancer).

[0056] For example, "anticancer drugs" promote the regression of cancer in a subject. In some embodiments, a therapeutically effective dose of a drug promotes cancer regression to the extent that it eliminates the cancer. "Promoting cancer regression" means that when an effective dose of a drug is administered alone or in combination with an anticancer drug, the result is a reduction 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 asymptomatic periods, or prevention of functional impairment or disability due to the suffering of the disease. Furthermore, the terms "effective" and "effective" in relation to treatment include both pharmacological efficacy and physiological safety. Pharmacological efficacy refers to the ability of a drug to promote cancer regression in a patient. Physiological safety refers to the level of toxicity or other adverse physiological effects (side effects) at the cellular, organ, and / or biological levels resulting from the administration of a drug.

[0057] A "sustained response" refers to a sustained effect of suppressing tumor growth after discontinuation of treatment. For example, the tumor size is the same as or smaller than the size at the start of the treatment period. In some embodiments, the sustained response lasts for at least the same duration as the treatment period, or at least 1.5, 2.0, 2.5, or 3.0 times the treatment period.

[0058] As used herein, "complete response" or "CR" means the disappearance of all target lesions; "partial response" or "PR" means a reduction of at least 30% of the sum of the longest diameters (SLD) of target lesions, based on the baseline sum of the longest diameters (SLD); and "stable disease" or "SD" means that there is no reduction in target lesions sufficient to qualify for a PR, nor is there an increase in size sufficient to qualify for "progressive disease" or "PD," based on the smallest SLD since the start of treatment.

[0059] As used herein, “progression-free survival” or “PFS” refers to the period during and after treatment in which the treated disease (e.g., cancer) does not worsen. Progression-free survival may include the period in which the patient experiences a complete or partial response, and the period in which the patient experiences stabilization of their disease.

[0060] As used herein, “objective response rate” or “ORR” refers to the sum of the complete response (CR) rate and the partial response (PR) rate.

[0061] As used herein, "overall survival" or "OS" refers to the proportion of individuals in a group that are likely to survive after a given period of time.

[0062] As used herein, the term "body weight-based dose" means that the dose administered to a patient is calculated based on the patient's body weight. For example, if a patient weighing 60 kg requires 2 mg / kg of anti-TF antibody-drug conjugate, the appropriate amount of anti-TF antibody-drug conjugate for administration (i.e., 120 mg) can be calculated and used.

[0063] The use of the term "flat dose" in relation to the methods and dosages of this disclosure means a dose administered to a patient without considering the patient's body weight or body surface area (BSA). Therefore, the flat dose is provided as an absolute amount of the drug (e.g., anti-TF antibody-drug conjugate) rather than as a dose in mg / kg. For example, a 60kg person and a 100kg person would receive the same dose of antibody-drug conjugate (e.g., 240mg of anti-TF antibody-drug conjugate).

[0064] The phrase "pharmaceutically acceptable" indicates that a substance or composition must be chemically and / or toxicologically compatible with the other components of the formulation and / or the mammal being treated with it.

[0065] As used herein, the term "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable organic or inorganic salt of the compound of the present invention. Exemplary salts include, but are not limited to, sulfates, citrates, acetates, oxalates, chlorides, bromides, iodides, nitrates, bisulfates, phosphates, acidic phosphates, isonicotinates, lactates, salicylates, acidic citrates, tartrates, oleates, tannates, pantothenates, bitartrates, ascorbicates, succinates, maleates, gentisinates, fumarates, glucons, glucurons, saccharates, formates, benzoates, glutamates, methanesulfonates "mesylates", ethanesulfonates, benzenesulfonates, p-toluenesulfonates, pamoic acid (i.e., 4,4'-methylene-bis-(2-hydroxy-3-naphthoic acid)) salts, alkali metal (e.g., sodium and potassium) salts, alkaline earth metal (e.g., magnesium) salts, and ammonium salts. A pharmaceutically acceptable salt may contain other molecules such as acetate ions, succinate ions, or other counterions. The counterion can be any organic or inorganic part that stabilizes the charge of the parent compound. Furthermore, a pharmaceutically acceptable salt may have multiple charged atoms within its structure. If multiple charged atoms are part of a pharmaceutically acceptable salt, it may have multiple counterions. Therefore, a pharmaceutically acceptable salt may have one or more charged atoms and / or one or more counterions.

[0066] "Administer" means physically introducing a therapeutic agent into a target using any of the various methods and delivery systems known to those skilled in the art. Exemplary routes of administration for anti-TF antibody-drug conjugates 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, "parenteral administration" means, and is not limited to, methods of administration other than enteral and topical administration, usually by injection, including: intravenous, intramuscular, intra-arterial, subarachnoid, intralymphatic, intrafocal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal injections and infusions, as well as in vivo electroporation. The therapeutic agent may be administered via non-parenteral routes or orally. Other non-extraintestinal routes of administration include topical, epidermal, or mucosal routes, such as intranasal, intravaginal, intrarectal, sublingual, or topical administration. Administration can also be, for example, a single dose, multiple doses, and / or over one or more extended periods.

[0067] The terms “baseline” or “baseline value,” as used interchangeably herein, may refer to the measurement or characterization of symptoms before administration of a therapeutic agent (e.g., the antibody-drug conjugate described herein) or at the start of therapeutic agent administration. The baseline value may be compared to a reference value to determine the reduction or improvement of symptoms of TF-related diseases (e.g., cervical cancer) as intended herein. The terms “reference” or “reference value,” as used interchangeably herein, may refer to the measurement or characterization of symptoms after administration of a therapeutic agent (e.g., the antibody-drug conjugate described herein). The reference value may be measured once or more times during a dosing regimen or treatment cycle, or at the completion of a dosing regimen or treatment cycle. The “reference value” may be an absolute value; a relative value; a value with upper and / or lower limits; a range of values; an average value; a median; a mean value; or a value compared to the baseline value.

[0068] Similarly, the “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; a mean value; or a value compared to a reference value. The reference value and / or baseline value can be obtained from one individual, from two different individuals, or from a population (e.g., a group of 2, 3, 4, 5 or more individuals).

[0069] As used herein, the term “monotherapy” means that an antibody-drug conjugate is the only anticancer agent administered to the subject during a treatment cycle. However, other therapeutic agents may also be administered to the subject. For example, anti-inflammatory agents 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, may be administered during a monotherapy period.

[0070] As used herein, “adverse event” (AE) is an undesirable, generally unintended, or unwanted sign (including abnormal laboratory findings), symptom, or illness associated with the use of a medical procedure. A medical procedure may cause one or more associated AEs, and the severity of each AE may be the same or different. References to ways that can “modify an adverse event” mean a treatment regimen that reduces the incidence and / or severity of one or more AEs associated with the use of a different treatment regimen.

[0071] 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” means an event in which the patient was at risk of death at the time of the adverse event; it does not mean an event that, if it had been more serious, might have caused death. • To result in permanent or significant disability / incapacity. • Causes congenital abnormalities / congenital defects. • Defined as an event of medical importance, meaning one that could endanger the patient or require medical or surgical intervention to prevent one of the above consequences. Medical and scientific judgment is required when determining whether an AE is "medically important." Hospitalization or extension of the current hospital stay is required, except for: 1) routine treatment or monitoring of an underlying condition unrelated to the worsening of the patient's condition; 2) elective or pre-planned treatment for an existing condition unrelated to the indication under investigation and which has not worsened since the signing of informed consent; and social reasons and respite care when there is no deterioration in the patient's overall condition.

[0072] The use of options (e.g., "or") should be understood to mean one, both, or any combination thereof of the options. Where used herein, the indefinite article "a" or "an" should be understood to refer to "one or more" of the listed or enumerated components.

[0073] The terms “approximately” or “essentially consisting of” refer to a value or composition that falls within the tolerance range of a particular value or composition as determined by those skilled in the art, and this depends in part on how that value or composition is measured and determined, i.e., the limits of the measuring system. For example, “approximately” or “essentially consisting of” may mean within one or more standard deviations per implementation in the art. Or, “approximately” or “essentially consisting of” may mean a range of up to 20%. Furthermore, particularly with respect to biological systems or processes, these terms may mean up to 10 times or up to 5 times the value. Where a particular value or composition is provided in this application and claims, unless otherwise specified, the meaning of “approximately” or “essentially consisting of” should be considered to be within the tolerance range of that particular value or composition.

[0074] The terms “about once a week,” “about once every two weeks,” “about once every three weeks,” or other similar dosing interval terms as used herein mean approximate numbers. “About once a week” may include every 7 ± 1 days, i.e., every 6 to 8 days. “About once every two weeks” may include every 14 ± 2 days, i.e., every 12 to 16 days. “About once every three weeks” may include every 21 ± 3 days, i.e., every 18 to 24 days. Similar approximations apply, for example, to every 4 weeks, every 5 weeks, every 6 weeks, every 12 weeks, etc. In some embodiments, a dosing interval of about 6 weeks or every 12 weeks means that the initial dose can be administered on any day in week 1, and the next dose can then be administered on any day in week 6 or week 12, respectively. In other embodiments, an interval of approximately 6 weeks or approximately 12 weeks means administering the initial dose on a specific day in week 1 (e.g., Monday), and then subsequent doses on the same day in weeks 6 or 12, respectively (i.e., Monday).

[0075] Any concentration ranges, percentage ranges, ratio ranges, or integer ranges described herein should be understood, unless otherwise specified, to include any integer values ​​within the listed ranges, and, where appropriate, fractions thereof (such as one-tenth and one-hundredth of an integer).

[0076] Various aspects of this disclosure are described in more detail in the following subsections.

[0077] II. Antibody-drug conjugates The present invention provides an anti-TF antibody-drug conjugate useful for the treatment of cancer in a subject. In some embodiments, the cancer is cervical cancer. In some embodiments, the cervical cancer is advanced-stage cervical cancer (e.g., stage 3 or stage 4 cervical cancer or metastatic cervical cancer). In some embodiments, the advanced cervical cancer is metastatic cancer. In some embodiments, the subject has relapsing, recurrent, and / or metastatic cervical cancer. In some embodiments, the anti-TF antibody-drug conjugate is tisotumab vedotin. As described in the examples herein in a Phase II clinical trial, tisotumab vedotin is effective in the treatment of relapsing, recurrent, and / or metastatic cervical cancer. Therapeutic responses were observed in various subgroups of interest, including cancer histological type, line of treatment, prior cisplatin and radiotherapy, prior bevacizumab in combination with doublet chemotherapy, and ECOG performance status. Remarkably, tisotumab vedotin was able to effectively treat subjects who had previously been treated with bevacizumab; this has not been demonstrated with other therapies such as pembrolizumab. Tisotumab vedotin was also effective in treating both squamous and non-squamous cervical cancer, whereas pembrolizumab has not been demonstrated to be effective in treating non-squamous cervical cancer. Furthermore, treatment with tisotumab vedotin resulted in a clinically meaningful 24% (CI: 15.9%–33.3%) confirmed ORR (by IRC) in subjects who had previously been treated for recurrent or metastatic cervical cancer, with 7 subjects achieving CR (6.9%). The response was sustained, with a median DOR of 8.3 months [95% CI 4.3, NR]. Overall survival was 12.1 months. In addition, an estimated 67% of responses to tisotumab vedotin remained active at 6 months. The following table summarizes the treatment outcomes of other monotherapy for 2L+ cervical cancer: TIFF2026082887000003.tif165161NR=No report;NA=Not applicable Citations: Alberts, et al., (2012) Gynecol Oncol. 127(3):451-5; Garcia, et al., (2007) Am J Clin Oncol. 30:428-31; Angioli et al., (2007) Int J Gynecol Cancer 17(1):88-93; Rose, et al. (2006) Gynecol. Oncol. 102(2):210-3; Coronel, et al. (2009) Med Oncol. 26(2):210-4; Fiorica, et al. (2009) Gynecol Oncol. 115(2):285-9; Schilder, et al., (2005) Gynecol Oncol 96:103-7; Schilder, et al. (2009) Int J Gynecol Cancer 19(5):929-33; Monk, et al., (2009) J Clin Oncol. 27:1069-1074; Chung, et al. (2019) J. Clin. Oncol. 37(17):1470-78; Verschraegen, et al., (1997) (2):625-31; Bookman, et al., (2000) Gynecol Oncol. 77:446-9; Muggia et al., (2004) Gynecol Oncol. 92:639-43。

[0078] A. Anti-TF antibody In general, the anti-TF antibodies of this disclosure bind to TF (e.g., human TF) and exert cell proliferation inhibitory and cytotoxic effects against malignant cells such as cervical cancer cells. The anti-TF antibodies of this disclosure are preferably monoclonal and may be multispecific, human, humanized or chimeric antibodies, single-chain antibodies, Fab fragments, F(ab') fragments, fragments created by Fab expression libraries, and any of the above TF-binding fragments. In some embodiments, the anti-TF antibodies of this disclosure bind specifically to TF. The immunoglobulin molecules of this disclosure may be 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 molecules.

[0079] In certain aspects of this disclosure, the anti-TF antibody is an antigen-binding fragment described herein (e.g., a human antigen-binding fragment), but is not limited to Fab, Fab' and F(ab')2, Fd, single-chain Fv(scFv), single-chain antibody, disulfide-bonded Fv(sdFv), and V L or V H The fragments include any of the domains. Antigen-binding fragments, such as single-chain antibodies, may include the variable region alone or in combination with all or part of the hinge region, CH1, CH2, CH3, and CL domains. The disclosure also includes antigen-binding fragments that include any combination of the variable region and the hinge region, CH1, CH2, CH3, and CL domains. In some embodiments, the anti-TF antibody or its antigen-binding fragment is an antibody from a human, mouse (e.g., mouse and rat), donkey, sheep, rabbit, goat, guinea pig, camel, horse, or chicken.

[0080] The anti-TF antibodies of this disclosure may be described or identified in terms of the specific CDRs they contain. The precise amino acid sequence boundaries of a given CDR or FR can be easily determined using one of several well-known schemes; such schemes include: Kabat et al. (1991), "Sequences of Proteins of Immunological Interest," 5th edition, Public Health Service, National Institutes of Health, Bethesda, MD ("Kabat" numbering scheme); Al-Lazikani et al., (1997) JMB 273, 927-948 ("Chothia" numbering scheme); MacCallum et al., J. Mol. Biol. 262:732-745 (1996), "Antibody-antigen interactions: Contact analysis and binding site topography," J. Mol. Biol. 262, 732-745 ("Contact" numbering scheme); Lefranc MP et al., "IMGT unique numbering for immunoglobulin and T cell receptor variable domains and Ig superfamily "V-like domains," Dev Comp Immunol, 2003 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 for identification. In some aspects, the "CDR" or "complementarity-determining region" of a given antibody or its region (e.g., its variable region) or individual identified CDRs (e.g., CDR-H1, CDR-H2, CDR-H3) should be understood to encompass the CDR (or specific CDR) defined by any of the aforementioned schemes. For example, if a specific CDR (e.g., CDR-H3) is a given V. H or V L When a description states that a region contains the amino acid sequence of a corresponding CDR, it is understood that such a CDR has the sequence of a corresponding CDR (e.g., CDR-H3) within a variable region defined by one of the schemes described above. For example, a scheme can be specified to identify a particular CDR, such as a CDR defined by Kabat, Chothia, AbM, or IMGT.

[0081] The CDR sequences of the anti-TF antibodies in the anti-TF antibody-drug conjugates provided herein follow the IMGT numbering scheme described in Lefranc, MP et al., Dev. Comp. Immunol., 2003, 27, 55-77.

[0082] In certain embodiments, the antibody of this disclosure comprises one or more CDRs of antibody 011. See WO 2011 / 157741 and WO 2010 / 066803. This disclosure encompasses an antibody or derivative thereof comprising a heavy chain or light chain variable domain; the variable domain comprises (a) a set of three CDRs (the set of CDRs derived from monoclonal antibody 011) and (b) a set of four framework regions (the set of framework regions differs 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 binds specifically to TF. In certain embodiments, the anti-TF antibody is 011. Antibody 011 is also known as tisotumab.

[0083] In one aspect, anti-TF antibodies that compete with tisotumab for binding to TF are also provided herein. Anti-TF antibodies that bind to the same epitope as tisotumab are also provided herein.

[0084] In one aspect, anti-TF antibodies containing 1, 2, 3, 4, 5, or 6 CDR sequences of tisotumab are provided herein.

[0085] In one aspect, an anti-TF antibody comprising a heavy chain variable region and a light chain variable region is provided herein; the heavy chain variable region comprises (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO:1, (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO:2, and (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO:3, and / or the light chain variable region comprises (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO:4, (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO:5, and (iii) CDR-L3 comprising the amino acid sequence of SEQ ID NO:6, wherein the CDRs of the anti-TF antibody are defined by the IMGT numbering scheme.

[0086] The anti-TF antibodies described herein may contain any suitable framework variable domain sequences, provided that the antibody retains the ability to bind to TF (e.g., human TF). As used herein, the heavy chain framework region is designated as "HC-FR1~FR4" and the light chain framework region is designated as "LC-FR1~FR4". In some embodiments, the anti-TF antibody contains the heavy chain variable domain framework sequences of SEQ ID NO: 9, 10, 11, and 12 (HC-FR1, HC-FR2, HC-FR3, and HC-FR4, respectively). In some embodiments, the anti-TF antibody contains the light chain variable domain framework sequences of SEQ ID NO: 13, 14, 15, and 16 (LC-FR1, LC-FR2, LC-FR3, and LC-FR4, respectively).

[0087] In some embodiments of the anti-TF antibody described herein, its heavy chain variable domain has the following amino acid sequence: It contains TIFF2026082887000004.tif19159, and its light chain variable domain has the following amino acid sequence: Includes TIFF2026082887000005.tif11161.

[0088] In some embodiments of the anti-TF antibody described herein, its heavy chain CDR sequence is Includes TIFF2026082887000006.tif19128.

[0089] In some embodiments of the anti-TF antibody described herein, the heavy chain FR sequence is Includes TIFF2026082887000007.tif33152.

[0090] In some embodiments of the anti-TF antibody described herein, its light chain CDR sequence is Includes TIFF2026082887000008.tif19128.

[0091] In some embodiments of the anti-TF antibody described herein, its light chain FR sequence is Includes TIFF2026082887000009.tif33154.

[0092] In some embodiments, anti-TF antibodies that bind to TF (e.g., human TF) are provided herein; the antibody comprises a heavy chain variable region and a light chain variable region, wherein the antibody is (a)(1)HC-FR1 containing the amino acid sequence of SEQ ID NO:9; (2) CDR-H1 containing the amino acid sequence of SEQ ID NO:1; (3) HC-FR2 containing the amino acid sequence of SEQ ID NO:10; (4) CDR-H2 containing the amino acid sequence of SEQ ID NO:2; (5) HC-FR3 containing the amino acid sequence of SEQ ID NO:11; (6) CDR-H3 containing the amino acid sequence of SEQ ID NO:3; and (7) HC-FR4 containing the amino acid sequence of SEQ ID NO:12; Heavy chain variable domains including, and / or (b)(1)LC-FR1 containing the amino acid sequence of SEQ ID NO:13; (2) CDR-L1 containing the amino acid sequence of SEQ ID NO:4; (3) LC-FR2 containing the amino acid sequence of SEQ ID NO:14; (4) CDR-L2 containing the amino acid sequence of SEQ ID NO:5; (5) LC-FR3 containing the amino acid sequence of SEQ ID NO:15; (6) CDR-L3 containing the amino acid sequence of SEQ ID NO:6; and (7) LC-FR4 containing the amino acid sequence of SEQ ID NO:16; Light chain variable domains including Includes.

[0093] In one aspect, an anti-TF antibody is provided herein that comprises a heavy chain variable domain containing the amino acid sequence of SEQ ID NO:7, or a light chain variable domain containing the amino acid sequence of SEQ ID NO:8.

[0094] In some embodiments, anti-TF antibodies are provided herein that include 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 with respect to the amino acid sequence of SEQ ID NO:7. In certain embodiments, the heavy chain variable domain comprising an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with respect to the amino acid sequence of SEQ ID NO:7 comprises substitutions (e.g., conservative substitutions), insertions, or deletions with respect to the reference sequence and retains the ability to bind to TF (e.g., human TF). In certain embodiments, a total of 1 to 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 located in the outer region (i.e., FR) of the CDR. In some embodiments, the anti-TF antibody contains the heavy chain variable domain sequence of SEQ ID NO:7, including its post-translational modifications. In a particular embodiment, the heavy chain variable domain contains one, two, or three CDRs selected from: (a) CDR-H1 containing the amino acid sequence of SEQ ID NO:1, (b) CDR-H2 containing the amino acid sequence of SEQ ID NO:2, and (c) CDR-H3 containing the amino acid sequence of SEQ ID NO:3.

[0095] In some embodiments, anti-TF antibodies are provided herein, comprising a light chain variable domain containing 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 with respect to the amino acid sequence of SEQ ID NO:8. In certain embodiments, the light chain variable domain containing 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 with respect to the amino acid sequence of SEQ ID NO:8 includes substitutions (e.g., conservative substitutions), insertions, or deletions with respect to the reference sequence and retains the ability to bind to TF (e.g., human TF). In certain embodiments, a total of 1 to 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 located in the outer region (i.e., FR) of the CDR. In some embodiments, the anti-TF antibody contains the light chain variable domain sequence of SEQ ID NO:8, including its post-translational modifications. In a particular embodiment, the light chain variable domain contains one, two, or three CDRs selected from: (a) CDR-L1 containing the amino acid sequence of SEQ ID NO:4, (b) CDR-L2 containing the amino acid sequence of SEQ ID NO:5, and (c) CDR-L3 containing the amino acid sequence of SEQ ID NO:6.

[0096] In some embodiments, the anti-TF antibody comprises a heavy chain variable domain as described in any of the embodiments provided above and a light chain variable domain as described in any of the embodiments provided above. In one embodiment, the antibody comprises a heavy chain variable domain sequence with SEQ ID NO:7 and a light chain variable domain sequence with SEQ ID NO:8, and also comprises post-translational modifications of these sequences.

[0097] In some embodiments, the anti-TF antibody in the anti-TF antibody-drug conjugate comprises i) a heavy chain CDR1 containing the amino acid sequence of SEQ ID NO:1, a heavy chain CDR2 containing the amino acid sequence of SEQ ID NO:2, a heavy chain CDR3 containing the amino acid sequence of SEQ ID NO:3; and ii) a light chain CDR1 containing the amino acid sequence of SEQ ID NO:4, a light chain CDR2 containing the amino acid sequence of SEQ ID NO:5, and a light chain CDR3 containing the amino acid sequence of SEQ ID NO:6, where the CDRs of the anti-TF antibody are defined by the IMGT numbering scheme.

[0098] In some embodiments, the anti-TF antibody in the anti-TF antibody-drug conjugate comprises i) an amino acid sequence having at least 85% sequence identity with a heavy chain variable region containing 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 containing the amino acid sequence of SEQ ID NO:8.

[0099] In some embodiments, the anti-TF antibody in the anti-TF antibody-drug conjugate comprises i) an amino acid sequence having at least 85% sequence identity to a heavy chain containing the amino acid sequence of SEQ ID NO: 17, and ii) an amino acid sequence having at least 85% sequence identity to a light chain containing the amino acid sequence of SEQ ID NO: 18.

[0100] In one embodiment, the antibody comprises a heavy chain sequence with SEQ ID NO:17 and a light chain sequence with SEQ ID NO:18, and includes post-translational modifications of these sequences. In another embodiment, the antibody comprises a heavy chain sequence with SEQ ID NO:17 and a light chain sequence with SEQ ID NO:18.

[0101] In some embodiments, the anti-TF antibody in the anti-TF antibody-drug conjugate is a monoclonal antibody.

[0102] In some embodiments, the anti-TF antibody in the anti-TF antibody-drug conjugate is tisotumab, also known as antibody 011 as described in WO 2011 / 157741 and WO 2010 / 066803.

[0103] The anti-TF antibody of the present invention may also be described or specified in terms of its binding affinity to TF (e.g., human TF). Preferred binding affinity may include the dissociation constant or K d 5 x 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.

[0104] Immunoglobulins are classified into five classes: IgA, IgD, IgE, IgG, and IgM, each possessing a heavy chain designated as α, δ, ε, γ, and μ, respectively. The γ and α classes are further subdivided 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 (discussed in Jefferis and Lefranc 2009. mAbs Vol 1 Issue 4 1-7), all of which are suitable for use in some embodiments of this specification. Common allotype variants in the human population are designated as a, f, n, z, or combinations thereof. In any embodiment of this specification, the antibody may contain a heavy chain Fc region containing a human IgG Fc region. In further embodiments, the human IgG Fc region contains human IgG1.

[0105] The antibody also includes modified derivatives, i.e., derivatives modified by covalent bonding of any type of molecule to the antibody, provided that the covalent bonding does not prevent the antibody from binding to TF or exerting a cell proliferation inhibitory 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, or binding to cell ligands or other proteins. Many of these chemical modifications can be carried out by known techniques, including but not limited to specific chemical cleavage, acetylation, formylation, or metabolic synthesis of tunicamycin. Furthermore, the derivative may contain one or more non-classical amino acids.

[0106] TIFF2026082887000010.tif210161

[0107] B. Structure of antibody-drug conjugates In some aspects, the anti-TF antibody-drug conjugate described herein includes a linker between the anti-TF antibody or its antigen-binding fragment and a cell proliferation inhibitory or cytotoxic drug. In some embodiments, the linker is indestructible. In some embodiments, the linker is cleavable.

[0108] In some embodiments, the linker is a cleavable peptide linker comprising maleimidocaproyl (MC), dipeptide valine-citrulline (vc), and p-aminobenzylcarbamate (PAB). In some embodiments, the cleavable peptide linker has the formula:MC-vc-PAB-, where, a) MC is The filename is TIFF2026082887000011.tif31128. b) vc is a dipeptide valine-citrulline, c) PAB is The filename is TIFF2026082887000012.tif32128.

[0109] 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 filename is TIFF2026082887000013.tif30128.

[0110] In some embodiments, the linker binds to a sulfhydryl residue of an anti-TF antibody or its antigen-binding fragment obtained by partial or complete reduction of the anti-TF antibody or its antigen-binding fragment. In some embodiments, the linker binds to a sulfhydryl residue of an anti-TF antibody or its antigen-binding fragment obtained by partial reduction of the anti-TF antibody or its antigen-binding fragment. In some embodiments, the linker binds to a sulfhydryl residue of an anti-TF antibody or its antigen-binding fragment obtained by complete reduction of the anti-TF antibody or its antigen-binding fragment.

[0111] In some aspects, the anti-TF antibody-drug conjugates described herein include a linker described herein between the anti-TF antibody or its antigen-binding fragment and a cell proliferation inhibitory or cytotoxic drug. Auristatins have been shown to interfere with microtubule dynamics, GTP hydrolysis, and nuclear and cell division (see Woyke et al (2001) Antimicrob. Agents and Chemother. 45(12): 3580-3584), and to possess anticancer activity (see U.S. Patent No. 5663149) 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 typical auristatin derivatives include AFP, MMAF (monomethyl auristatin F), and MMAE (monomethyl auristatin E). Suitable auristatins, auristatin analogs, derivatives, and prodrugs, as well as linkers suitable for conjugation of auristatin to its abs, are described, for example, in U.S. Patents 5,635,483, 5,780,588, 6,214,345, and International Patent Application Publications WO02088172, WO2004010957, WO2005081711, WO2005084390, WO2006132670, WO03026577, WO200700860, WO207011968, and WO205082023. In some embodiments of the anti-TF antibody-drug conjugates described herein, the cell proliferation inhibitory or cytotoxic drug is auristatin or a functional analogue (e.g., its functional peptide) or a functional derivative thereof. In some embodiments, the auristatin is monomethyl auristatin or a functional analogue (e.g., its functional peptide) or a functional derivative thereof.

[0112] In one embodiment, auristatin is monomethyl auristatin E (MMAE): The file is TIFF2026082887000014.tif36155, where the wavy lines indicate the linker connection points.

[0113] In one embodiment, auristatin is monomethyl auristatin F (MMAF): The file is TIFF2026082887000015.tif36154, where the wavy lines indicate the linking points to the linker.

[0114] In one embodiment, the cleavable peptide linker has the formula:MC-vc-PAB- and binds to MMAE. The resulting linker-aulistatin, MC-vc-PAB-MMAE, is also represented as vcMMAE. The vcMMAE drug linker portion and conjugation methods are disclosed in WO2004010957, US7659241, US7829531 and US7851437. When vcMMAE binds to the anti-TF antibody or its antigen-binding fragment described herein, the resulting structure is: The formula is TIFF2026082887000016.tif31161, where p represents a number from 1 to 8 (e.g., 1, 2, 3, 4, 5, 6, 7, or 8), for example p may be 3 to 5, S represents a sulfhydryl residue of the anti-TF antibody, and Ab represents the anti-TF antibody or its antigen-binding fragment as described herein. In one embodiment, the mean value of p in a population of antibody-drug conjugates is about 4. In some embodiments, p is measured by hydrophobic interaction chromatography (HIC), for example, by splitting the drug-loaded species based on increasing hydrophobicity, with the least hydrophobic non-conjugate form eluting first and the most hydrophobic drug form eluting last; in this case, the area percentage of the peaks 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), for example, 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 loading forms on an RP column; in this case, the peak percentage is obtained from the integral of the light and heavy chain peaks and is used in combination with the drug loading assigned to each peak to calculate the weighted average drug-to-antibody ratio. See Ouyang, J., 2013, Antibody-Drug Conjugates, Methods in Molecular Biology (Methods and Protocols).

[0115] In one embodiment, the cleavable peptide linker has the formula:MC-vc-PAB- and binds to MMAF. The resulting linker-aulistatin, MC-vc-PAB-MMAF, is also represented as vcMMAF. In another embodiment, the non-cleavable linker MC binds to MMAF. The resulting linker-aulistatin MC-MMAF, is also represented as mcMMAF. Both vcMMAF and mcMMAF drug linker moieties and conjugation methods are disclosed in WO2005081711 and US7498298. When vcMMAF or mcMMAF binds to the anti-TF antibody or its antigen-binding fragment described herein, the resulting structure is: The reference number is TIFF2026082887000017.tif85164, where p represents a number from 1 to 8 (e.g., 1, 2, 3, 4, 5, 6, 7, or 8), for example p may be 3 to 5, S represents a sulfhydryl residue of the anti-TF antibody, and Ab or mAb represents the anti-TF antibody or its antigen-binding fragment as described herein. In one embodiment, the mean value of p in a population of antibody-drug conjugates is about 4. In some embodiments, p is measured by hydrophobic interaction chromatography (HIC), for example, by splitting the drug-loaded species based on increasing hydrophobicity, with the least hydrophobic non-conjugate form eluting first and the most hydrophobic drug form eluting last; in this case, the area percentage of the peaks 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), for example, 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 loading forms on an RP column; in this case, the peak percentage is obtained from the integral of the light and heavy chain peaks and is used in combination with the drug loading assigned to each peak to calculate the weighted average drug-to-antibody ratio. See Ouyang, J., 2013, Antibody-Drug Conjugates, Methods in Molecular Biology (Methods and Protocols).

[0116] In one embodiment, the antibody-drug conjugate is tisotumab vedotin or a biosimilar thereof.

[0117] In one embodiment, the antibody-drug conjugate is tisotumab vedotin.

[0118] C. Nucleic acids, host cells, and methods for production. In some aspects, nucleic acids encoding the anti-TF antibody or its antigen-binding fragment described herein are also provided herein. Vectors comprising the nucleic acid encoding the anti-TF antibody or its antigen-binding fragment described herein are further provided herein. Host cells expressing the nucleic acid encoding the anti-TF antibody or its antigen-binding fragment described herein are further provided herein. Host cells possessing vectors comprising the nucleic acid encoding the anti-TF antibody or its antigen-binding fragment described herein are further provided herein. Methods for producing anti-TF antibodies, linkers, and antibody-drug conjugates are described herein in U.S. Patent No. 9,168,314.

[0119] The anti-TF antibodies described herein can be prepared by known recombinant techniques using well-known expression vector systems and host cells. In one embodiment, the antibody is prepared in CHO cells using a GS expression vector system, as disclosed in De la Cruz Edmunds et al., 2006, Molecular Biotechnology 34; 179-190; EP216846; U.S. Patent No. 5,981,216; WO 87 / 04462; EP323997; U.S. Patent No. 5,591,639; U.S. Patent No. 5,658,759; EP338841; U.S. Patent No. 5,879,936; and U.S. Patent No. 5,891,693.

[0120] After isolating and purifying antibodies from cell culture using techniques well known in the art, they are conjugated with auristatin via a linker, as described in U.S. Patent No. 9,168,314.

[0121] The monoclonal anti-TF antibodies described herein may be prepared, for example, by the hybridoma method first described in Kohler et al., Nature, 256, 495 (1975), or by the recombinant DNA method. Monoclonal antibodies can also be isolated from phage antibody libraries using, for example, 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. For example, monoclonal antibodies can be obtained from hybridomas prepared from mouse spleen B cells derived from mice immunized with the antigen of interest, for example, in the form of cells expressing the antigen on their surface, or in the form of nucleic acids encoding the antigen of interest. Monoclonal antibodies can also be obtained from hybridomas derived from antibody-expressing cells of immunized human or non-human mammals, such as rats, dogs, and primates.

[0122] In one embodiment, the antibody of the present invention is a human antibody. Human monoclonal antibodies against tissue factor can be produced using transgenic or transchromosomal mice that possess a part of the human immune system rather than a mouse strain. Such transgenic and transchromosomic mice include mice referred to herein as HuMAb mice and KM mice, respectively, and are collectively referred to herein as "transgenic mice."

[0123] HuMAb mice contain human immunoglobulin gene minilocuses encoding unrearranged human heavy chain (μ and γ) and κ light chain immunoglobulin sequences, along with targeted mutations that inactivate endogenous μ and κ chain loci (Lonberg, N. et al., Nature, 368, 856-859 (1994)). As a result, these 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 produce high-affinity human IgG,κ monoclonal antibodies (Lonberg, N. et al. (1994), previously cited; published in Lonberg, N. 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 creation of HuMAb mice is described in detail in the following literature: Taylor, L. et al., Nucleic Acids Research. 20:6287-6295 (1992); Chen, J. et al., International Immunology. 5:647-656 (1993); Tuaillon et 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. Patents 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.

[0124] HCo7 mice possess JKD disruption of their endogenous light chain (κ) gene (described in Chen et al, EMBO J. 12:821-830 (1993)), CMD disruption of their endogenous heavy chain gene (described in Example 1 of WO 01 / 14424), KCo5 human κ light chain transgene (described in Fishwild et al., Nature Biotechnology, 14:845-851 (1996)), and HCo7 human heavy chain transgene (described in U.S. Patent No. 5,770,429).

[0125] HCo12 mice possess JKD disruption of their endogenous light chain (κ) gene (described in Chen et al, EMBO J. 12:821-830 (1993)), CMD disruption of their 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).

[0126] The HCo17 transgenic mouse strain (see also US 2010 / 0077497) was created by simultaneous injection of an 80kb pHC2 insert (Taylor et al. (1994) Int. Immunol., 6:579-591), a kb pVX6 insert, and a ~460kb yeast artificial chromosome fragment of the yIgH24 chromosome. This strain was named (HCo17) 25950. Next, the (HCo17) 25950 line was 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 chain and κ light chain transgenes in a homozygous background due to disruption of endogenous mouse heavy chain and κ light chain loci.

[0127] The HCo20 transgenic mouse line was obtained by simultaneously injecting the minilocust 30 heavy chain transgene pHC2, germline variable region (Vh)-containing YAC yIgH10, and the minilocust construct pVx6 (described in WO09097006). Next, this (HCo20) line was 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 chain and κ light chain transgenes in a homozygous background due to disruption of endogenous mouse heavy chain and κ light chain loci.

[0128] To create HuMab mice possessing the beneficial characteristics of the Balb / c strain, Kco05 [MIK] (Balb) mice were produced by backcrossing the KCo5 strain (described in Fishwild et al, (1996) Nature Biotechnology, 14:845-851) with wild-type Balb / c mice. These Kco05 [MIK] (Balb) mice were then crossed with HuMab mice to produce the mouse described in WO09097006. Using this cross, Balb / c hybrids were created for the HCo12, HCo17, and HCo20 strains.

[0129] In the KM mouse strain, the endogenous mouse κ 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 possesses a human κ light chain transgene, as described in Fishwild et al., Nature Biotechnology, 14:845-851 (1996). This mouse strain also possesses a human heavy chain transchromosome consisting of chromosome 14 fragment hCF(SC20), as described in WO 02 / 43478.

[0130] Using splenocytes derived from these transgenic mice, hybridomas secreting human monoclonal antibodies can be produced according to known techniques. The human monoclonal or polyclonal antibodies of the present invention, or antibodies of the present invention derived from other species, can also be genetically produced by creating another non-human mammal or plant in which the immunoglobulin heavy and light chain sequences of interest are transgenic, and then producing the antibodies in a recoverable form therefrom. In relation to transgenic production in mammals, the antibodies can be produced in goats, cattle, or other mammals and recovered from their milk. See, for example, U.S. Patents 5,827,690, 5,756,687, 5,750,172, and 5,741,957.

[0131] Furthermore, the human antibodies of the present invention or antibodies derived from other species can be produced by display techniques, such as, but not limited to, phage display, retrovirus display, ribosome display, and other techniques, 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 USA, 87:6378-6382 (1990); Russel et al., Nucl. Acids Research, 21:1081-4085 (1993); 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). If display technology is used to produce antibodies that are not human antibodies, such antibodies may be humanized.

[0132] III. Treatment method A. Cervical cancer Despite advances in screening, diagnosis, prevention, and treatment, cervical cancer remains a leading cause of cancer-related death in women. It accounts for approximately 4% of all newly diagnosed cancers and 4% of all cancer deaths. (See Zhu et al., 2016, Drug Des. Devel. Ther. 10:1885-1895.) Cervical cancer is the seventh most common cancer in women worldwide and the 16th most common in the European Union. Depending on the stage at initial onset, cervical cancer recurs in 25–61% of women. (See Tempfer et al., 2016, Oncol. Res. Treat. 39:525-533.) In most cases, recurrent disease is diagnosed within two years of initial treatment and can be observed in various locations. Chemotherapy is the standard treatment for these patients. (See Zhu et al., 2016, Drug Des. Devel. Ther. 10:1885-1895.) Currently, the median overall survival is over one year, but the 5-year relative survival rate for stage IV cervical cancer is only 15%, indicating a great need for improved treatments for cervical cancer.

[0133] The present invention provides a method for treating cervical cancer using an antibody-drug conjugate described herein. In a preferred aspect, the antibody-drug conjugate is tisotumab vedotin. In one aspect, the antibody-drug conjugate described herein is for use in a method for treating cervical cancer in a subject. In some aspects, the subject has not previously received treatment for cervical cancer. In some aspects, the subject has received at least one prior treatment for cervical cancer. In some aspects, the subject has been previously treated with bevacizumab. In some aspects, the subject has been previously treated with paclitaxel and cisplatin. In some aspects, the subject has been previously treated with paclitaxel and carboplatin. In some aspects, the subject has been previously treated with paclitaxel and topotecan. In some aspects, the subject has been previously treated with bevacizumab, paclitaxel, and cisplatin. In some embodiments, the subject has been previously treated with bevacizumab, paclitaxel, and carboplatin. In some embodiments, the subject has been previously treated with bevacizumab, paclitaxel, and topotecan. In some embodiments, the subject has not been previously treated with bevacizumab. In some embodiments, the subject is ineligible for treatment with bevacizumab. In some embodiments, the subject is not a candidate for curative treatment. In some embodiments, curative treatment is radiotherapy and / or visceral resection. In some embodiments, curative treatment is radiotherapy. In some embodiments, curative treatment is visceral resection. In some embodiments, the subject is 15 to 25 years old. In some embodiments, the subject is 20 to 25 years old. In some embodiments, the subject is 25 to 30 years old. In some embodiments, the subject is 30 to 35 years old. In some embodiments, the subject is 35 to 44 years old. In some embodiments, the target age is 35 to 40 years old. In some embodiments, the target age is 40 to 45 years old. In some embodiments, the target age is 45 to 50 years old. In some embodiments, the target age is 50 to 55 years old. In some embodiments, the target age is 55 to 60 years old. In some embodiments, the target age is 60 to 65 years old.In some embodiments, the subjects are 65 to 70 years old. In some embodiments, the subjects are 70 to 75 years old. In some embodiments, the subjects are 75 to 80 years old. In some embodiments, the subjects are under 65 years old. In some embodiments, the subjects are 65 years of age or older. In some embodiments, the subjects have at least a TF histological score of 1. The TF histological score is determined by analyzing membrane and cytoplasmic TF expression in biopsy samples derived from the subjects using an analytically validated immunohistochemical assay. The TF histological score (H score) is calculated based on the percentage of tumor tissue with low (1+), medium (2+), and high (3+) membrane or cytoplasmic TF expression in evaluable samples using the following formula: H score = (1 × [% cells 1+]) + (2 × [% cells 2+]) + (3 × [% cells 3+]). In some embodiments, the subjects have an East Coast Clinical Oncology Group (ECOG) score of 0. In some embodiments, the subject has an ECOG score of 1. In some embodiments, the subject has an ECOG score of 2. In some embodiments, the subject has an ECOG score of 3. In some embodiments, the subject has an ECOG score of 4. In certain embodiments, the subject is a human.

[0134] In some aspects of the methods or uses provided herein, cervical cancer is adenocarcinoma, adenosquamous cell carcinoma, squamous cell carcinoma, small cell carcinoma, neuroendocrine tumor, glassy cell carcinoma, or villoglandular adenocarcinoma. In some aspects, cervical cancer is adenocarcinoma, adenosquamous cell carcinoma, or squamous cell carcinoma. In some aspects, cervical cancer is adenocarcinoma. In some aspects, cervical cancer is adenosquamous cell carcinoma. In some aspects, cervical cancer is squamous cell carcinoma. In some aspects, cervical cancer is non-squamous cell carcinoma. 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 cervical cancer cells express TF. In some embodiments, the percentage of cells expressing TF is determined by immunohistochemistry (IHC). In some embodiments, the percentage of cells expressing TF is determined by flow cytometry. In some embodiments, the percentage of cells expressing TF is determined by enzyme-linked immunosorbent assay (ELISA).

[0135] In some aspects of the methods or uses provided herein, cervical cancer is stage 0, 1, 2, 3, or 4. In some aspects, cervical cancer is stage 0, 1A, 1B, 2A, 2B, 3A, 3B, 4A, or 4B. In some aspects, cervical cancer is staged according to the International Federation of Gynecology and Obstetrics (FIGO) staging system. In some aspects, staging is based on clinical examination. In some aspects, stage 0 cervical cancer is characterized by cancer confined to the superficial layers of the cervix (the cells lining the inside of the cervix). In some aspects, stage 1 cervical cancer is characterized by cancer growing deep into the cervix but not yet spreading beyond it. In some aspects, stage 1A cervical cancer is characterized by invasive cancer that can only be diagnosed by microscopic examination, with maximum invasion less than 5 mm and maximum progression less than 7 mm. In some embodiments, stage 1B cervical cancer is characterized by lesions that are clinically visible to the naked eye and confined to the cervix. In some embodiments, stage 2 cervical cancer is characterized by cervical cancer that has invaded beyond the uterus but not into the pelvic wall or the lower third of the vagina. In some embodiments, stage 2A cervical cancer is characterized by no parametrial invasion. In some embodiments, stage 2B cervical cancer is characterized by parametrial invasion. In some embodiments, stage 3 cervical cancer is characterized by tumors that have spread to the pelvic wall and / or invade the lower third of the vagina and / or cause hydronephrosis or a non-functional kidney. In some embodiments, stage 3A cervical cancer is characterized by tumors that invade the lower third of the vagina but not into the pelvic wall. In some embodiments, stage 3B cervical cancer is characterized by cancer that has invaded the pelvic wall and / or causes hydronephrosis or a non-functional kidney. In some embodiments, stage 4 cervical cancer is characterized by the cancer extending beyond the true pelvis or invading the mucous membrane of the bladder or rectum. In some embodiments, stage 4A cervical cancer is characterized by the tumor spreading to adjacent organs. In some embodiments, stage 4B cervical cancer is characterized by the tumor spreading to distant organs.In some embodiments, cervical cancer is advanced cervical cancer, e.g., grade 3 or grade 4 cervical cancer. In some embodiments, advanced cervical cancer is metastatic cervical cancer. In some embodiments, cervical cancer is metastatic and recurrent cervical cancer. In some embodiments, cervical cancer is metastatic cervical cancer. In some embodiments, cervical cancer is recurrent cervical cancer.

[0136] In some aspects of the methods or uses provided herein, the subject had previously received treatment for cervical cancer. In some aspects, the subject did not respond to treatment (e.g., the subject experienced disease progression during treatment). In some aspects, one or more therapeutic agents administered to the subject were not the anti-TF antibody-drug conjugates described herein. In some aspects, one or more therapeutic agents administered to the subject were paclitaxel, cisplatin, carboplatin, topotecan, gemcitabine, fluorouracil, ixabepyrone, imatinib mesylate, docetaxel, gefitinib, nab-paclitaxel, pemetrexed, vinorelbine, doxil, cetuximab, pembrolizumab, nivolumab, bevacizumab, or any combination thereof. In some aspects, one or more therapeutic agents administered to the subject was gemcitabine. In some embodiments, one or more therapeutic agents administered to the subjects were fluorouracil. In some embodiments, one or more therapeutic agents administered to the subjects were ixabepyrone. In some embodiments, one or more therapeutic agents administered to the subjects were imatinib mesylate. In some embodiments, one or more therapeutic agents administered to the subjects were docetaxel. In some embodiments, one or more therapeutic agents administered to the subjects were gefitinib. In some embodiments, one or more therapeutic agents administered to the subjects were nab-paclitaxel. In some embodiments, one or more therapeutic agents administered to the subjects were pemetrexed. In some embodiments, one or more therapeutic agents administered to the subjects were vinorelbine. In some embodiments, one or more therapeutic agents administered to the subjects were doxil. In some embodiments, one or more therapeutic agents administered to the subjects were cetuximab. In some embodiments, one or more therapeutic agents administered to the subjects were pembrolizumab. In some embodiments, one or more therapeutic agents administered to the subjects were nivolumab. In some embodiments, one or more therapeutic agents administered to the subjects were bevacizumab. In some embodiments, one or more therapeutic agents administered to the subjects were platinum-based therapeutic agents.In some embodiments, one or more therapeutic agents administered to the subjects were gemcitabine and fluorouracil. In some embodiments, one or more therapeutic agents administered to the subjects were paclitaxel and cisplatin. In some embodiments, one or more therapeutic agents administered to the subjects were paclitaxel and carboplatin. In some embodiments, one or more therapeutic agents administered to the subjects were paclitaxel and topotecan. In some embodiments, one or more therapeutic agents administered to the subjects was bevacizumab. In some embodiments, one or more therapeutic agents administered to the subject were selected from the group consisting of chemotherapeutic agents, 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 embodiments, one or more therapeutic agents administered to the subject were chemotherapeutic agents. In some embodiments, one or more therapeutic agents administered to the subject were cisplatin. In some embodiments, one or more therapeutic agents administered to the subject were carboplatin. In some embodiments, one or more therapeutic agents administered to the subjects were paclitaxel. In some embodiments, one or more therapeutic agents administered to the subjects were topotecan. In some embodiments, one or more therapeutic agents administered to the subjects were a combination of bevacizumab and paclitaxel. In some embodiments, one or more therapeutic agents administered to the subjects were a combination of bevacizumab and cisplatin. In some embodiments, one or more therapeutic agents administered to the subjects were a combination of bevacizumab and carboplatin. In some embodiments, one or more therapeutic agents administered to the subjects were a combination of paclitaxel and topotecan.In some embodiments, one or more therapeutic agents administered to the subject were a combination of bevacizumab and topotecan. In some embodiments, one or more therapeutic agents administered to the subject were a combination of bevacizumab, cisplatin, and paclitaxel. In some embodiments, one or more therapeutic agents administered to the subject were a combination of bevacizumab, carboplatin, and paclitaxel. In some embodiments, one or more therapeutic agents administered to the subject were a combination of bevacizumab, paclitaxel, and topotecan. In some embodiments, the subject received irradiation treatment for cervical cancer but did not respond to irradiation. In some embodiments, the subject did not respond to prior treatment with two or fewer systemic treatment regimens. In some embodiments, the subject did not respond to prior treatment with one or two systemic treatment regimens. In some embodiments, the subject did not respond to prior treatment with one systemic treatment regimen. In some embodiments, the subject did not respond to prior treatment with two systemic treatment regimens.

[0137] In some aspects of the methods or uses provided herein, the subject has previously been treated for cervical cancer with one or more therapeutic agents. In some aspects, the subject experienced a relapse after such treatment. In some aspects, the one or more therapeutic agents administered to the subject were not the anti-TF antibody-drug conjugates described herein. In some aspects, the one or more therapeutic agents administered to the subject were paclitaxel, cisplatin, carboplatin, topotecan, gemcitabine, fluorouracil, ixabepyrone, imatinib mesylate, docetaxel, gefitinib, nab-paclitaxel, pemetrexed, vinorelbine, doxil, cetuximab, pembrolizumab, nivolumab, bevacizumab, or any combination thereof. In some aspects, the one or more therapeutic agents administered to the subject was gemcitabine. In some aspects, the one or more therapeutic agents administered to the subject was fluorouracil. In some embodiments, one or more therapeutic agents administered to the subjects were ixabepyrone. In some embodiments, one or more therapeutic agents administered to the subjects were imatinib mesylate. In some embodiments, one or more therapeutic agents administered to the subjects were docetaxel. In some embodiments, one or more therapeutic agents administered to the subjects were gefitinib. In some embodiments, one or more therapeutic agents administered to the subjects were nab-paclitaxel. In some embodiments, one or more therapeutic agents administered to the subjects were pemetrexed. In some embodiments, one or more therapeutic agents administered to the subjects were vinorelbine. In some embodiments, one or more therapeutic agents administered to the subjects were doxil. In some embodiments, one or more therapeutic agents administered to the subjects were cetuximab. In some embodiments, one or more therapeutic agents administered to the subjects were pembrolizumab. In some embodiments, one or more therapeutic agents administered to the subjects were nivolumab. In some embodiments, one or more therapeutic agents administered to the subjects were bevacizumab. In some embodiments, one or more therapeutic agents administered to the subjects were platinum-based therapeutic agents.In some embodiments, one or more therapeutic agents administered to the subjects were gemcitabine and fluorouracil. In some embodiments, one or more therapeutic agents administered to the subjects were paclitaxel and cisplatin. In some embodiments, one or more therapeutic agents administered to the subjects were paclitaxel and carboplatin. In some embodiments, one or more therapeutic agents administered to the subjects were paclitaxel and topotecan. In some embodiments, one or more therapeutic agents administered to the subjects was bevacizumab. In some embodiments, one or more therapeutic agents administered to the subject were selected from the group consisting of chemotherapeutic agents, 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 embodiments, one or more therapeutic agents administered to the subject were chemotherapeutic agents. In some embodiments, one or more therapeutic agents administered to the subject were cisplatin. In some embodiments, one or more therapeutic agents administered to the subject were carboplatin. In some embodiments, one or more therapeutic agents administered to the subjects were paclitaxel. In some embodiments, one or more therapeutic agents administered to the subjects were topotecan. In some embodiments, one or more therapeutic agents administered to the subjects were a combination of bevacizumab and paclitaxel. In some embodiments, one or more therapeutic agents administered to the subjects were a combination of bevacizumab and cisplatin. In some embodiments, one or more therapeutic agents administered to the subjects were a combination of bevacizumab and carboplatin. In some embodiments, one or more therapeutic agents administered to the subjects were a combination of paclitaxel and topotecan.In some embodiments, one or more therapeutic agents administered to the subject were a combination of bevacizumab and topotecan. In some embodiments, one or more therapeutic agents administered to the subject were a combination of bevacizumab, cisplatin, and paclitaxel. In some embodiments, one or more therapeutic agents administered to the subject were a combination of bevacizumab, carboplatin, and paclitaxel. In some embodiments, one or more therapeutic agents administered to the subject were a combination of bevacizumab, paclitaxel, and topotecan. In some embodiments, the subject received treatment for cervical cancer by radiation but experienced a relapse after radiation treatment. In some embodiments, the subject experienced a relapse after prior treatment with two or fewer systemic treatment regimens. In some embodiments, the subject experienced a relapse after prior treatment with one or two systemic treatment regimens. In some embodiments, the subject experienced a relapse after prior treatment with one systemic treatment regimen. In some cases, the subjects experienced relapse after prior treatment with two systemic treatment regimens.

[0138] In some aspects of the methods or uses provided herein, the subject has previously been treated for cervical cancer with one or more therapeutic agents. In some aspects, the subject experienced disease progression after such treatment. In some aspects, the one or more therapeutic agents administered to the subject were not the anti-TF antibody-drug conjugates described herein. In some aspects, the one or more therapeutic agents administered to the subject were paclitaxel, cisplatin, carboplatin, topotecan, gemcitabine, fluorouracil, ixabepyrone, imatinib mesylate, docetaxel, gefitinib, nab-paclitaxel, pemetrexed, vinorelbine, doxil, cetuximab, pembrolizumab, nivolumab, bevacizumab, or any combination thereof. In some aspects, the one or more therapeutic agents administered to the subject was gemcitabine. In some aspects, the one or more therapeutic agents administered to the subject was fluorouracil. In some embodiments, one or more therapeutic agents administered to the subjects were ixabepyrone. In some embodiments, one or more therapeutic agents administered to the subjects were imatinib mesylate. In some embodiments, one or more therapeutic agents administered to the subjects were docetaxel. In some embodiments, one or more therapeutic agents administered to the subjects were gefitinib. In some embodiments, one or more therapeutic agents administered to the subjects were nab-paclitaxel. In some embodiments, one or more therapeutic agents administered to the subjects were pemetrexed. In some embodiments, one or more therapeutic agents administered to the subjects were vinorelbine. In some embodiments, one or more therapeutic agents administered to the subjects were doxil. In some embodiments, one or more therapeutic agents administered to the subjects were cetuximab. In some embodiments, one or more therapeutic agents administered to the subjects were pembrolizumab. In some embodiments, one or more therapeutic agents administered to the subjects were nivolumab. In some embodiments, one or more therapeutic agents administered to the subjects were bevacizumab. In some embodiments, one or more therapeutic agents administered to the subjects were platinum-based therapeutic agents.In some embodiments, one or more therapeutic agents administered to the subjects were gemcitabine and fluorouracil. In some embodiments, one or more therapeutic agents administered to the subjects were paclitaxel and cisplatin. In some embodiments, one or more therapeutic agents administered to the subjects were paclitaxel and carboplatin. In some embodiments, one or more therapeutic agents administered to the subjects were paclitaxel and topotecan. In some embodiments, one or more therapeutic agents administered to the subjects was bevacizumab. In some embodiments, one or more therapeutic agents administered to the subject were selected from the group consisting of chemotherapeutic agents, 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 embodiments, one or more therapeutic agents administered to the subject were chemotherapeutic agents. In some embodiments, one or more therapeutic agents administered to the subject were cisplatin. In some embodiments, one or more therapeutic agents administered to the subject were carboplatin. In some embodiments, one or more therapeutic agents administered to the subjects were paclitaxel. In some embodiments, one or more therapeutic agents administered to the subjects were topotecan. In some embodiments, one or more therapeutic agents administered to the subjects were a combination of bevacizumab and paclitaxel. In some embodiments, one or more therapeutic agents administered to the subjects were a combination of bevacizumab and cisplatin. In some embodiments, one or more therapeutic agents administered to the subjects were a combination of bevacizumab and carboplatin. In some embodiments, one or more therapeutic agents administered to the subjects were a combination of paclitaxel and topotecan.In some embodiments, one or more therapeutic agents administered to the subject were a combination of bevacizumab and topotecan. In some embodiments, one or more therapeutic agents administered to the subject were a combination of bevacizumab, cisplatin, and paclitaxel. In some embodiments, one or more therapeutic agents administered to the subject were a combination of bevacizumab, carboplatin, and paclitaxel. In some embodiments, one or more therapeutic agents administered to the subject were a combination of bevacizumab, paclitaxel, and topotecan. In some embodiments, the subject had received prior treatment for cervical cancer by radiation but experienced disease progression after radiation treatment. In some embodiments, the subject experienced disease progression after prior treatment with two or fewer systemic treatment regimens. In some embodiments, the subject experienced disease progression after prior treatment with one or two systemic treatment regimens. In some embodiments, the subject experienced disease progression after prior treatment with one systemic treatment regimen. In some cases, the subjects experienced disease progression after prior treatment with two systemic treatment regimens.

[0139] In some aspects, eligible subjects had second-line or third-line recurrent or metastatic cervical cancer and, if eligible for bevacizumab administration according to local standards, had experienced disease progression during or after administration of a chemotherapy doublet (paclitaxel + cisplatin / carboplatin, or paclitaxel + topotecan). Prior chemoradiotherapy was not considered a line of treatment. Bevacizumab in combination with cisplatin / carboplatin + paclitaxel, or paclitaxel + topotecan, will hereafter be referred to as "bevacizumab + chemotherapy doublet."

[0140] B. Route of administration The antibody-drug conjugates or antigen-binding fragments described herein can be administered via any suitable route and method. Suitable routes of administration for the antibody-drug conjugates of the present invention are well known in the art and can be selected by those skilled in the art. In one embodiment, the antibody-drug conjugate is administered parenterally. Parenteral administration refers to methods of administration other than enteral administration and topical application, usually by injection, and includes injections and infusions in the epidermis, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, intratendinous, intratracheal, subcutaneous, subepidermal, intraarticular, subcapsular, subarachnoid, intraspinal, intracranial, intrathoracic, epidural, and intrasternal regions. In some embodiments, the route of administration for the antibody-drug conjugates or antigen-binding fragments described herein is intravenous injection or infusion. In some embodiments, the route of administration for the antibody-drug conjugates or antigen-binding fragments described herein is intravenous infusion.

[0141] C. Dosage and frequency of administration In one aspect, the present invention provides a method for treating a subject having cervical cancer as described herein using a specific dose of the antibody-drug conjugate or antigen-binding fragment described herein, wherein the subject is administered the antibody-drug conjugate or antigen-binding fragment described herein at a specific frequency until disease progression or unacceptable toxicity occurs.

[0142] In one embodiment of the method or use provided herein, the antibody-drug conjugate or its antigen-binding fragment described herein is administered to the subject in a dose ranging from about 1.5 mg to about 2.1 mg per kg of body weight. In certain embodiments, the dose is 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 one embodiment, the dose is 2.0 mg / kg. In several embodiments, the dose is 2.0 mg / kg, and the antibody-drug conjugate is tisotumab vedotin.

[0143] In one embodiment of the methods, uses, or manufactured articles for use provided herein, the anti-TF antibody-drug conjugate or its antigen-binding fragment described herein is administered to the subject in a dose ranging from about 0.65 mg to about 2.1 mg per kg of body weight of the subject. In a particular embodiment, the dose is about 0.65 mg / kg, about 0.7 mg / kg, about 0.75 mg / kg, about 0.8 mg / kg, about 0.85 mg / kg, 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 0.65 mg / kg. In another embodiment, the dose is about 0.9 mg / kg. In one embodiment, the dose is approximately 1.3 mg / kg. In another embodiment, the dose is approximately 2.0 mg / kg. In a specific embodiment, the dose is 0.65 mg / kg, 0.7 mg / kg, 0.75 mg / kg, 0.8 mg / kg, 0.85 mg / kg, 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 0.65 mg / kg. In another embodiment, the dose is 0.9 mg / kg. In another embodiment, the dose is 1.3 mg / kg. In another embodiment, the dose is 2.0 mg / kg. In some embodiments, the dose is 0.65 mg / kg and the anti-TF antibody-drug conjugate is tisotumab vedotin. In some embodiments, the dose is 0.9 mg / kg and the anti-TF antibody-drug conjugate is tisotumab vedotin. In some embodiments, the dose is 1.3 mg / kg and the anti-TF antibody-drug conjugate is tisotumab vedotin. In some embodiments, the dose is 2.0 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.

[0144] In one embodiment of the method or use provided herein, the antibody-drug conjugate or antigen-binding fragment described herein is administered to a subject once every 1 to 4 weeks. In a particular embodiment, the antibody-drug conjugate or antigen-binding fragment described herein is administered once every 1 week, once every 2 weeks, once every 3 weeks, or once every 4 weeks. In one embodiment, the antibody-drug conjugate or antigen-binding fragment described herein is administered once every 3 weeks. In one embodiment, the antibody-drug conjugate or antigen-binding fragment described herein is administered once every 3 weeks. In some embodiments, the dose is approximately 0.65 mg / kg and is administered once every 1 week. In some embodiments, the dose is approximately 0.65 mg / kg and is administered once every 2 weeks. In some embodiments, the dose is approximately 0.65 mg / kg and is administered once every 3 weeks. In some embodiments, the dose is approximately 0.65 mg / kg and is administered once every 4 weeks. In some embodiments, the dose is approximately 0.7 mg / kg and is administered about once a week. In some embodiments, the dose is approximately 0.7 mg / kg and is administered about once every two weeks. In some embodiments, the dose is approximately 0.7 mg / kg and is administered about once every three weeks. In some embodiments, the dose is approximately 0.7 mg / kg and is administered about once every four weeks. In some embodiments, the dose is approximately 0.75 mg / kg and is administered about once a week. In some embodiments, the dose is approximately 0.75 mg / kg and is administered about once every two weeks. In some embodiments, the dose is approximately 0.75 mg / kg and is administered about once every three weeks. In some embodiments, the dose is approximately 0.75 mg / kg and is administered about once every four weeks. In some embodiments, the dose is approximately 0.8 mg / kg and is administered about once a week. In some embodiments, the dose is approximately 0.8 mg / kg and is administered about once every two weeks. In some embodiments, the dose is approximately 0.8 mg / kg and is administered once every three weeks. In some embodiments, the dose is approximately 0.8 mg / kg and is administered once every four weeks. In some embodiments, the dose is approximately 0.85 mg / kg and is administered once every week.In some embodiments, the dose is approximately 0.85 mg / kg and is administered once every two weeks. In some embodiments, the dose is approximately 0.85 mg / kg and is administered once every three weeks. In some embodiments, the dose is approximately 0.85 mg / kg and is administered once every four weeks. In some embodiments, the dose is approximately 0.9 mg / kg and is administered once every week. In some embodiments, the dose is approximately 0.9 mg / kg and is administered once every two weeks. In some embodiments, the dose is approximately 0.9 mg / kg and is administered once every three weeks. In some embodiments, the dose is approximately 0.9 mg / kg and is administered once every four weeks. In some embodiments, the dose is approximately 1.0 mg / kg and is administered once every week. In some embodiments, the dose is approximately 1.0 mg / kg and is administered once every two weeks. In some embodiments, the dose is approximately 1.0 mg / kg and is administered once every three weeks. In some embodiments, the dose is approximately 1.0 mg / kg and is administered once every four weeks. In some embodiments, the dose is approximately 1.1 mg / kg and is administered once every week. In some embodiments, the dose is approximately 1.1 mg / kg and is administered once every two weeks. In some embodiments, the dose is approximately 1.1 mg / kg and is administered once every three weeks. In some embodiments, the dose is approximately 1.1 mg / kg and is administered once every four weeks. In some embodiments, the dose is approximately 1.2 mg / kg and is administered once every week. In some embodiments, the dose is approximately 1.2 mg / kg and is administered once every two weeks. In some embodiments, the dose is approximately 1.2 mg / kg and is administered once every three weeks. In some embodiments, the dose is approximately 1.2 mg / kg and is administered once every four weeks. In some embodiments, the dose is approximately 1.3 mg / kg and is administered once every week. In some embodiments, the dose is approximately 1.3 mg / kg and is administered once every two weeks. In some embodiments, the dose is approximately 1.3 mg / kg and is administered once every three weeks. In some embodiments, the dose is approximately 1.3 mg / kg and is administered once every four weeks. In some embodiments, the dose is approximately 1.4 mg / kg and is administered once every week.In some embodiments, the dose is approximately 1.4 mg / kg and is administered once every two weeks. In some embodiments, the dose is approximately 1.4 mg / kg and is administered once every three weeks. In some embodiments, the dose is approximately 1.4 mg / kg and is administered once every four weeks. In some embodiments, the dose is approximately 1.5 mg / kg and is administered once every week. In some embodiments, the dose is approximately 1.5 mg / kg and is administered once every two weeks. In some embodiments, the dose is approximately 1.5 mg / kg and is administered once every three weeks. In some embodiments, the dose is approximately 1.5 mg / kg and is administered once every four weeks. In some embodiments, the dose is approximately 1.6 mg / kg and is administered once every week. In some embodiments, the dose is approximately 1.6 mg / kg and is administered once every two weeks. In some embodiments, the dose is approximately 1.6 mg / kg and is administered once every three weeks. In some embodiments, the dose is approximately 1.6 mg / kg and is administered once every four weeks. In some embodiments, the dose is approximately 1.7 mg / kg and is administered once every week. In some embodiments, the dose is approximately 1.7 mg / kg and is administered once every two weeks. In some embodiments, the dose is approximately 1.7 mg / kg and is administered once every three weeks. In some embodiments, the dose is approximately 1.7 mg / kg and is administered once every four weeks. In some embodiments, the dose is approximately 1.8 mg / kg and is administered once every week. In some embodiments, the dose is approximately 1.8 mg / kg and is administered once every two weeks. In some embodiments, the dose is approximately 1.8 mg / kg and is administered once every three weeks. In some embodiments, the dose is approximately 1.8 mg / kg and is administered once every four weeks. In some embodiments, the dose is approximately 1.9 mg / kg and is administered once every week. In some embodiments, the dose is approximately 1.9 mg / kg and is administered once every two weeks. In some embodiments, the dose is approximately 1.9 mg / kg and is administered once every three weeks. In some embodiments, the dose is approximately 1.9 mg / kg and is administered once every four weeks. In some embodiments, the dose is approximately 2.0 mg / kg and is administered once every week.In some embodiments, the dose is approximately 2.0 mg / kg and is administered once every two weeks. In some embodiments, the dose is approximately 2.0 mg / kg and is administered once every three weeks. In some embodiments, the dose is approximately 2.0 mg / kg and is administered once every four weeks. In some embodiments, the dose is approximately 2.1 mg / kg and is administered once every week. In some embodiments, the dose is approximately 2.1 mg / kg and is administered once every two weeks. In some embodiments, the dose is approximately 2.1 mg / kg and is administered once every three weeks. In some embodiments, the dose is approximately 2.1 mg / kg and is administered once every four weeks. In some embodiments, the dose is 0.65 mg / kg and is administered once every week. In some embodiments, the dose is 0.65 mg / kg and is administered once every two weeks. In some embodiments, the dose is 0.65 mg / kg and is administered once every three weeks. In some embodiments, the dose is 0.65 mg / kg and is administered approximately once every four weeks. In some embodiments, the dose is 0.7 mg / kg and is administered approximately once every week. In some embodiments, the dose is 0.7 mg / kg and is administered approximately once every two weeks. In some embodiments, the dose is 0.7 mg / kg and is administered approximately once every three weeks. In some embodiments, the dose is 0.7 mg / kg and is administered approximately once every four weeks. In some embodiments, the dose is 0.75 mg / kg and is administered approximately once every week. In some embodiments, the dose is 0.75 mg / kg and is administered approximately once every two weeks. In some embodiments, the dose is 0.75 mg / kg and is administered approximately once every three weeks. In some embodiments, the dose is 0.75 mg / kg and is administered approximately once every four weeks. In some embodiments, the dose is 0.8 mg / kg and is administered approximately once every week. In some embodiments, the dose is 0.8 mg / kg and is administered approximately once every two weeks. In some embodiments, the dose is 0.8 mg / kg and is administered approximately once every three weeks. In some embodiments, the dose is 0.8 mg / kg and is administered approximately once every four weeks. In some embodiments, the dose is 0.85 mg / kg and is administered approximately once every week.In some embodiments, the dose is 0.85 mg / kg and is administered approximately once every two weeks. In some embodiments, the dose is 0.85 mg / kg and is administered approximately once every three weeks. In some embodiments, the dose is 0.85 mg / kg and is administered approximately once every four weeks. In some embodiments, the dose is 0.9 mg / kg and is administered approximately once every week. In some embodiments, the dose is 0.9 mg / kg and is administered approximately once every two weeks. In some embodiments, the dose is 0.9 mg / kg and is administered approximately once every three weeks. In some embodiments, the dose is 0.9 mg / kg and is administered approximately once every four weeks. In some embodiments, the dose is 1.0 mg / kg and is administered approximately once every week. In some embodiments, the dose is 1.0 mg / kg and is administered approximately once every two weeks. In some embodiments, the dose is 1.0 mg / kg and is administered approximately once every three weeks. In some embodiments, the dose is 1.0 mg / kg and is administered approximately once every four weeks. In some embodiments, the dose is 1.1 mg / kg and is administered approximately once every week. In some embodiments, the dose is 1.1 mg / kg and is administered approximately once every two weeks. In some embodiments, the dose is 1.1 mg / kg and is administered approximately once every three weeks. In some embodiments, the dose is 1.1 mg / kg and is administered approximately once every four weeks. In some embodiments, the dose is 1.2 mg / kg and is administered approximately once every week. In some embodiments, the dose is 1.2 mg / kg and is administered approximately once every two weeks. In some embodiments, the dose is 1.2 mg / kg and is administered approximately once every three weeks. In some embodiments, the dose is 1.2 mg / kg and is administered approximately once every four weeks. In some embodiments, the dose is 1.3 mg / kg and is administered approximately once every week. In some embodiments, the dose is 1.3 mg / kg and is administered approximately once every two weeks. In some embodiments, the dose is 1.3 mg / kg and is administered approximately once every three weeks. In some embodiments, the dose is 1.3 mg / kg and is administered approximately once every four weeks. In some embodiments, the dose is 1.4 mg / kg and is administered approximately once every week.In some embodiments, the dose is 1.4 mg / kg and is administered approximately once every two weeks. In some embodiments, the dose is 1.4 mg / kg and is administered approximately once every three weeks. In some embodiments, the dose is 1.4 mg / kg and is administered approximately once every four weeks. In some embodiments, the dose is 1.5 mg / kg and is administered approximately once every week. In some embodiments, the dose is 1.5 mg / kg and is administered approximately once every two weeks. In some embodiments, the dose is 1.5 mg / kg and is administered approximately once every three weeks. In some embodiments, the dose is 1.5 mg / kg and is administered approximately once every four weeks. In some embodiments, the dose is 1.6 mg / kg and is administered approximately once every week. In some embodiments, the dose is 1.6 mg / kg and is administered approximately once every two weeks. In some embodiments, the dose is 1.6 mg / kg and is administered approximately once every three weeks. In some embodiments, the dose is 1.6 mg / kg and is administered approximately once every four weeks. In some embodiments, the dose is 1.7 mg / kg and is administered approximately once every week. In some embodiments, the dose is 1.7 mg / kg and is administered approximately once every two weeks. In some embodiments, the dose is 1.7 mg / kg and is administered approximately once every three weeks. In some embodiments, the dose is 1.7 mg / kg and is administered approximately once every four weeks. In some embodiments, the dose is 1.8 mg / kg and is administered approximately once every week. In some embodiments, the dose is 1.8 mg / kg and is administered approximately once every two weeks. In some embodiments, the dose is 1.8 mg / kg and is administered approximately once every three weeks. In some embodiments, the dose is 1.8 mg / kg and is administered approximately once every four weeks. In some embodiments, the dose is 1.9 mg / kg and is administered approximately once every week. In some embodiments, the dose is 1.9 mg / kg and is administered approximately once every two weeks. In some embodiments, the dose is 1.9 mg / kg and is administered approximately once every three weeks. In some embodiments, the dose is 1.9 mg / kg and is administered approximately once every four weeks. In some embodiments, the dose is 2.0 mg / kg. It is administered approximately once a week. In some embodiments, the dose is 2.0 mg / kg and is administered approximately once every two weeks. In some embodiments, the dose is 2.0 mg / kg and is administered approximately once every three weeks. In some embodiments, the dose is 2.0 mg / kg and is administered approximately once every four weeks. In some embodiments, the dose is 2.1 mg / kg and is administered approximately once a week. In some embodiments, the dose is 2.1 mg / kg and is administered approximately once every two weeks. In some embodiments, the dose is 2.1 mg / kg and is administered approximately once every three weeks. In some embodiments, the dose is 2.1 mg / kg and is administered approximately once every four weeks. In some embodiments, the dose is 2.0 mg / kg and is administered approximately once every three weeks (e.g., ±3 days). In some embodiments, the dose is 2.0 mg / kg and is administered once every three weeks. In some embodiments, the dose is 2.0 mg / kg, administered once every three weeks, and the antibody-drug conjugate is tisotumab vedotin. In some embodiments, the dose is 2.0 mg / kg, administered once every three weeks, and the antibody-drug conjugate is tisotumab vedotin, and the dose is reduced to 1.3 mg / kg if one or more adverse events occur. In some embodiments, the dose is 2.0 mg / kg, administered once every three weeks, and the antibody-drug conjugate is tisotumab vedotin, and the dose is reduced to 1.3 mg / kg if one or more adverse events occur, and one or more adverse events are ocular adverse events. In some embodiments, the dose is 2.0 mg / kg, administered once every three weeks, and the antibody-drug conjugate is tisotumab vedotin, and the dose is reduced to 1.3 mg / kg if one or more adverse events occur, and one or more adverse events are peripheral neuropathy. 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, and the antibody-drug conjugate is tisotumab vedotin, and the dose is reduced to 0.9 mg / kg if one or more adverse events occur.In some embodiments, the dose is 1.3 mg / kg, 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, and one or more adverse events are ocular adverse events. In some embodiments, the dose is 1.3 mg / kg, 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, and one or more adverse events are peripheral neuropathy. In some embodiments, the dose is approximately 0.9 mg / kg, administered approximately once every week, and the antibody-drug conjugate is tisotumab vedotin. In some embodiments, the dose is 0.9 mg / kg, administered once every week, and the antibody-drug conjugate is tisotumab vedotin. In some embodiments, the dose is approximately 0.65 mg / kg, administered approximately once a week, and the antibody-drug conjugate is tisotumab vedotin. In some embodiments, the dose is 0.65 mg / kg, administered once a week, and the antibody-drug conjugate is tisotumab vedotin. In some embodiments, for subjects weighing more than 100 kg, the dose of the anti-TF antibody-drug conjugate administered is the amount administered if the subject weighs 100 kg. In some embodiments, for subjects weighing more than 100 kg, the dose of the anti-TF antibody-drug conjugate administered is 65 mg, 90 mg, 130 mg, or 200 mg.

[0145] In one embodiment of the method or use provided herein, the antibody-drug conjugate or antigen-binding fragment described herein is administered to a subject in a fixed dose of approximately 50 mg to approximately 200 mg, for example, a dose of approximately 50 mg, approximately 60 mg, approximately 70 mg, approximately 80 mg, approximately 90 mg, approximately 100 mg, approximately 110 mg, approximately 120 mg, approximately 130 mg, approximately 140 mg, approximately 150 mg, approximately 160 mg, approximately 170 mg, approximately 180 mg, approximately 190 mg, or approximately 200 mg. In some embodiments, the fixed dose is administered to the subject once every approximately 1 to 4 weeks. In certain embodiments, the fixed dose is administered to the subject once every approximately 1 week, once every approximately 2 weeks, once every approximately 3 weeks, or once every approximately 4 weeks. In some embodiments, a fixed dose is administered to the subject once every three weeks (e.g., ±3 days). In some embodiments, a fixed dose is administered to the subject once every three weeks. In some embodiments, a fixed dose is administered to the subject once every three weeks, and the antibody-drug conjugate is tisotumab vedotin.

[0146] In one embodiment of the method or use provided herein, the antibody-drug conjugate or antigen-binding fragment described herein is administered to a subject in a fixed dose of 50 mg to 200 mg, for example, in doses of 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, or 200 mg. In some embodiments, the fixed dose is administered to the subject once every 1 to 4 weeks. In certain embodiments, the fixed dose is administered to the subject once every 1 week, once every 2 weeks, once every 3 weeks, or once every 4 weeks. In some embodiments, a fixed dose is administered to the subject once every three weeks (e.g., ±3 days). In some embodiments, a fixed dose is administered to the subject once every three weeks. In some embodiments, a fixed dose is administered to the subject once every three weeks, and the antibody-drug conjugate is tisotumab vedotin.

[0147] In some embodiments, the treatment or method of use provided herein further comprises the administration of one or more additional therapeutic agents. In some embodiments, one or more additional therapeutic agents are administered simultaneously with the antibody-drug conjugate or its antigen-binding fragment described herein, such as tisotumab vedotin. In some embodiments, one or more additional therapeutic agents and the antibody-drug conjugate or its antigen-binding fragment described herein are administered sequentially.

[0148] D. Treatment outcome In one aspect, the treatment methods for cervical cancer using the antibody-drug conjugate or antigen-binding fragment described herein result in an improvement in one or more therapeutic effects in the subject after administration of the antibody-drug conjugate compared to baseline. In some embodiments, one or more therapeutic effects are the size of the cervical cancer-derived tumor, the objective response rate, the duration of response, the time to response, progression-free survival, overall survival, or any combination thereof. In one embodiment, one or more therapeutic effects is the size of the cervical cancer-derived tumor. In one embodiment, one or more therapeutic effects is a reduction in tumor size. In one embodiment, one or more therapeutic effects is disease stabilization. In one embodiment, one or more therapeutic effects are partial response. In one embodiment, one or more therapeutic effects are complete response. In one embodiment, one or more therapeutic effects are the objective response rate. In one embodiment, one or more therapeutic effects are the duration of response. In one embodiment, one or more therapeutic effects are the time to response. In one embodiment, one or more therapeutic effects are progression-free survival. In one embodiment, one or more therapeutic effects are overall survival. In another embodiment, one or more therapeutic effects are cancer regression.

[0149] In the methods or embodiments of use provided herein, the response to treatment with the antibody-drug conjugate or its antigen-binding fragment described herein may include the following criteria (RECIST Criterion 1.1): TIFF2026082887000018.tif111161

[0150] In one aspect of the method or use provided herein, the efficacy of treatment with the antibody-drug conjugate or its antigen-binding fragment described herein is evaluated by measuring the objective response rate. In some aspects, the objective response rate is the percentage of patients who show a predetermined reduction in tumor size in the shortest time. In some aspects, the objective response rate is based on RECIST v1.1. In one aspect, 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 aspect, the objective response rate is at least about 20% to 80%. In one aspect, the objective response rate is at least about 30% to 80%. In one aspect, the objective response rate is at least about 40% to 80%. In one aspect, the objective response rate is at least about 50% to 80%. In one aspect, the objective response rate is at least about 60% to 80%. In one embodiment, the objective performance rate is at least approximately 70% to 80%. In one embodiment, the objective performance rate is at least approximately 80%. In one embodiment, the objective performance rate is at least approximately 85%. In one embodiment, the objective performance rate is at least approximately 90%. In one embodiment, the objective performance rate is at least approximately 95%. In one embodiment, the objective performance rate is at least approximately 98%. In one embodiment, the objective performance rate is at least approximately 99%. In one embodiment, the objective performance rate is 100%. In one embodiment, the objective performance rate is approximately 13% to 35%. In one embodiment, the objective performance rate is at least approximately 14%. In one embodiment, the objective performance rate is at least approximately 19%. In one embodiment, the objective performance rate is at least approximately 21%. In one embodiment, the objective performance rate is at least approximately 23.8%. In one embodiment, the objective performance rate is 23.8%. In one embodiment, the objective performance rate is at least approximately 24%. In one embodiment, the objective response rate is at least approximately 25%. In another embodiment, the objective response rate is at least approximately 26%. In another embodiment, the objective response rate is at least approximately 28%. In another embodiment, the objective response rate is at least approximately 30%. In another embodiment, the objective response rate is at least approximately 33%.In some embodiments, the objective response rate was approximately 13% to 35%, and the patient had previously received pelvic radiation. In some embodiments, the objective response rate was approximately 13% to 35%, the patient had previously received pelvic radiation, and the patient experienced disease progression after pelvic radiation. In some embodiments, the objective response rate was approximately 13% to 35%, and the patient had never previously received pelvic radiation. In some embodiments, the objective response rate was at least approximately 28.2%, and the patient had previously received one systemic treatment regimen. In some embodiments, the objective response rate was at least approximately 13.3%, and the patient had previously received two systemic treatment regimens. In some embodiments, the objective response rate was at least approximately 28.2%, the patient had previously received one systemic treatment regimen, and the patient experienced disease progression after the previous systemic treatment regimen. In some embodiments, the objective response rate was at least approximately 13.3%, the patient had previously received two systemic treatment regimens, and the patient experienced disease progression after the two previous systemic treatment regimens. In some embodiments, the prior systemic therapy was bevacizumab. In some embodiments, the prior systemic therapy was chemotherapy. In some embodiments, the prior systemic therapy was a combination of chemotherapy and bevacizumab. In some embodiments, the prior systemic therapy was a combination of doublet chemotherapy and bevacizumab. In some embodiments, the doublet chemotherapy was a combination of paclitaxel and cisplatin. In some embodiments, the doublet chemotherapy was a combination of paclitaxel and carboplatin. In some embodiments, the doublet chemotherapy was a combination of paclitaxel and topotecan. In some embodiments, the prior systemic therapy was a checkpoint inhibitor. In some embodiments, the prior systemic therapy was pembrolizumab. In some embodiments, the objective response rate was at least approximately 25.5%, and the subjects had received prior cisplatin and radiation therapy. In some embodiments, the objective response rate was at least approximately 21.7%, and the subjects had not received prior cisplatin and radiation therapy. In some aspects, the objective response rate was at least approximately 18.8%, and the subjects had received prior treatment with bevacizumab in combination with a chemotherapy doublet.In some embodiments, the objective response rate was at least approximately 32.4%, and the subjects had not received prior treatment with bevacizumab in combination with a chemotherapy doublet. In some embodiments, the objective response rate was at least approximately 26.3%, and the cervical cancer responded to the previous last systemic treatment regimen. In some embodiments, the objective response rate was at least approximately 21.1%, and the cervical cancer did not respond to the previous last systemic treatment regimen. In some embodiments, the objective response rate was at least approximately 23.2%, and the cervical cancer was squamous cell carcinoma. In some embodiments, the objective response rate was at least approximately 25.0%, and the cervical cancer had a non-squamous histological type. In some embodiments, the objective response rate was at least approximately 25.0%, and the cervical cancer was adenocarcinoma. In some embodiments, the objective response rate was at least approximately 25.0%, and the cervical cancer was adenosquamous cell carcinoma. In some embodiments, the objective response rate was at least approximately 30.5%, and the subjects had an East Coast Clinical Oncology Group (ECOG) score of 0. See, for example, Oken M, Creech R, Tormey D, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5:649-655. In some embodiments, the objective response rate is at least about 14.3%, and subjects have an ECOG score of 1. In some embodiments, the objective response rate is about 13% to about 35%, and subjects have an ECOG score of 2. In some embodiments, the objective response rate is about 13% to about 35%, and subjects have an ECOG score of 3. In some embodiments, the objective response rate is about 13% to about 35%, and subjects have an ECOG score of 4. In some embodiments, the objective response rate is about 13% to about 35%, and cervical cancer cells are positive for membrane TF expression. In some embodiments, the objective response rate is about 13% to about 35%, and cervical cancer cells are positive for cytoplasmic TF expression. In some embodiments, positive TF expression is defined as 1% or more of cervical cancer cells expressing TF. In some embodiments, the objective response rate is approximately 13% to 35%, and subjects have at least one TF histological score (H score).In some embodiments, the objective response rate is at least approximately 27.3%, and the subjects are under 65 years of age. In some embodiments, the objective response rate is approximately 13% to approximately 35%, and the subjects are 65 years of age or older. In some embodiments, the objective response rate is approximately 13% to approximately 35%, and the cervical cancer is stage 3. In some embodiments, the objective response rate is approximately 13% to approximately 35%, and the cervical cancer is stage 4.

[0151] In one embodiment of the method or use provided herein, the response to treatment with the antibody-drug conjugate or its antigen-binding fragment described herein is evaluated by measuring the size of cervical cancer-derived tumors. In one embodiment, the size of cervical cancer-derived tumors 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 cervical cancer-derived tumors before administration of the antibody-drug conjugate. In one embodiment, the size of cervical cancer-derived tumors is reduced by at least about 10% to 80%. In one embodiment, the size of cervical cancer-derived tumors is reduced by at least about 20% to 80%. In one embodiment, the size of cervical cancer-derived tumors is reduced by at least about 30% to 80%. In one embodiment, the size of cervical cancer-derived tumors is reduced by at least about 40% to 80%. In one embodiment, the size of tumors originating from cervical cancer is reduced by at least approximately 50% to 80%. In one embodiment, the size of tumors originating from cervical cancer is reduced by at least approximately 60% to 80%. In one embodiment, the size of tumors originating from cervical cancer is reduced by at least approximately 70% to 80%. In one embodiment, the size of tumors originating from cervical cancer is reduced by at least approximately 80%. In one embodiment, the size of tumors originating from cervical cancer is reduced by at least approximately 85%. In one embodiment, the size of tumors originating from cervical cancer is reduced by at least approximately 90%. In one embodiment, the size of tumors originating from cervical cancer is reduced by at least approximately 95%. In one embodiment, the size of tumors originating from cervical cancer is reduced by at least approximately 98%. In one embodiment, the size of tumors originating from cervical cancer is reduced by at least approximately 99%. In one embodiment, the size of tumors originating from cervical cancer is reduced by 100%. In one embodiment, the size of tumors originating from cervical cancer is reduced by at least approximately 30%. In one embodiment, the size of tumors originating from cervical cancer is measured by magnetic resonance imaging (MRI). In one embodiment, the size of a tumor originating from cervical cancer is measured by computed tomography (CT). In several embodiments, the size of a tumor originating from cervical cancer is measured by a pelvic examination.See Choi et al., 2008, J. Gynecol. Oncol. 19(3):205.

[0152] In one aspect of the method or use provided herein, the response to treatment with the antibody-drug conjugate or its antigen-binding fragment described herein, such as tisotumab vedotin, promotes regression of cervical cancer-derived tumors. In one aspect, the cervical cancer-derived tumors regress 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 cervical cancer-derived tumors before administration of the antibody-drug conjugate. In one aspect, the cervical cancer-derived tumors regress by at least about 10% to 80%. In one aspect, the cervical cancer-derived tumors regress by at least about 20% to 80%. In one aspect, the cervical cancer-derived tumors regress by at least about 30% to 80%. In one embodiment, tumors originating from cervical cancer regress by at least approximately 40% to 80%. In one embodiment, tumors originating from cervical cancer regress by at least approximately 50% to 80%. In one embodiment, tumors originating from cervical cancer regress by at least approximately 60% to 80%. In one embodiment, tumors originating from cervical cancer regress by at least approximately 70% to 80%. In one embodiment, tumors originating from cervical cancer regress by at least approximately 80%. In one embodiment, tumors originating from cervical cancer regress by at least approximately 85%. In one embodiment, tumors originating from cervical cancer regress by at least approximately 90%. In one embodiment, tumors originating from cervical cancer regress by at least approximately 95%. In one embodiment, tumors originating from cervical cancer regress by at least approximately 98%. In one embodiment, tumors originating from cervical cancer regress by at least approximately 99%. In one embodiment, tumors originating from cervical cancer regress by 100%. In one embodiment, tumors originating from cervical cancer regress by at least approximately 30%. In one embodiment, tumor regression is determined by measuring the size of the tumor using magnetic resonance imaging (MRI). In another embodiment, tumor regression is determined by measuring the size of the tumor using computed tomography (CT). In several embodiments, tumor regression is determined by measuring the size of the tumor using pelvic examination. See Choi et al., 2008, J. Gynecol. Oncol. 19(3):205.

[0153] In the methods or embodiments of use described herein, the response to treatment with the antibody-drug conjugate or its antigen-binding fragment described herein is evaluated by measuring progression-free survival after administration of the antibody-drug conjugate. In some embodiments, subjects exhibit progression-free survival of at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 18 months, at least about 2 years, at least about 3 years, at least about 4 years, or at least about 5 years after administration of the antibody-drug conjugate. In some embodiments, subjects exhibit progression-free survival of at least about 6 months after administration of the antibody-drug conjugate. In some embodiments, subjects exhibit progression-free survival of at least about 1 year after administration of the antibody-drug conjugate. In some embodiments, subjects exhibit progression-free survival of at least about 2 years after administration of the antibody-drug conjugate. In some embodiments, subjects demonstrate a progression-free survival of at least approximately 3 years after administration of the antibody-drug conjugate. In some embodiments, subjects demonstrate a progression-free survival of at least approximately 4 years after administration of the antibody-drug conjugate. In some embodiments, subjects demonstrate a progression-free survival of at least approximately 5 years after administration of the antibody-drug conjugate. In some embodiments, subjects demonstrate a progression-free survival of at least approximately 3 months after administration of the antibody-drug conjugate. In some embodiments, subjects demonstrate a progression-free survival of at least approximately 4 months after administration of the antibody-drug conjugate. In some embodiments, subjects demonstrate a progression-free survival of at least approximately 4.2 months after administration of the antibody-drug conjugate. In some embodiments, subjects demonstrate a progression-free survival of at least 4.2 months after administration of the antibody-drug conjugate. In some embodiments, subjects demonstrate a progression-free survival of at least approximately 5 months after administration of the antibody-drug conjugate. In some aspects, subjects demonstrated progression-free survival of at least approximately 3 months after administration of the antibody-drug conjugate, and the patients had previously received pelvic radiation therapy.In some embodiments, subjects demonstrated progression-free survival of at least approximately 3 months after administration of the antibody-drug conjugate, had previously received pelvic radiation, and experienced disease progression after the previous pelvic radiation. In some embodiments, subjects demonstrated progression-free survival of at least approximately 3 months after administration of the antibody-drug conjugate, and had not previously received pelvic radiation. In some embodiments, subjects demonstrated progression-free survival of at least approximately 3 months after administration of the antibody-drug conjugate, and had previously received one systemic treatment regimen. In some embodiments, subjects demonstrated progression-free survival of at least approximately 3 months after administration of the antibody-drug conjugate, and had previously received two systemic treatment regimens. In some embodiments, subjects demonstrated progression-free survival of at least approximately 3 months after administration of the antibody-drug conjugate, had previously received one systemic treatment regimen, and experienced disease progression after the previous systemic treatment regimen. In some embodiments, subjects demonstrated progression-free survival of at least approximately 3 months after administration of an antibody-drug conjugate, had previously received two systemic therapy regimens, and had experienced disease progression after the two previous systemic therapy regimens. In some embodiments, the prior systemic therapy was bevacizumab. In some embodiments, the prior systemic therapy was chemotherapy. In some embodiments, the prior systemic therapy was a combination of chemotherapy and bevacizumab. In some embodiments, the prior systemic therapy was a combination of doublet chemotherapy and bevacizumab. In some embodiments, the doublet chemotherapy was a combination of paclitaxel and cisplatin. In some embodiments, the doublet chemotherapy was a combination of paclitaxel and carboplatin. In some embodiments, the doublet chemotherapy was a combination of paclitaxel and topotecan. In some embodiments, the prior systemic therapy was a checkpoint inhibitor. In some embodiments, the prior systemic therapy was pembrolizumab. In some embodiments, subjects exhibit a progression-free survival of at least approximately 3 months after administration of an antibody-drug conjugate, and the cervical cancer is squamous cell carcinoma. In some embodiments, subjects exhibit a progression-free survival of at least approximately 3 months after administration of an antibody-drug conjugate, and the cervical cancer is adenocarcinoma.In some embodiments, subjects exhibit a progression-free survival of at least approximately 3 months after administration of an antibody-drug conjugate, and the cervical cancer is adenosquamous carcinoma. In some embodiments, subjects exhibit a progression-free survival of at least approximately 3 months after administration of an antibody-drug conjugate, and the subjects have an ECOG score of 0. In some embodiments, subjects exhibit a progression-free survival of at least approximately 3 months after administration of an antibody-drug conjugate, and the subjects have an ECOG score of 1. In some embodiments, subjects exhibit a progression-free survival of at least approximately 3 months after administration of an antibody-drug conjugate, and the subjects have an ECOG score of 2. In some embodiments, subjects exhibit a progression-free survival of at least approximately 3 months after administration of an antibody-drug conjugate, and the subjects have an ECOG score of 3. In some embodiments, subjects exhibit a progression-free survival of at least approximately 3 months after administration of an antibody-drug conjugate, and the subjects have an ECOG score of 4. In some embodiments, subjects demonstrate a progression-free survival of at least approximately 3 months after administration of the antibody-drug conjugate, and cervical cancer cells are positive for membrane TF expression. In some embodiments, subjects demonstrate a progression-free survival of at least approximately 3 months after administration of the antibody-drug conjugate, and cervical cancer cells are positive for cytoplasmic TF expression. In some embodiments, positive TF expression is defined as 1% or more of cervical cancer cells expressing TF. In some embodiments, subjects demonstrate a progression-free survival of at least approximately 3 months after administration of the antibody-drug conjugate, and subjects have at least a TF histological score (H score) of 1. In some embodiments, subjects demonstrate a progression-free survival of at least approximately 3 months after administration of the antibody-drug conjugate, and subjects are under 65 years of age. In some embodiments, subjects demonstrate a progression-free survival of at least approximately 3 months after administration of the antibody-drug conjugate, and subjects are 65 years of age or older. In some embodiments, subjects demonstrate a progression-free survival of at least approximately 3 months after administration of the antibody-drug conjugate, and their cervical cancer is stage 3. In some embodiments, subjects demonstrate a progression-free survival of at least approximately 3 months after administration of the antibody-drug conjugate, and their cervical cancer is stage 4.

[0154] In the methods or embodiments of use described herein, the response to treatment with the antibody-drug conjugate or its antigen-binding fragment described herein is evaluated by measuring the time to response to administration of the antibody-drug conjugate. In some embodiments, the time to response is shorter than approximately 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months after administration of the antibody-drug conjugate. In some embodiments, the time to response is less than approximately 1 month after administration of the antibody-drug conjugate. In some embodiments, the time to response is less than approximately 1.2 months after administration of the antibody-drug conjugate. In some embodiments, the time to response is less than approximately 1.4 months after administration of the antibody-drug conjugate. In some embodiments, the time to response is less than approximately 2 months after administration of the antibody-drug conjugate. In some embodiments, the time to response is less than approximately 3 months after administration of the antibody-drug conjugate. In some embodiments, the time to response is less than approximately 4 months after administration of the antibody-drug conjugate. In some embodiments, the time to response is less than approximately 5 months after administration of the antibody-drug conjugate. In some embodiments, the time to response is less than approximately 6 months after administration of the antibody-drug conjugate. In some embodiments, the time to response is less than approximately 6 months after administration of the antibody-drug conjugate. In some embodiments, the time to response is less than approximately 6 months after administration of the antibody-drug conjugate, and the patient had previously received pelvic radiation therapy. In some embodiments, the time to response is less than approximately 6 months after administration of the antibody-drug conjugate, the patient had previously received pelvic radiation therapy, and the patient experienced disease progression after the previous pelvic radiation therapy. In some embodiments, the time to response was less than approximately 6 months after administration of the antibody-drug conjugate, and the patient had not previously received pelvic radiation. In some embodiments, the time to response was less than approximately 6 months after administration of the antibody-drug conjugate, and the patient had previously received one systemic treatment regimen.In some embodiments, the time to response was less than approximately 6 months after administration of the antibody-drug conjugate, and the patient had previously received two systemic treatment regimens. In some embodiments, the time to response was less than approximately 6 months after administration of the antibody-drug conjugate, the patient had previously received one systemic treatment regimen, and the patient had experienced disease progression after the previous systemic treatment regimen. In some embodiments, the time to response was less than approximately 6 months after administration of the antibody-drug conjugate, the patient had previously received two systemic treatment regimens, and the patient had experienced disease progression after the two previous systemic treatment regimens. In some embodiments, the previous systemic therapy was bevacizumab. In some embodiments, the previous systemic therapy was chemotherapy. In some embodiments, the previous systemic therapy was a combination of chemotherapy and bevacizumab. In some embodiments, the previous systemic therapy was a combination of doublet chemotherapy and bevacizumab. In some embodiments, the doublet chemotherapy was a combination of paclitaxel and cisplatin. In some embodiments, doublet chemotherapy is a combination of paclitaxel and carboplatin. In some embodiments, doublet chemotherapy is a combination of paclitaxel and topotecan. In some embodiments, the prior systemic therapy was a checkpoint inhibitor. In some embodiments, the prior systemic therapy was pembrolizumab. In some embodiments, the time to response is less than approximately 6 months after administration of the antibody-drug conjugate, and the cervical cancer is squamous cell carcinoma. In some embodiments, the time to response is less than approximately 6 months after administration of the antibody-drug conjugate, and the cervical cancer is adenocarcinoma. In some embodiments, the time to response is less than approximately 6 months after administration of the antibody-drug conjugate, and the cervical cancer is adenosquamous carcinoma. In some embodiments, the time to response is less than approximately 6 months after administration of the antibody-drug conjugate, and the subjects have an ECOG score of 0. In some embodiments, the time to response is less than approximately 6 months after administration of the antibody-drug conjugate, and the subjects have an ECOG score of 1. In some embodiments, the time to response is less than approximately 6 months after administration of the antibody-drug conjugate, and the subjects have an ECOG score of 2.In some embodiments, the time to response is less than approximately 6 months after administration of the antibody-drug conjugate, and the subjects have an ECOG score of 3. In some embodiments, the time to response is less than approximately 6 months after administration of the antibody-drug conjugate, and the subjects have an ECOG score of 4. In some embodiments, the time to response is less than approximately 6 months after administration of the antibody-drug conjugate, and the cervical cancer cells are positive for membrane TF expression. In some embodiments, the time to response is less than approximately 6 months after administration of the antibody-drug conjugate, and the cervical cancer cells are positive for cytoplasmic TF expression. In some embodiments, positive TF expression is defined as 1% or more of the cervical cancer cells expressing TF. In some embodiments, the time to response is less than approximately 6 months after administration of the antibody-drug conjugate, and the subjects have at least one TF histological score (H score). In some embodiments, the time to response is less than approximately 6 months after administration of the antibody-drug conjugate, and the subjects are under 65 years of age. In some embodiments, the time to response is less than approximately 6 months after administration of the antibody-drug conjugate, and the subjects are 65 years of age or older. In some embodiments, the time to response is less than approximately 6 months after administration of the antibody-drug conjugate, and the cervical cancer is stage 3. In some embodiments, the time to response is less than approximately 6 months after administration of the antibody-drug conjugate, and the cervical cancer is stage 4.

[0155] In one aspect of the method or use described herein, the response to treatment with the antibody-drug conjugate or its antigen-binding fragment described herein is evaluated by measuring overall survival after administration of the antibody-drug conjugate. In some aspects, subjects exhibit an overall survival of at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 18 months, at least about 2 years, at least about 3 years, at least about 4 years, or at least about 5 years after administration of the antibody-drug conjugate. In some aspects, subjects exhibit an overall survival of at least about 6 months after administration of the antibody-drug conjugate. In some aspects, subjects exhibit an overall survival of at least about 10 months after administration of the antibody-drug conjugate. In some aspects, subjects exhibit an overall survival of at least about 11 months after administration of the antibody-drug conjugate. In some embodiments, subjects exhibit an overall survival of at least approximately one year after administration of the antibody-drug conjugate. In some embodiments, subjects exhibit an overall survival of at least approximately 13 months after administration of the antibody-drug conjugate. In some embodiments, subjects exhibit an overall survival of at least approximately two years after administration of the antibody-drug conjugate. In some embodiments, subjects exhibit an overall survival of at least approximately three years after administration of the antibody-drug conjugate. In some embodiments, subjects exhibit an overall survival of at least approximately four years after administration of the antibody-drug conjugate. In some embodiments, subjects exhibit an overall survival of at least approximately five years after administration of the antibody-drug conjugate. In some embodiments, subjects exhibit an overall survival of at least approximately ten months after administration of the antibody-drug conjugate. In some embodiments, subjects exhibit an overall survival of at least approximately ten months after administration of the antibody-drug conjugate, and the patients had previously received pelvic radiation therapy. In some aspects, subjects demonstrated an overall survival of at least approximately 10 months after administration of the antibody-drug conjugate, had previously received pelvic radiation, and had experienced disease progression after prior pelvic radiation.In some embodiments, subjects demonstrated an overall survival of at least approximately 10 months after administration of the antibody-drug conjugate, and the patients had not previously received pelvic radiation. In some embodiments, subjects demonstrated an overall survival of at least approximately 10 months after administration of the antibody-drug conjugate, and the patients had previously received one systemic treatment regimen. In some embodiments, subjects demonstrated an overall survival of at least approximately 10 months after administration of the antibody-drug conjugate, and the patients had previously received two systemic treatment regimens. In some embodiments, subjects demonstrated an overall survival of at least approximately 10 months after administration of the antibody-drug conjugate, and the patients had previously received one systemic treatment regimen, and the patients had experienced disease progression after the previous systemic treatment regimen. In some embodiments, subjects demonstrated an overall survival of at least approximately 10 months after administration of the antibody-drug conjugate, and the patients had previously received two systemic treatment regimens, and the patients had experienced disease progression after the two previous systemic treatment regimens. In some embodiments, the prior systemic therapy was bevacizumab. In some embodiments, the prior systemic therapy was chemotherapy. In some embodiments, the prior systemic therapy was a combination of chemotherapy and bevacizumab. In some embodiments, the prior systemic therapy was a combination of doublet chemotherapy and bevacizumab. In some embodiments, the doublet chemotherapy was a combination of paclitaxel and cisplatin. In some embodiments, the doublet chemotherapy was a combination of paclitaxel and carboplatin. In some embodiments, the doublet chemotherapy was a combination of paclitaxel and topotecan. In some embodiments, the prior systemic therapy was a checkpoint inhibitor. In some embodiments, the prior systemic therapy was pembrolizumab. In some embodiments, subjects demonstrated an overall survival of at least approximately 10 months after administration of an antibody-drug conjugate, and the cervical cancer was squamous cell carcinoma. In some embodiments, subjects demonstrated an overall survival of at least approximately 10 months after administration of an antibody-drug conjugate, and the cervical cancer was adenocarcinoma. In some embodiments, subjects demonstrated an overall survival of at least approximately 10 months after administration of an antibody-drug conjugate, and the cervical cancer was adenosquamous carcinoma.In some embodiments, subjects exhibit an overall survival of at least approximately 10 months after administration of the antibody-drug conjugate, and have an ECOG score of 0. In some embodiments, subjects exhibit an overall survival of at least approximately 10 months after administration of the antibody-drug conjugate, and have an ECOG score of 1. In some embodiments, subjects exhibit an overall survival of at least approximately 10 months after administration of the antibody-drug conjugate, and have an ECOG score of 2. In some embodiments, subjects exhibit an overall survival of at least approximately 10 months after administration of the antibody-drug conjugate, and have an ECOG score of 3. In some embodiments, subjects exhibit an overall survival of at least approximately 10 months after administration of the antibody-drug conjugate, and have an ECOG score of 4. In some embodiments, subjects exhibit an overall survival of at least approximately 10 months after administration of the antibody-drug conjugate, and cervical cancer cells are positive for membrane TF expression. In some embodiments, subjects demonstrate an overall survival of at least approximately 10 months after administration of the antibody-drug conjugate, and the cervical cancer cells are positive for cytoplasmic TF expression. In some embodiments, positive TF expression is defined as 1% or more of the cervical cancer cells expressing TF. In some embodiments, subjects demonstrate an overall survival of at least approximately 10 months after administration of the antibody-drug conjugate, and the subjects have at least a TF histological score (H score) of 1. In some embodiments, subjects demonstrate an overall survival of at least approximately 10 months after administration of the antibody-drug conjugate, and the subjects are under 65 years of age. In some embodiments, subjects demonstrate an overall survival of at least approximately 10 months after administration of the antibody-drug conjugate, and the subjects are 65 years of age or older. In some embodiments, subjects demonstrate an overall survival of at least approximately 10 months after administration of the antibody-drug conjugate, and the cervical cancer is stage 3. In some embodiments, subjects demonstrated an overall survival of at least approximately 10 months after administration of an antibody-drug conjugate, and their cervical cancer was stage 4.

[0156] In the methods or embodiments of use described herein, the response to treatment with the antibody-drug conjugate or its antigen-binding fragment described herein is evaluated by measuring the duration of response to the antibody-drug conjugate after administration of the antibody-drug conjugate. In some embodiments, the duration of response to the antibody-drug conjugate is at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 18 months, at least about 2 years, at least about 3 years, at least about 4 years, or at least about 5 years after administration of the antibody-drug conjugate. In some embodiments, the duration of response to the antibody-drug conjugate is at least about 6 months after administration of the antibody-drug conjugate. In some embodiments, the duration of response to the antibody-drug conjugate is at least about 7 months after administration of the antibody-drug conjugate. In some embodiments, the duration of response to the antibody-drug conjugate is at least approximately 8 months after administration of the antibody-drug conjugate. In some embodiments, the duration of response to the antibody-drug conjugate is at least approximately 10 months after administration of the antibody-drug conjugate. In some embodiments, the duration of response to the antibody-drug conjugate is at least approximately 1 year after administration of the antibody-drug conjugate. In some embodiments, the duration of response to the antibody-drug conjugate is at least approximately 2 years after administration of the antibody-drug conjugate. In some embodiments, the duration of response to the antibody-drug conjugate is at least approximately 3 years after administration of the antibody-drug conjugate. In some embodiments, the duration of response to the antibody-drug conjugate is at least approximately 4 years after administration of the antibody-drug conjugate. In some embodiments, the duration of response to the antibody-drug conjugate is at least approximately 5 years after administration of the antibody-drug conjugate. In some embodiments, the duration of response to antibody-drug conjugates is at least approximately 8.3 months after administration of the antibody-drug conjugate.In some embodiments, the duration of response to antibody-drug conjugates was at least approximately 6 months after administration of the antibody-drug conjugate, and the patient had previously received pelvic radiation. In some embodiments, the duration of response to antibody-drug conjugates was at least approximately 6 months after administration of the antibody-drug conjugate, the patient had previously received pelvic radiation, and the patient experienced disease progression after the previous pelvic radiation. In some embodiments, the duration of response to antibody-drug conjugates was at least approximately 6 months after administration of the antibody-drug conjugate, and the patient had not previously received pelvic radiation. In some embodiments, the duration of response to antibody-drug conjugates was at least approximately 6 months after administration of the antibody-drug conjugate, and the patient had previously received one systemic treatment regimen. In some embodiments, the duration of response to antibody-drug conjugates was at least approximately 6 months after administration of the antibody-drug conjugate, and the patient had previously received two systemic treatment regimens. In some embodiments, the duration of response to the antibody-drug conjugate was at least approximately 6 months after administration of the antibody-drug conjugate, the patient had previously received one systemic treatment regimen, and the patient experienced disease progression after the previous systemic treatment regimen. In some embodiments, the duration of response to the antibody-drug conjugate was at least approximately 6 months after administration of the antibody-drug conjugate, the patient had previously received two systemic treatment regimens, and the patient experienced disease progression after the two previous systemic treatment regimens. In some embodiments, the prior systemic therapy was bevacizumab. In some embodiments, the prior systemic therapy was chemotherapy. In some embodiments, the prior systemic therapy was a combination of chemotherapy and bevacizumab. In some embodiments, the prior systemic therapy was a combination of doublet chemotherapy and bevacizumab. In some embodiments, the doublet chemotherapy was a combination of paclitaxel and cisplatin. In some embodiments, the doublet chemotherapy was a combination of paclitaxel and carboplatin. In some embodiments, doublet chemotherapy is a combination of paclitaxel and topotecan. In some embodiments, the prior systemic therapy was a checkpoint inhibitor.In some embodiments, the prior systemic therapy was pembrolizumab. In some embodiments, the duration of response to the antibody-drug conjugate is at least approximately 6 months after administration of the antibody-drug conjugate, and the cervical cancer is squamous cell carcinoma. In some embodiments, the duration of response to the antibody-drug conjugate is at least approximately 6 months after administration of the antibody-drug conjugate, and the cervical cancer is adenocarcinoma. In some embodiments, the duration of response to the antibody-drug conjugate is at least approximately 6 months after administration of the antibody-drug conjugate, and the cervical cancer is adenosquamous carcinoma. In some embodiments, the duration of response to the antibody-drug conjugate is at least approximately 6 months after administration of the antibody-drug conjugate, and the subject has an ECOG score of 0. In some embodiments, the duration of response to the antibody-drug conjugate is at least approximately 6 months after administration of the antibody-drug conjugate, and the subject has an ECOG score of 1. In some embodiments, the duration of response to the antibody-drug conjugate is at least approximately 6 months after administration of the antibody-drug conjugate, and the subjects have an ECOG score of 2. In some embodiments, the duration of response to the antibody-drug conjugate is at least approximately 6 months after administration of the antibody-drug conjugate, and the subjects have an ECOG score of 3. In some embodiments, the duration of response to the antibody-drug conjugate is at least approximately 6 months after administration of the antibody-drug conjugate, and the subjects have an ECOG score of 4. In some embodiments, the duration of response to the antibody-drug conjugate is at least approximately 6 months after administration of the antibody-drug conjugate, and the cervical cancer cells are positive for membrane TF expression. In some embodiments, the duration of response to the antibody-drug conjugate is at least approximately 6 months after administration of the antibody-drug conjugate, and the cervical cancer cells are positive for cytoplasmic TF expression. In some embodiments, positive TF expression is defined as 1% or more of the cervical cancer cells expressing TF. In some embodiments, the duration of response to the antibody-drug conjugate is at least approximately 6 months after administration of the antibody-drug conjugate, and the subjects have at least one TF histological score (H score).In some embodiments, the duration of response to the antibody-drug conjugate is at least approximately 6 months after administration of the antibody-drug conjugate, and the subjects are under 65 years of age. In some embodiments, the duration of response to the antibody-drug conjugate is at least approximately 6 months after administration of the antibody-drug conjugate, and the subjects are 65 years of age or older. In some embodiments, the duration of response to the antibody-drug conjugate is at least approximately 6 months after administration of the antibody-drug conjugate, and the cervical cancer is stage 3. In some embodiments, the duration of response to the antibody-drug conjugate is at least approximately 6 months after administration of the antibody-drug conjugate, and the cervical cancer is stage 4.

[0157] In some embodiments, the treatment methods for cervical cancer using the antibody-drug conjugate or antigen-binding fragment described herein result in an improvement in one or more therapeutic effects in the subject after administration of the antibody-drug conjugate compared to baseline. In some embodiments, one or more therapeutic effects are the size of the cervical cancer-derived tumor, the objective response rate, the duration of response, the time to response, progression-free survival, overall survival, or any combination thereof. In one embodiment, one or more therapeutic effects is the size of the cervical cancer-derived tumor. In one embodiment, one or more therapeutic effects is a reduction in tumor size. In one embodiment, one or more therapeutic effects is disease stabilization. In one embodiment, one or more therapeutic effects are partial response. In one embodiment, one or more therapeutic effects are complete response. In one embodiment, one or more therapeutic effects are the objective response rate. In one embodiment, one or more therapeutic effects are the duration of response. In one embodiment, one or more therapeutic effects are the time to response. In one embodiment, one or more therapeutic effects are progression-free survival. In one embodiment, one or more therapeutic effects are overall survival. In one embodiment, one or more therapeutic effects are cancer regression. In some embodiments, the objective response rate is approximately 13% to approximately 35%, and in some cases, the objective response rate is at least approximately 14%, approximately 19%, approximately 21%, 23.8%, approximately 24%, approximately 25%, approximately 26%, approximately 28%, approximately 30%, or approximately 33%, and the size of cervical cancer-derived tumors in the subjects is reduced by at least approximately 30%. In some embodiments, the objective response rate is approximately 13% to approximately 35%, and in some cases, the objective response rate is at least approximately 14%, approximately 19%, approximately 21%, 23.8%, approximately 24%, approximately 25%, approximately 26%, approximately 28%, approximately 30%, or approximately 33%, and the size of cervical cancer-derived tumors in the subjects regresses by at least approximately 30%.In some embodiments, the objective response rate is approximately 13% to 35%, and in some cases, the objective response rate is at least approximately 14%, 19%, 21%, 23.8%, 24%, 25%, 26%, 28%, 30%, or 33%, and subjects show progression-free survival of at least approximately 3 months after administration of the antibody-drug conjugate, and in some cases, subjects show progression-free survival of at least approximately 4 months, 5 months, or 6 months after administration of the antibody-drug conjugate. In some embodiments, the objective response rate is approximately 13% to 35%, and in some cases, the objective response rate is at least approximately 14%, 19%, 21%, 23.8%, 24%, 25%, 26%, 28%, 30%, or 33%, and the time to response is less than approximately 6 months after administration of the antibody-drug conjugate, and in some cases, the time to response is shorter than approximately 4 months, 2 months, 1.4 months, or 1.2 months after administration of the antibody-drug conjugate. In some embodiments, the objective response rate is approximately 13% to 35%, and in some cases, the objective response rate is at least approximately 14%, 19%, 21%, 23.8%, 24%, 25%, 26%, 28%, 30%, or 33%, and subjects show an overall survival of at least approximately 10 months after administration of the antibody-drug conjugate, and in some cases, subjects show an overall survival of at least approximately 11 months, 12 months, 13 months, or 14 months after administration of the antibody-drug conjugate. In some embodiments, the objective response rate is approximately 13% to 35%, and in some cases, the objective response rate is at least approximately 14%, 19%, 21%, 23.8%, 24%, 25%, 26%, 28%, 30%, or 33%, and the duration of response to the antibody-drug conjugate is at least approximately 6 months after administration of the antibody-drug conjugate, and in some cases, the duration of response to the antibody-drug conjugate is at least approximately 7 months, 8 months, or 10 months after administration of the antibody-drug conjugate.In some embodiments, subjects exhibited progression-free survival of at least approximately 3 months after administration of the antibody-drug conjugate, and in some cases, subjects exhibited progression-free survival of at least approximately 4 months, approximately 5 months, or approximately 6 months after administration of the antibody-drug conjugate, with a time to response of less than approximately 6 months after administration of the antibody-drug conjugate, and in some cases, a time to response shorter than approximately 4 months, approximately 2 months, 1.4 months, or approximately 1.2 months after administration of the antibody-drug conjugate. In some embodiments, subjects demonstrate a progression-free survival of at least approximately 3 months after administration of the antibody-drug conjugate, and in some cases, subjects demonstrate a progression-free survival of at least approximately 4 months, approximately 5 months, or approximately 6 months after administration of the antibody-drug conjugate, and subjects demonstrate an overall survival of at least approximately 10 months after administration of the antibody-drug conjugate, and in some cases, subjects demonstrate an overall survival of at least approximately 11 months, approximately 12 months, approximately 13 months, or 14 months after administration of the antibody-drug conjugate. In some embodiments, subjects exhibit a progression-free survival of at least approximately 3 months after administration of the antibody-drug conjugate, and in some cases, subjects exhibit a progression-free survival of at least approximately 4 months, approximately 5 months, or approximately 6 months after administration of the antibody-drug conjugate, and the duration of response to the antibody-drug conjugate is at least approximately 6 months after administration of the antibody-drug conjugate, and in some cases, the duration of response to the antibody-drug conjugate is at least approximately 7 months, 8 months, or approximately 10 months after administration of the antibody-drug conjugate. In some embodiments, the time to response is less than approximately 6 months after administration of the antibody-drug conjugate, and in some cases, the time to response is shorter than approximately 4 months, 2 months, 1.4 months, or 1.2 months after administration of the antibody-drug conjugate, and subjects show an overall survival of at least approximately 10 months after administration of the antibody-drug conjugate, and in some cases, subjects show an overall survival of at least approximately 11 months, 12 months, 13 months, or 14 months after administration of the antibody-drug conjugate.In some embodiments, the time to response is less than approximately 6 months after administration of the antibody-drug conjugate, and in some cases, the time to response is shorter than approximately 4 months, 2 months, 1.4 months, or 1.2 months after administration of the antibody-drug conjugate, and the duration of response to the antibody-drug conjugate is at least approximately 6 months after administration of the antibody-drug conjugate, and in some cases, the duration of response to the antibody-drug conjugate is at least approximately 7 months, 8 months, or 10 months after administration of the antibody-drug conjugate. In some embodiments, subjects exhibited an overall survival of at least approximately 10 months after administration of the antibody-drug conjugate, and in some cases, subjects exhibited an overall survival of at least approximately 11 months, approximately 12 months, approximately 13 months, or 14 months after administration of the antibody-drug conjugate, and the duration of response to the antibody-drug conjugate was at least approximately 6 months after administration of the antibody-drug conjugate, and in some cases, the duration of response to the antibody-drug conjugate was at least approximately 7 months, 8 months, or approximately 10 months after administration of the antibody-drug conjugate. In some embodiments, the objective response rate is approximately 13% to 35%, and in some cases, the objective response rate is at least approximately 14%, 19%, 21%, 23.8%, 24%, 25%, 26%, 28%, 30%, or 33%, and subjects show progression-free survival of at least approximately 3 months after administration of the antibody-drug conjugate, and in some cases, subjects show progression-free survival of at least approximately 4 months, 5 months, or 6 months after administration of the antibody-drug conjugate, and subjects show overall survival of at least approximately 10 months after administration of the antibody-drug conjugate, and in some cases, subjects show overall survival of at least approximately 11 months, 12 months, 13 months, or 14 months after administration of the antibody-drug conjugate.In some embodiments, the objective response rate is approximately 13% to 35%, and in some cases, the objective response rate is at least approximately 14%, 19%, 21%, 23.8%, 24%, 25%, 26%, 28%, 30%, or 33%, and subjects show progression-free survival of at least approximately 3 months after administration of the antibody-drug conjugate, and in some cases, subjects show progression-free survival of at least approximately 4 months, 5 months, or 6 months after administration of the antibody-drug conjugate, and the duration of response to the antibody-drug conjugate is at least approximately 6 months after administration of the antibody-drug conjugate, and in some cases, the duration of response to the antibody-drug conjugate is at least approximately 7 months, 8 months, or 10 months after administration of the antibody-drug conjugate. In some embodiments, the objective response rate was approximately 13% to 35%, and in some cases, the objective response rate was at least approximately 14%, 19%, 21%, 23.8%, 24%, 25%, 26%, 28%, 30%, or 33%, and subjects showed progression-free survival of at least approximately 3 months after administration of the antibody-drug conjugate, and in some cases, subjects showed progression-free survival of at least approximately 4 months, 5 months, or 6 months after administration of the antibody-drug conjugate, and the time to response was less than approximately 6 months after administration of the antibody-drug conjugate, and in some cases, the time to response was shorter than approximately 4 months, 2 months, 1.4 months, or 1.2 months after administration of the antibody-drug conjugate.In some embodiments, the objective response rate is approximately 13% to 35%, and in some cases, the objective response rate is at least approximately 14%, 19%, 21%, 23.8%, 24%, 25%, 26%, 28%, 30%, or 33%, the duration of response to the antibody-drug conjugate is at least approximately 6 months after administration of the antibody-drug conjugate, and in some cases, the duration of response to the antibody-drug conjugate is at least approximately 7 months, 8 months, or 10 months after administration of the antibody-drug conjugate, and subjects show an overall survival of at least approximately 10 months after administration of the antibody-drug conjugate, and in some cases, subjects show an overall survival of at least approximately 11 months, 12 months, 13 months, or 14 months after administration of the antibody-drug conjugate. In some embodiments, the objective response rate is approximately 13% to 35%, and in some cases, the objective response rate is at least approximately 14%, 19%, 21%, 23.8%, 24%, 25%, 26%, 28%, 30%, or 33%, the duration of response to the antibody-drug conjugate is at least approximately 6 months after administration of the antibody-drug conjugate, and in some cases, the duration of response to the antibody-drug conjugate is at least approximately 7 months, 8 months, or 10 months after administration of the antibody-drug conjugate, and the time to response is less than approximately 6 months after administration of the antibody-drug conjugate, and in some cases, the time to response is shorter than approximately 4 months, 2 months, 1.4 months, or 1.2 months after administration of the antibody-drug conjugate.In some embodiments, the objective response rate is approximately 13% to 35%, and in some cases, the objective response rate is at least approximately 14%, 19%, 21%, 23.8%, 24%, 25%, 26%, 28%, 30%, or 33%, and the duration of response to the antibody-drug conjugate is at least approximately 6 months after administration of the antibody-drug conjugate, and in some cases, the duration of response to the antibody-drug conjugate is at least approximately 7 months, approximately 8 months, and The overall survival period is approximately 10 months, with subjects showing an overall survival of at least approximately 10 months after administration of the antibody-drug conjugate, and in some cases, subjects showing an overall survival of at least approximately 11 months, 12 months, 13 months, or 14 months after administration of the antibody-drug conjugate, and subjects showing a progression-free survival of at least approximately 3 months after administration of the antibody-drug conjugate, and in some cases, subjects showing a progression-free survival of at least approximately 4 months, 5 months, or 6 months after administration of the antibody-drug conjugate. In some embodiments, the objective response rate is approximately 13% to 35%, and in some cases, the objective response rate is at least approximately 14%, 19%, 21%, 23.8%, 24%, 25%, 26%, 28%, 30%, or 33%, and the duration of response to the antibody-drug conjugate is at least approximately 6 months after administration of the antibody-drug conjugate, and in some cases, the duration of response to the antibody-drug conjugate is at least approximately 7 months, 8 months, or 10 months after administration of the antibody-drug conjugate. The subjects showed an overall survival of at least approximately 10 months after administration of the antibody-drug conjugate, and in some cases, an overall survival of at least approximately 11 months, approximately 12 months, approximately 13 months, or 14 months after administration of the antibody-drug conjugate, and the time to response was less than approximately 6 months after administration of the antibody-drug conjugate, and in some cases, the time to response was shorter than approximately 4 months, approximately 2 months, 1.4 months, or approximately 1.2 months after administration of the antibody-drug conjugate. In some embodiments, the objective response rate is approximately 13% to 35%, and in some cases, the objective response rate is at least approximately 14%, 19%, 21%, 23.8%, 24%, 25%, 26%, 28%, 30%, or 33%, and the duration of response to the antibody-drug conjugate is at least approximately 6 months after administration of the antibody-drug conjugate, and in some cases, the duration of response to the antibody-drug conjugate is at least approximately 7 months, and in some cases, approximately 8 months after administration of the antibody-drug conjugate. The time to response is 1.5 months or approximately 10 months, and subjects demonstrate a progression-free survival of at least approximately 3 months after administration of the antibody-drug conjugate, and in some cases, subjects demonstrate a progression-free survival of at least approximately 4 months, approximately 5 months, or approximately 6 months after administration of the antibody-drug conjugate, and the time to response is less than approximately 6 months after administration of the antibody-drug conjugate, and in some cases, the time to response is shorter than approximately 4 months, approximately 2 months, 1.4 months, or approximately 1.2 months after administration of the antibody-drug conjugate.In some aspects, the objective response rate was approximately 13% to 35%, and in some cases, the objective response rate was at least approximately 14%, 19%, 21%, 23.8%, 24%, 25%, 26%, 28%, 30%, or 33%; the duration of response to the antibody-drug conjugate was at least approximately 6 months after administration of the antibody-drug conjugate, and in some cases, the duration of response to the antibody-drug conjugate was at least approximately 7 months, 8 months, or 10 months after administration of the antibody-drug conjugate; and subjects demonstrated progression-free survival of at least approximately 3 months after administration of the antibody-drug conjugate. In some cases, subjects demonstrate progression-free survival of at least approximately 4 months, 5 months, or 6 months after administration of the antibody-drug conjugate, and subjects demonstrate overall survival of at least approximately 10 months after administration of the antibody-drug conjugate, and in some cases, subjects demonstrate overall survival of at least approximately 11 months, 12 months, 13 months, or 14 months after administration of the antibody-drug conjugate, and the time to response is less than approximately 6 months after administration of the antibody-drug conjugate, and in some cases, the time to response is shorter than approximately 4 months, 2 months, 1.4 months, or 1.2 months after administration of the antibody-drug conjugate. In some embodiments, subjects have an ECOG score of 0. In some embodiments, subjects have an ECOG score of 1. In some embodiments, subjects are under 65 years of age. In some embodiments, subjects have been previously treated with bevacizumab. In some embodiments, subjects have not been previously treated with bevacizumab. In some aspects, the subjects have been previously treated with paclitaxel and cisplatin. In some aspects, the subjects have been previously treated with paclitaxel and carboplatin. In some aspects, the subjects have been previously treated with paclitaxel and topotecan. In some aspects, the subjects have been previously treated with bevacizumab, paclitaxel, and cisplatin. In some aspects, the subjects have been previously treated with bevacizumab, paclitaxel, and carboplatin. In some aspects, the subjects have been previously treated with bevacizumab, paclitaxel, and topotecan.

[0158] E. Adverse Events In one aspect, a method of treating cervical cancer using an antibody-drug conjugate or antigen-binding fragment described herein may result in a subject developing one or more adverse events. In some embodiments, the subject is administered additional therapeutic agents to eliminate or reduce the severity of the adverse events. In some embodiments, the one or more adverse events developed by the subject may be anemia, abdominal pain, bleeding-related adverse events, hypokalemia, hyponatremia, epistaxis, fatigue, nausea, alopecia, conjunctivitis, constipation, loss of appetite, diarrhea, vomiting, peripheral neuropathy, deterioration of general health, or any combination thereof. In some embodiments, the adverse event developed by the subject is anemia. In some embodiments, the adverse event developed by the subject is abdominal pain. In some embodiments, the adverse event developed by the subject is a bleeding-related adverse event. In some embodiments, the adverse event developed by the subject is hypokalemia. In some embodiments, the adverse event developed by the subject is hyponatremia. In some embodiments, the adverse event developed by the subject is epistaxis. In some embodiments, the adverse event developed by the subject is fatigue. In some embodiments, the adverse event the subject experiences is nausea. In some embodiments, the adverse event the subject experiences is alopecia. In some embodiments, the adverse event the subject experiences is conjunctivitis. In some embodiments, the adverse event the subject experiences is constipation. In some embodiments, the adverse event the subject experiences is decreased appetite. In some embodiments, the adverse event the subject experiences is diarrhea. In some embodiments, the adverse event the subject experiences is vomiting. In some embodiments, the adverse event the subject experiences is peripheral neuropathy. In some embodiments, the adverse event the subject experiences is deterioration of overall health. In some embodiments, one or more adverse events are grade 1 or higher. In some embodiments, one or more adverse events are grade 2 or higher. In some embodiments, one or more adverse events are grade 3 or higher. In some embodiments, one or more adverse events are grade 1. In some embodiments, one or more adverse events are grade 2. In some embodiments, one or more adverse events are grade 3.In some embodiments, one or more adverse events are Grade 4 adverse events. In some embodiments, one or more adverse events are treatment-related adverse events that occur during treatment. In some embodiments, one or more adverse events are serious adverse events. In some embodiments, one or more adverse events are conjunctivitis and / or keratitis, and the additional therapeutic agent is a preservative-free lubricating eye drop, an ocular vasoconstrictor, a steroid eye drop, or any combination thereof. In some embodiments, one or more adverse events are conjunctivitis and keratitis, and the additional therapeutic agent is a preservative-free lubricating eye drop, an ocular vasoconstrictor, a steroid eye drop, or any combination thereof. In some embodiments, one or more adverse events are conjunctivitis, and the additional therapeutic agent is a preservative-free lubricating eye drop, an ocular vasoconstrictor, a steroid eye drop, or any combination thereof. In some embodiments, one or more adverse events are keratitis, and the additional therapeutic agent is a preservative-free lubricating eye drop, an ocular vasoconstrictor, a steroid eye drop, or any combination thereof. In some aspects of this specification, the subject is treated with an additional therapeutic agent to eliminate or reduce the severity of adverse events (e.g., conjunctivitis and / or keratitis). In some aspects, the treatment is an ocular vasoconstrictor. In some aspects, the ocular vasoconstrictor is brimonidine tartrate 0.2% ophthalmic solution. In some aspects, three drops of brimonidine tartrate 0.2% ophthalmic solution are administered immediately before the start of administration of the antibody-drug conjugate. In some aspects, the treatment is an ocular cooling pad (e.g., THERA PEARL eye mask or similar). In some aspects, the ocular cooling pad is used during administration of the antibody-drug conjugate. In some aspects, the ocular cooling pad is applied 5 minutes before the start of administration of the antibody-drug conjugate and left in place for the entire duration of the antibody-drug conjugate infusion. In some embodiments, a cooling pad for the eye is applied 5 minutes before the start of administration of the antibody-drug conjugate and left in place for the entire duration of the antibody-drug conjugate infusion and for at least approximately 30 minutes after the completion of the infusion. In some embodiments, the treatment is a steroid eye drop.In some embodiments, the steroid eye drops are dexamethasone 0.1% ophthalmic solution. In some embodiments, the steroid eye drops are administered for a total of 4 days, before and after each infusion of the antibody-drug conjugate. In some embodiments, the steroid eye drops are administered from approximately 24 hours before the start of the antibody-drug conjugate infusion until approximately 72 hours after the end of the antibody-drug conjugate infusion. In some embodiments, the steroid eye drops are administered one drop to each eye three times a day. In some embodiments, the treatment is a lubricating eye drop. In some embodiments, the lubricating eye drops are administered from the first infusion of the antibody-drug conjugate until 30 days after the final infusion of the antibody-drug conjugate. In some embodiments, the lubricating eye drops are administered daily. In some embodiments, one or more adverse events are recurrent infusion-related reactions, and additional therapeutic agents are antihistamines, acetaminophen, and / or corticosteroids. In some embodiments, one or more adverse events are neutropenia, and the additional therapeutic agent is growth factor support (G-CSF).

[0159] In one aspect, subjects treated with the antibody-drug conjugate or antigen-binding fragment described herein are at risk of developing one or more adverse events. In some embodiments, subjects are administered additional therapeutic agents to prevent the development of adverse events or to reduce the severity of adverse events. In some embodiments, the one or more adverse events that subjects are at risk of developing are anemia, bleeding-related adverse events, abdominal pain, hypokalemia, hyponatremia, epistaxis, fatigue, nausea, alopecia, conjunctivitis, constipation, loss of appetite, diarrhea, vomiting, peripheral neuropathy, deterioration of general health, or any combination thereof. In some embodiments, the adverse event that subjects are at risk of developing is anemia. In some embodiments, the adverse event that subjects are at risk of developing is abdominal pain. In some embodiments, the adverse event that subjects are at risk of developing is bleeding-related adverse events. In some embodiments, the adverse event that subjects are at risk of developing is hypokalemia. In some embodiments, the adverse event that subjects are at risk of developing is hyponatremia. In some embodiments, the adverse event at risk for the subject is epistaxis. In some embodiments, the adverse event at risk for the subject is fatigue. In some embodiments, the adverse event at risk for the subject is nausea. In some embodiments, the adverse event at risk for the subject is alopecia. In some embodiments, the adverse event at risk for the subject is conjunctivitis. In some embodiments, the adverse event at risk for the subject is constipation. In some embodiments, the adverse event at risk for the subject is decreased appetite. In some embodiments, the adverse event at risk for the subject is diarrhea. In some embodiments, the adverse event at risk for the subject is vomiting. In some embodiments, the adverse event at risk for the subject is peripheral neuropathy. In some embodiments, the adverse event at risk for the subject is deterioration of overall health. In some embodiments, one or more adverse events are grade 1 or higher. In some embodiments, one or more adverse events are grade 2 or higher. In some embodiments, one or more adverse events are grade 3 or higher.In some embodiments, one or more adverse events are Grade 1 adverse events. In some embodiments, one or more adverse events are Grade 2 adverse events. In some embodiments, one or more adverse events are Grade 3 adverse events. In some embodiments, one or more adverse events are Grade 4 adverse events. In some embodiments, one or more adverse events are treatment-related adverse events that occur during treatment. In some embodiments, one or more adverse events are serious adverse events. In some embodiments, one or more adverse events are conjunctivitis and / or keratitis, and the additional treatment is a preservative-free lubricating eye drop, an ocular vasoconstrictor, a steroid eye drop, or any combination thereof. In some embodiments, one or more adverse events are conjunctivitis and keratitis, and the additional treatment is a preservative-free lubricating eye drop, an ocular vasoconstrictor, a steroid eye drop, or any combination thereof. In some embodiments, one or more adverse events are conjunctivitis, and the additional treatment is a preservative-free lubricating eye drop, an ocular vasoconstrictor, a steroid eye drop, or any combination thereof. In some embodiments, one or more adverse events are keratitis, and the additional therapeutic agent is a preservative-free lubricating eye drop, an ocular vasoconstrictor, a steroid eye drop, or any combination thereof. In any embodiment herein, the subject is treated with an additional therapeutic agent to prevent the onset of an adverse event (e.g., conjunctivitis and / or keratitis) or to reduce the severity of an adverse event. In some embodiments, the treatment is an ocular vasoconstrictor. In some embodiments, the ocular vasoconstrictor is brimonidine tartrate 0.2% eye drops. In some embodiments, three drops of brimonidine tartrate 0.2% eye drops are administered immediately before the start of administration of the antibody-drug conjugate. In some embodiments, the treatment is an ocular cooling pad (e.g., THERA PEARL eye mask or similar). In some embodiments, the ocular cooling pad is used during administration of the antibody-drug conjugate. In some embodiments, an eye cooling pad is applied 5 minutes before the start of administration of the antibody-drug conjugate and left in place for the entire duration of the antibody-drug conjugate infusion.In some embodiments, a cooling pad for the eye is applied 5 minutes before the start of administration of the antibody-drug conjugate and left in place for the duration of the entire antibody-drug conjugate infusion and for at least approximately 30 minutes after the completion of the antibody-drug conjugate infusion. In some embodiments, the treatment is a steroid eye drop. In some embodiments, the steroid eye drop is dexamethasone 0.1% eye drop. In some embodiments, the steroid eye drop is administered for a total of 4 days, before and after each infusion of the antibody-drug conjugate. In some embodiments, the steroid eye drop is administered from approximately 24 hours before the start of administration of the antibody-drug conjugate until approximately 72 hours after the completion of administration of the antibody-drug conjugate. In some embodiments, the steroid eye drop is administered one drop to each eye three times a day. In some embodiments, the treatment is a lubricating eye drop. In some embodiments, the lubricating eye drop is administered from the first infusion of the antibody-drug conjugate and continues until 30 days after the final infusion of the antibody-drug conjugate. In some embodiments, a lubricating eye drop is administered daily. In some embodiments, one or more adverse events are recurrent infusion-related reactions, and additional therapeutic agents are antihistamines, acetaminophen, and / or corticosteroids. In some embodiments, one or more adverse events are neutropenia, and additional therapeutic agents are growth factor support (G-CSF).

[0160] IV. Composition In some aspects, compositions (e.g., pharmaceutical compositions) comprising any of the anti-TF antibody-drug conjugates described herein are also provided herein.

[0161] Therapeutic formulations are prepared for storage by mixing the active ingredient of the desired purity with a pharmaceutically acceptable carrier, excipient, or stabilizer (Remington: The Science and Practice of Pharmacy, 20th edition, published by Lippincott Williams & Wiklins, edited by Gennaro, Philadelphia, Pennsylvania, 2000).

[0162] Acceptable carriers, excipients, or stabilizers are nontoxic to the recipient at the dosage and concentration used and include: buffers; antioxidants, e.g., ascorbic acid, methionine, vitamin E, sodium metabisulfite; preservatives; isotonic agents; stabilizers; metal complexes (e.g., Zn-protein complexes); chelating agents, e.g., EDTA; and / or nonionic surfactants.

[0163] Buffers may be used to adjust the pH to a range that optimizes the therapeutic effect, especially when the stability is pH-dependent. Buffers may be present in concentrations ranging from about 50 mM to about 250 mM. Suitable buffers for use in this 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. Furthermore, buffers may consist of histidine and trimethylamine salts such as Tris.

[0164] Preservatives can be added to prevent microbial growth and are typically present in concentrations ranging from approximately 0.2% to 1.0% (w / v). Suitable preservatives for use in this invention include: octadecyldimethylbenzylammonium chloride; hexamethonium chloride; benzalkonium halides (e.g., chlorides, bromides, iodides), benzethonium chloride; thimerosal, phenol, butyl or benzyl alcohol; alkylparabens, e.g., methyl or propylparaben; catechol; resorcinol; cyclohexanol, 3-pentanol, and m-cresol.

[0165] Isotonic agents, sometimes also known as “stabilizers,” may be present to adjust or maintain the osmotic pressure of a liquid in a composition. When used with large charged biomolecules such as proteins and antibodies, they are often called “stabilizers” because they interact with the charged groups of amino acid side chains, thereby reducing the possibility of intermolecular and intramolecular interactions. Isotonic agents can be present in amounts 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, isotonic agents include polyhydric sugar alcohols, trihydric or higher sugar alcohols, such as glycerin, erythritol, arabitol, xylitol, sorbitol, and mannitol.

[0166] Additional excipients include additives that may function as one or more of the following: (1) bulking agents, (2) dissolution accelerators, (3) stabilizers, and (4) additives that prevent denaturation or adhesion to the container wall. Examples of such excipients include: polyhydric sugar alcohols (listed above); amino acids, e.g., alanine, glycine, glutamine, asparagine, histidine, arginine, lysine, ornithine, leucine, 2-phenylalanine, glutamic acid, threonine, etc.; organic sugars or sugar alcohols, e.g., sucrose, lactose, lactitol, trehalose, stachyose, mannose, sorbose, xylose, ribose, ribitol, myoinisitose, myoinositol, galactose, galactitol, glycerol, cyclitol (examples). (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.

[0167] Nonionic surfactants or detergents (also known as "wetting agents") may be present to aid in the solubilization of the therapeutic agent and to protect the therapeutic protein from aggregation induced by agitation, and it also allows the formulation to be exposed to shear surface stress without causing denaturation of the active therapeutic protein or antibody. Nonionic surfactants are present in concentrations ranging from 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, nonionic surfactants are present in concentrations ranging from 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.

[0168] Suitable nonionic surfactants include: polysorbates (20, 40, 60, 65, 80, etc.), polyoxomers (184, 188, etc.), PLURONIC® polyols, TRITON®, polyoxyethylene sorbitan monoethers (TWEEN®-20, TWEEN®-80, etc.), lauromacrogol 400, polyoxyl stearate 40, 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, sodium dioctyl sulfosuccinate, and sodium dioctyl sulfonate. Cationic detergents include benzalkonium chloride or benzethonium chloride.

[0169] Formulations containing the anti-TF antibody conjugate described herein for use in the therapeutic methods provided herein are described in WO2015 / 075201. In some embodiments, the anti-TF antibody-drug conjugate described herein exists as a formulation containing the anti-TF antibody-drug conjugate, histidine, sucrose, and D-mannitol, and this formulation has a pH of about 6.0. In some embodiments, the anti-TF antibody-drug conjugate described herein exists as a formulation containing 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, and this formulation has a pH of about 6.0. In some embodiments, the anti-TF antibody-drug conjugate described herein exists as a formulation comprising an 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, and 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, and D-mannitol at a concentration of 165 mM, and has a pH of 6.0.

[0170] In some embodiments provided herein, the formulations comprising the anti-TF antibody conjugate described herein are surfactant-free.

[0171] For formulations to be used for in vivo administration, they must be sterile. Formulations can be sterilized by filtration through a sterile filtration membrane. The therapeutic compositions described herein are generally placed in containers with sterile access ports, such as intravenous infusion bags or vials with stoppers that can be pierced by a subcutaneous needle.

[0172] The route of administration shall be in accordance with known and accepted methods, for example, by single or multiple bolus administration, or by appropriate methods of long-term infusion, such as injection or infusion via subcutaneous, intravenous, intraperitoneal, intramuscular, intraarterial, intrafocal, or intra-articular routes, local administration, inhalation, or by continuous release or sustained-release means.

[0173] The formulations described herein may also include, as necessary for the specific indication being treated, multiple active compounds, preferably having complementary activities that do not adversely affect one another. Alternatively, the composition may further include cytotoxic agents, cytokines, or growth inhibitors. Such molecules are appropriately present in combination in amounts effective for the intended purpose.

[0174] The present invention provides compositions comprising a group of anti-TF antibody-drug conjugates or antigen-binding fragments thereof, for use in the method for treating cervical cancer described herein. In some aspects, compositions comprising a group of antibody-drug conjugates are provided herein, wherein the antibody-drug conjugate comprises a linker conjugated to MMAE, and the antibody-drug conjugate has the following structure: TIFF2026082887000019.tif31163 Here, p represents a number from 1 to 8, S represents a sulfhydryl residue of the anti-TF antibody or its antigen-binding fragment, and Ab represents the anti-TF antibody or its antigen-binding fragment as described herein, e.g., tisotumab. In some embodiments, p represents a number from 3 to 5. In some embodiments, the mean 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 homogeneous population of antibody-drug conjugates, where each antibody-drug conjugate has the same value for p.

[0175] In some embodiments, a composition comprising the antibody-drug conjugate described herein is co-administered with one or more therapeutic agents. In some embodiments, co-administration is simultaneous or sequential. In some embodiments, the antibody-drug conjugate described herein is administered simultaneously with one or more therapeutic agents. In some embodiments, simultaneous means that the antibody-drug conjugate and one or more therapeutic agents are administered to a subject at intervals of less than one hour, for example, less than about 30 minutes, less than about 15 minutes, less than about 10 minutes, or less than about 5 minutes. In some embodiments, the antibody-drug conjugate described herein is administered sequentially with one or more therapeutic agents. In some embodiments, sequential administration means that the antibody-drug conjugate and one or more therapeutic agents are administered to a subject at intervals of at least 1 hour, at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, at least 9 hours, at least 10 hours, at least 11 hours, at least 12 hours, at least 13 hours, at least 14 hours, at least 15 hours, at least 16 hours, at least 17 hours, at least 18 hours, at least 19 hours, at least 20 hours, at least 21 hours, at least 22 hours, at least 23 hours, at least 24 hours, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 5 days, at least 7 days, at least 2 weeks, at least 3 weeks, or at least 4 weeks. In some embodiments, the composition comprising the antibody-drug conjugate described herein is co-administered with one or more therapeutic agents for eliminating or reducing the severity of one or more adverse events. In some embodiments, the composition comprising the antibody-drug conjugate described herein is co-administered with one or more therapeutic agents for preventing the onset of an adverse event or reducing the severity of an adverse event.

[0176] In some embodiments, a composition comprising the antibody-drug conjugate described herein is co-administered with one or more therapeutic agents for eliminating or reducing the severity of one or more adverse events. In some embodiments, the co-administration is simultaneous or sequential. In some embodiments, the antibody-drug conjugate described herein is administered simultaneously with one or more therapeutic agents for eliminating or reducing the severity of one or more adverse events. In some embodiments, simultaneous means that the antibody-drug conjugate and one or more therapeutic agents for eliminating or reducing the severity of one or more adverse events are administered to a subject at intervals of less than one hour, for example, less than about 30 minutes, less than about 15 minutes, less than about 10 minutes, or less than about 5 minutes. In some embodiments, the antibody-drug conjugate described herein is administered sequentially with one or more therapeutic agents for eliminating or reducing the severity of one or more adverse events. In some embodiments, sequential administration means that the antibody-drug conjugate and one or more additional therapeutic agents are administered to a subject at intervals of at least 1 hour, at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, at least 9 hours, at least 10 hours, at least 11 hours, at least 12 hours, at least 13 hours, at least 14 hours, at least 15 hours, at least 16 hours, at least 17 hours, at least 18 hours, at least 19 hours, at least 20 hours, at least 21 hours, at least 22 hours, at least 23 hours, at least 24 hours, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 5 days, at least 7 days, at least 2 weeks, at least 3 weeks, or at least 4 weeks. In some embodiments, the antibody-drug conjugate is administered before one or more therapeutic agents to eliminate or reduce the severity of one or more adverse events.In some embodiments, one or more therapeutic agents for eliminating or reducing the severity of one or more adverse events are administered prior to the antibody-drug conjugate.

[0177] V. Manufactured articles and kits In another aspect, a manufactured article or kit comprising the anti-TF antibody-drug conjugate described herein is provided. The manufactured article or kit may further include instructions for using the antibody in the manner of the present invention. Thus, in certain embodiments, the manufactured article or kit includes instructions for using the anti-TF antibody-drug conjugate in a method for treating cervical cancer in a subject, comprising the step of administering an effective amount of the anti-TF antibody-drug conjugate to the subject. In some embodiments, the cervical cancer is advanced cervical cancer, such as grade 3 or grade 4 cervical cancer. In some embodiments, the advanced cervical cancer is metastatic cancer. In some embodiments, the cervical cancer is metastatic and recurrent cancer. In some embodiments, the cervical cancer is recurrent cancer. In some embodiments, the subject has been previously treated with one or more therapeutic agents and has not responded to that treatment, has relapsed after treatment, or has experienced disease progression during treatment. In some embodiments of the prior treatment described herein, one or more therapeutic agents are not antibody-drug conjugates. In some embodiments, the subject is human.

[0178] The manufactured article or kit may further include 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 made from a variety of materials such as glass or plastic. The container holds the formulation.

[0179] The manufactured article or kit may further include labels or accompanying documents affixed to or accompanying the container, which may indicate instructions for the reconstitution and / or use of the formulation. The labels or accompanying documents may further indicate that the formulation is useful or suitable for subcutaneous, intravenous (e.g., intravenous injection), or other methods of administration for the treatment of cervical cancer in subjects such as the cervical cancer described herein (e.g., advanced cervical cancer such as grade 3 or grade 4 or metastatic cervical cancer). 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 manufactured article or kit may further include a second container containing an appropriate diluent. The manufactured article or kit may further include other materials desirable from a commercial, therapeutic, and user standpoint, such as other buffers, diluents, filters, needles, syringes, and accompanying documents including instructions for use.

[0180] The manufactured article or kit described herein optionally further comprises a container containing a second drug, in which case the anti-TF antibody-drug conjugate is the first drug; the manufactured article or kit further includes instructions on the label or accompanying leaflet for treating a subject with an effective amount of the second drug. In some embodiments, the label or accompanying leaflet indicates that the first drug and the second drug should be administered sequentially or concurrently, as described herein.

[0181] The manufactured article or kit described herein optionally further comprises a container containing a second drug, wherein the second drug is for eliminating or reducing the severity of one or more adverse events, and the anti-TF antibody-drug conjugate is the first drug, and the manufactured article or kit further includes instructions on the label or accompanying leaflet for treating the subject with an effective amount of the second drug. In some embodiments, the label or accompanying leaflet indicates that the first and second drugs should be administered sequentially or simultaneously, as described herein, for example, that the label or accompanying leaflet indicates that the anti-TF antibody-drug conjugate should be administered first, followed by the second drug.

[0182] In some embodiments, the anti-TF antibody-drug conjugate described herein is present in a container as a lyophilized powder. In some embodiments, the lyophilized powder is contained in a sealed container, such as a vial, ampoule, or pouch, indicating the amount of the active drug. If the drug is administered by injection, an ampoule of sterile water or saline for injection may optionally be provided as part of the kit, for example, so that the components can be mixed before administration. Such a kit may further include, as necessary, one or more different conventional pharmaceutical components, such as a container containing one or more pharmaceutically acceptable carriers, or additional containers, as will be readily apparent to those skilled in the art. A printed instruction manual, as a package insert or label, indicating the amount of the component to be administered, guidelines for administration, and / or guidelines for mixing the components may also be included in the kit.

[0183] VI. Exemplary Examples Treatment method 1A. A method for treating cervical cancer in a subject, comprising the step of administering to the subject an antibody-drug conjugate conjugate bound to tissue factor (TF), wherein the antibody-drug conjugate comprises an anti-TF antibody or its antigen-binding fragment conjugated to monomethyl auristatin or a functional analog or functional derivative thereof, the antibody-drug conjugate is administered in a dose ranging from about 0.9 mg / kg to about 2.1 mg / kg, and the subject has been previously treated with bevacizumab. 2A. The method according to embodiment 1A, wherein the subject has an ECOG score of 0. 3A. The method according to embodiment 1A, wherein the subject has an ECOG score of 1. 4A. The method according to any one of the embodiments 1A to 3A, wherein the subject is under 65 years of age. 5A. The subject is, a) Paclitaxel and cisplatin; b) Paclitaxel and carboplatin; or c) Paclitaxel and Topotecan The method described in any one of the embodiments 1A to 4A, which has been previously used for treatment. 6A. A method for treating cervical cancer in a subject, comprising the step of administering to the subject an antibody-drug conjugate conjugate bound to tissue factor (TF), wherein the antibody-drug conjugate comprises an anti-TF antibody or its antigen-binding fragment conjugated to monomethyl auristatin or a functional analog or functional derivative thereof, the antibody-drug conjugate is administered in a dose in the range of about 0.9 mg / kg to about 2.1 mg / kg, and the subject has not been previously treated with bevacizumab. 7A. The method according to embodiment 6A, wherein the subject has an ECOG score of 0. 8A. The method according to embodiment 6A, wherein the subject has an ECOG score of 1. 9A. The method according to any one of the embodiments 6A to 8A, wherein the subject is under 65 years of age. 10A. The above subject is, a) Paclitaxel and cisplatin; b) Paclitaxel and carboplatin; or c) Paclitaxel and Topotecan The method according to any one of embodiments 6A to 9A, which has been previously used for treatment. 11A. A method for treating cervical cancer in a subject, comprising the step of administering to the subject an antibody-drug conjugate conjugate bound to tissue factor (TF), wherein the antibody-drug conjugate comprises an anti-TF antibody or its antigen-binding fragment conjugated to monomethyl auristatin or a functional analog or functional derivative thereof, the antibody-drug conjugate is administered in a dose in the range of about 0.9 mg / kg to about 2.1 mg / kg, and the subject has an East Coast Clinical Oncology Group (ECOG) score of 0. 12A. The method according to embodiment 11A, wherein the subject is under 65 years of age. 13A. The subject is, a) Paclitaxel and cisplatin; b) Paclitaxel and carboplatin; or c) Paclitaxel and Topotecan The method according to embodiment 11A or 12A, which has been previously used for treatment. 14A. A method for treating cervical cancer in a subject, comprising the step of administering to the subject an antibody-drug conjugate conjugate bound to tissue factor (TF), wherein the antibody-drug conjugate comprises an anti-TF antibody or its antigen-binding fragment conjugated to monomethyl auristatin or a functional analog or functional derivative thereof, the antibody-drug conjugate is administered in a dose in the range of about 0.9 mg / kg to about 2.1 mg / kg, and the subject has an ECOG score of 1. 15A. The method according to embodiment 14A, wherein the subject is under 65 years of age. 16A. The above subject is, a) Paclitaxel and cisplatin; b) Paclitaxel and carboplatin; or c) Paclitaxel and Topotecan The method according to aspect 14A or 15A, which has been previously used for treatment. 17A. A method for treating cervical cancer in a subject, comprising the step of administering to the subject an antibody-drug conjugate bound to tissue factor (TF), wherein the antibody-drug conjugate comprises an anti-TF antibody or its antigen-binding fragment conjugated to monomethyl auristatin or a functional analog or functional derivative thereof, the antibody-drug conjugate is administered in a dose in the range of about 0.9 mg / kg to about 2.1 mg / kg, and the subject is under 65 years of age. 18A. The method according to embodiment 17A, wherein the subject has an ECOG score of 0. 19A. The method according to embodiment 17A, wherein the subject has an ECOG score of 1. 20A. The above subject is, a) Paclitaxel and cisplatin; b) Paclitaxel and carboplatin; or c) Paclitaxel and Topotecan The method according to any one of embodiments 17A to 19A, which has been previously used for treatment. 21A. The method according to any one of embodiments 1A to 20A, wherein the objective response rate is approximately 13% to approximately 35%, and optionally, the objective response rate is at least approximately 14%, approximately 19%, approximately 21%, 23.8%, approximately 24%, approximately 25%, approximately 26%, approximately 28%, approximately 30%, or approximately 33%. 22A. The method according to any one of embodiments 1A to 21A, wherein the subject exhibits a progression-free survival period of at least approximately 3 months after administration of the antibody-drug conjugate, and optionally, the subject exhibits a progression-free survival period of at least approximately 4 months, approximately 5 months, or approximately 6 months after administration of the antibody-drug conjugate. 23A. The method according to any one of embodiments 1A to 22A, wherein the subject exhibits an overall survival of at least about 10 months after administration of the antibody-drug conjugate, and optionally, the subject exhibits an overall survival of at least about 11 months, about 12 months, about 13 months, or 14 months after administration of the antibody-drug conjugate. 24A. The method according to any one of embodiments 1A to 23A, wherein the duration of response to the antibody-drug conjugate is at least about 6 months after administration of the antibody-drug conjugate, and optionally, the duration of response to the antibody-drug conjugate is at least about 7 months, about 8 months, or about 10 months after administration of the antibody-drug conjugate. 25A. The method according to any one of embodiments 1A to 24A, wherein the time to response is less than approximately 6 months after administration of the antibody-drug conjugate, and optionally, the time to response is shorter than approximately 4 months, approximately 2 months, 1.4 months, or approximately 1.2 months after administration of the antibody-drug conjugate. 26A. A method for treating cervical cancer in a subject, comprising the step of administering to the subject an antibody-drug conjugate bound to tissue factor (TF), wherein the antibody-drug conjugate comprises an anti-TF antibody or its antigen-binding fragment conjugated to monomethyl auristatin or a functional analog or functional derivative thereof, wherein the antibody-drug conjugate is administered in a dose ranging from about 0.9 mg / kg to about 2.1 mg / kg, with an objective response rate of about 13% to about 35%, and optionally, an objective response rate of at least about 14%, about 19%, about 21%, 23.8%, about 24%, about 25%, about 26%, about 28%, about 30%, or about 33%. 27A. The method according to embodiment 26A, wherein the subject exhibits a progression-free survival of at least approximately 3 months after administration of the antibody-drug conjugate, and optionally, the subject exhibits a progression-free survival of at least approximately 4 months, approximately 5 months, or approximately 6 months after administration of the antibody-drug conjugate. 28A. The method according to embodiment 26A or 27A, wherein the subject exhibits an overall survival of at least about 10 months after administration of the antibody-drug conjugate, and optionally, the subject exhibits an overall survival of at least about 11 months, about 12 months, about 13 months, or 14 months after administration of the antibody-drug conjugate. 29A. The method according to any one of embodiments 26A to 28A, wherein the duration of response to the antibody-drug conjugate is at least about 6 months after administration of the antibody-drug conjugate, and optionally, the duration of response to the antibody-drug conjugate is at least about 7 months, about 8 months, or about 10 months after administration of the antibody-drug conjugate. 30A. The method according to any one of embodiments 26A to 29A, wherein the time to response is less than approximately 6 months after administration of the antibody-drug conjugate, and optionally, the time to response is shorter than approximately 4 months, approximately 2 months, 1.4 months, or approximately 1.2 months after administration of the antibody-drug conjugate. 31A. A method for treating cervical cancer in a subject, comprising the step of administering to the subject an antibody-drug conjugate bound to tissue factor (TF), wherein the antibody-drug conjugate comprises an anti-TF antibody or its antigen-binding fragment conjugated to monomethyl auristatin or a functional analog or functional derivative thereof, the antibody-drug conjugate is administered in a dose in the range of about 0.9 mg / kg to about 2.1 mg / kg, and the subject exhibits a progression-free survival of at least about 3 months after administration of the antibody-drug conjugate, and optionally, the subject exhibits a progression-free survival of at least about 4 months, about 5 months, or about 6 months after administration of the antibody-drug conjugate. 32A. The method according to embodiment 31A, wherein the objective response rate is approximately 13% to approximately 35%, and optionally, the objective response rate is at least approximately 14%, approximately 19%, approximately 21%, 23.8%, approximately 24%, approximately 25%, approximately 26%, approximately 28%, approximately 30%, or approximately 33%. 33A. The method according to embodiment 31A or 32A, wherein the subject exhibits an overall survival of at least about 10 months after administration of the antibody-drug conjugate, and optionally, the subject exhibits an overall survival of at least about 11 months, about 12 months, about 13 months, or 14 months after administration of the antibody-drug conjugate. 34A. The method according to any one of embodiments 31A to 33A, wherein the duration of response to the antibody-drug conjugate is at least about 6 months after administration of the antibody-drug conjugate, and optionally, the duration of response to the antibody-drug conjugate is at least about 7 months, about 8 months, or about 10 months after administration of the antibody-drug conjugate. 35A. The method according to any one of embodiments 31A to 34A, wherein the time to response is less than approximately 6 months after administration of the antibody-drug conjugate, and optionally, the time to response is shorter than approximately 4 months, approximately 2 months, 1.4 months, or approximately 1.2 months after administration of the antibody-drug conjugate. 36A. A method for treating cervical cancer in a subject, comprising the step of administering to the subject an antibody-drug conjugate bound to tissue factor (TF), wherein the antibody-drug conjugate comprises an anti-TF antibody or its antigen-binding fragment conjugated to monomethyl auristatin or a functional analog or functional derivative thereof, the antibody-drug conjugate is administered in a dose ranging from about 0.9 mg / kg to about 2.1 mg / kg, and the subject exhibits an overall survival of at least about 10 months after administration of the antibody-drug conjugate, and optionally, the subject exhibits an overall survival of at least about 11 months, about 12 months, about 13 months, or 14 months after administration of the antibody-drug conjugate. 37A. The method according to embodiment 36A, wherein the subject exhibits a progression-free survival of at least approximately 3 months after administration of the antibody-drug conjugate, and optionally, the subject exhibits a progression-free survival of at least approximately 4 months, approximately 5 months, or approximately 6 months after administration of the antibody-drug conjugate. 38A. The method according to embodiment 36A or 37A, wherein the objective response rate is approximately 13% to approximately 35%, and optionally, the objective response rate is at least approximately 14%, approximately 19%, approximately 21%, 23.8%, approximately 24%, approximately 25%, approximately 26%, approximately 28%, approximately 30%, or approximately 33%. 39A. The method according to any one of embodiments 36A to 38A, wherein the duration of response to the antibody-drug conjugate is at least about 6 months after administration of the antibody-drug conjugate, and optionally, the duration of response to the antibody-drug conjugate is at least about 7 months, about 8 months, or about 10 months after administration of the antibody-drug conjugate. 40A. The method according to any one of embodiments 36A to 39A, wherein the time to response is less than approximately 6 months after administration of the antibody-drug conjugate, and optionally, the time to response is shorter than approximately 4 months, approximately 2 months, 1.4 months, or approximately 1.2 months after administration of the antibody-drug conjugate. 41A. A method for treating cervical cancer in a subject, comprising the step of administering to the subject an antibody-drug conjugate bound to tissue factor (TF), wherein the antibody-drug conjugate comprises an anti-TF antibody or its antigen-binding fragment conjugated to monomethyl auristatin or a functional analog or functional derivative thereof, the antibody-drug conjugate is administered in a dose in the range of about 0.9 mg / kg to about 2.1 mg / kg, the duration of response to the antibody-drug conjugate is at least about 6 months after administration of the antibody-drug conjugate, and optionally, the duration of response to the antibody-drug conjugate is at least about 7 months, about 8 months, or about 10 months after administration of the antibody-drug conjugate. 42A. The method according to embodiment 41A, wherein the subject exhibits a progression-free survival of at least approximately 3 months after administration of the antibody-drug conjugate, and optionally, the subject exhibits a progression-free survival of at least approximately 4 months, approximately 5 months, or approximately 6 months after administration of the antibody-drug conjugate. 43A. The method according to embodiment 41A or 42A, wherein the subject exhibits an overall survival of at least about 10 months after administration of the antibody-drug conjugate, and optionally, the subject exhibits an overall survival of at least about 11 months, about 12 months, about 13 months, or 14 months after administration of the antibody-drug conjugate. 44A. The method according to any one of embodiments 41A to 43A, wherein the objective response rate is approximately 13% to approximately 35%, and optionally, the objective response rate is at least approximately 14%, approximately 19%, approximately 21%, 23.8%, approximately 24%, approximately 25%, approximately 26%, approximately 28%, approximately 30%, or approximately 33%. 45A. The method according to any one of embodiments 41A to 44A, wherein the time to response is less than approximately 6 months after administration of the antibody-drug conjugate, and optionally, the time to response is shorter than approximately 4 months, approximately 2 months, 1.4 months, or approximately 1.2 months after administration of the antibody-drug conjugate. 46A. A method for treating cervical cancer in a subject, comprising the step of administering to the subject an antibody-drug conjugate bound to tissue factor (TF), wherein the antibody-drug conjugate comprises an anti-TF antibody or its antigen-binding fragment conjugated to monomethyl auristatin or a functional analog or functional derivative thereof, the antibody-drug conjugate is administered in a dose in the range of about 0.9 mg / kg to about 2.1 mg / kg, the time to response is less than about 6 months after administration of the antibody-drug conjugate, and optionally, the time to response is shorter than about 4 months, about 2 months, 1.4 months, or about 1.2 months after administration of the antibody-drug conjugate. 47A. The method according to embodiment 46A, wherein the subject exhibits a progression-free survival of at least approximately 3 months after administration of the antibody-drug conjugate, and optionally, the subject exhibits a progression-free survival of at least approximately 4 months, approximately 5 months, or approximately 6 months after administration of the antibody-drug conjugate. 48A. The method according to embodiment 46A or 47A, wherein the subject exhibits an overall survival of at least about 10 months after administration of the antibody-drug conjugate, and optionally, the subject exhibits an overall survival of at least about 11 months, about 12 months, about 13 months, or 14 months after administration of the antibody-drug conjugate. 49A. The method according to any one of embodiments 46A to 48A, wherein the duration of response to the antibody-drug conjugate is at least about 6 months after administration of the antibody-drug conjugate, and optionally, the duration of response to the antibody-drug conjugate is at least about 7 months, about 8 months, or about 10 months after administration of the antibody-drug conjugate. 50A. The method according to any one of embodiments 46A to 49A, wherein the objective response rate is at least about 13% to about 35%, and optionally, the objective response rate is at least about 14%, about 19%, about 21%, 23.8%, about 24%, about 25%, about 26%, about 28%, about 30%, or about 33%. 51A. The method according to any one of embodiments 26A to 50A, wherein the subject has been previously treated with bevacizumab. 52A. The method according to any one of embodiments 26A to 50A, wherein the subject has not been previously treated with bevacizumab. 53A. The subject is, a) Paclitaxel and cisplatin; b) Paclitaxel and carboplatin; c) Paclitaxel and topotecan; d) Bevacizumab, paclitaxel, and cisplatin; e) Bevacizumab, paclitaxel, and carboplatin; or f) Bevacizumab, paclitaxel, and topotecan The method according to any one of embodiments 26A to 52A, wherein the patient experiences disease progression during or after treatment with the method. 54A. The method according to any one of the embodiments 26A to 53A, wherein the subject is under 65 years of age. 55A. The method according to any one of embodiments 26A to 54A, wherein the subject has an ECOG score of 0. 56A. The method according to any one of embodiments 26A to 54A, wherein the subject has an ECOG score of 1. 57A. The method according to any one of embodiments 1A to 56A, wherein the cervical cancer is an adenocarcinoma. 58A. The method according to any one of embodiments 1A to 56A, wherein the cervical cancer is adenosquamous carcinoma. 59A. The method according to any one of embodiments 1A to 56A, wherein the cervical cancer is squamous cell carcinoma. 60A. The method according to any one of embodiments 1A to 56A, wherein the cervical cancer is non-squamous cell carcinoma. 61A. The method according to any one of embodiments 1A to 60A, wherein the dose is approximately 2.0 mg / kg. 62A. The method according to any one of embodiments 1A to 60A, wherein the dose is 2.0 mg / kg. 63A. The method according to any one of embodiments 1A to 62A, wherein the antibody-drug conjugate is administered once every approximately one week, two weeks, three weeks, or four weeks. 64A. The method according to any one of embodiments 1A to 62A, wherein the antibody-drug conjugate is administered approximately once every three weeks. 65A. The method according to any one of embodiments 1A to 64A, wherein the antibody-drug conjugate is administered once every three weeks. 66A. The method according to any one of embodiments 1A to 65A, wherein the cervical cancer is recurrent or metastatic cervical cancer. 67A. The method according to any one of embodiments 1A to 66A, wherein the subject has been previously treated with one or more therapeutic agents and has not responded to such treatment; wherein the one or more therapeutic agents are not the antibody-drug conjugate. 68A. The subject has been previously treated with one or more therapeutic agents and has experienced a relapse after such treatment; wherein the one or more therapeutic agents are not the antibody-drug conjugate, according to any one of embodiments 1A to 66A. 69A. The method according to any one of embodiments 1A to 66A, wherein the subject has been previously treated with one or more therapeutic agents and has experienced disease progression during such treatment; wherein the one or more therapeutic agents are not the antibody-drug conjugate. 70A. The method according to any one of embodiments 67A to 69A, wherein one or more therapeutic agents are platinum-based therapeutic agents. 71A. The method according to any one of embodiments 67A to 69A, wherein the one or more therapeutic agents are selected from the group consisting of paclitaxel, cisplatin, carboplatin, topotecan, gemcitabine, fluorouracil, ixabepyrone, imatinib mesylate, docetaxel, gefitinib, nab-paclitaxel, pemetrexed, vinorelbine, doxil, cetuximab, pembrolizumab, nivolumab, and bevacizumab. 72A. The method according to any one of embodiments 1A to 71A, wherein the subject is not a candidate for a curative treatment. 73A. The method according to embodiment 72A, wherein the curative treatment includes radiotherapy and / or viscerectomy. 74A. The method according to any one of embodiments 1A to 71A, wherein the subject has previously received radiation therapy to the pelvis. 75A. The method according to any one of embodiments 1A to 71A, wherein the subject has never previously received radiation to the pelvis. 76A. The method according to any one of embodiments 1A to 75A, wherein the subject has previously received one systemic therapy for recurrent, relapsed, or metastatic cancer. 77A. The method according to any one of embodiments 1A to 75A, wherein the subject has previously received two systemic therapies for recurrent, relapsed, or metastatic cancer. 78A. The method according to embodiment 76A or 77A, wherein the subject has not responded to prior systemic therapy. 79A. The method according to embodiment 76A or 77A, wherein the subject has experienced a relapse after prior treatment with systemic therapy. 80A. The method according to any one of embodiments 1A to 79A, wherein the cervical cancer is advanced cervical cancer, for example, stage 3 or stage 4 cervical cancer, for example, metastatic cervical cancer. 81A. The method according to any one of embodiments 1A to 80A, wherein the cervical cancer is recurrent cervical cancer. 82A. The method according to any one of embodiments 1A to 81A, wherein the monomethyl auristatin is monomethyl auristatin E (MMAE). 83A. The method according to any one of embodiments 1A to 82A, wherein the anti-TF antibody or its antigen-binding fragment of the antibody-drug conjugate is a monoclonal antibody or its monoclonal antigen-binding fragment. 84A. The anti-TF antibody or its antigen-binding fragment of the antibody-drug conjugate comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region (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 method according to any one of embodiments 1A to 83A, comprising; wherein the CDR of the anti-TF antibody or its antigen-binding fragment of the antibody-drug conjugate is defined by the IMGT numbering scheme. 85A. The method according to any one of embodiments 1A to 84A, wherein the anti-TF antibody or 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. 86A. The method according to any one of embodiments 1A to 85A, wherein the anti-TF antibody or 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. 87A. The method according to any one of embodiments 1A to 86A, wherein the anti-TF antibody of the antibody-drug conjugate is tisotumab. 88A. The method according to any one of aspects 1A to 87A, wherein the antibody-drug conjugate further comprises a linker between the anti-TF antibody or an antigen-binding fragment thereof and the monomethyl auristatin. 89A. The method according to aspect 88A, wherein the linker is a cleavable peptide linker. 90A. The cleavable peptide linker has the formula: -MC-vc-PAB-, wherein a) MC is TIFF2026082887000020.tif25128, and b) vc is valine-citrulline, a dipeptide, and c) PAB is TIFF2026082887000021.tif30128. The method according to aspect 89A. 91A. The method according to any one of aspects 88A to 90A, 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 an antigen-binding fragment thereof. 92A. The linker is bound to MMAE, and the antibody-drug conjugate has the following structure: TIFF2026082887000022.tif33170, where 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 an antigen-binding fragment thereof. The method according to aspect 91A. 93A. The method according to aspect 92A, wherein the average value of p in the population of the antibody-drug conjugate is about 4. 94A. The method according to any one of aspects 1A to 93A, wherein the antibody-drug conjugate is tisotumab vedotin or a biosimilar thereof. 95A. The method according to any one of aspects 1A to 94A, wherein the administration route of the antibody-drug conjugate is intravenous. 96A. The method according to any one of aspects 1A to 95A, wherein at least about 0.1%, at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, or at least about 80% of the cervical cancer cells express TF. 97A. The method according to any one of aspects 1A to 96A, wherein the subject has at least one TF histological score (H score). 98A. The method according to any one of aspects 1A to 97A, wherein the subject has one or more adverse events, and an additional therapeutic agent for eliminating or reducing the severity of the one or more adverse events is further administered. 99A. The method according to any one of aspects 1A to 97A, wherein the subject has a risk of developing one or more adverse events, and an additional therapeutic agent for preventing or reducing the severity of the one or more adverse events is further administered. 100A. The method according to any one of aspects 1A to 98A, wherein the subject has one or more adverse events, and the dose of the antibody-drug conjugate is reduced after the one or more adverse events. 101A. The method according to aspect 100A, wherein the dose is reduced from 2.0 mg / kg to 1.3 mg / kg. 102A. The method according to aspect 100A or 101A, wherein the dose is reduced from 1.3 mg / kg to 0.9 mg / kg. 103A. The method according to any one of aspects 98A to 102A, wherein the one or more adverse events are anemia, abdominal pain, hypokalemia, hyponatremia, epistaxis, fatigue, nausea, alopecia, conjunctivitis, constipation, anorexia, diarrhea, vomiting, peripheral neuropathy, or deterioration of the overall health condition. 104A. The method according to any one of embodiments 98A to 103A, wherein the one or more adverse events are grade 3 or higher adverse events. 105A. The method according to any one of embodiments 98A to 103A, wherein the one or more adverse events are serious adverse events. 106A. Embodiment 98A or the method of 98A, wherein the one or more adverse events are conjunctivitis and / or keratitis, and the additional therapeutic agent is a preservative-free lubricating eye drop, an ocular vasoconstrictor, and / or a steroid eye drop. 107A. The method according to any one of embodiments 1A to 106A, wherein the antibody-drug conjugate is administered as monotherapy. 108A. The method according to any one of embodiments 1A to 107A, wherein the subject is a human. 109A. The method according to any one of embodiments 1A to 108A, wherein the antibody-drug conjugate is present in a pharmaceutical composition comprising the antibody-drug conjugate and a pharmaceutically acceptable carrier.

[0184] Antibody-drug conjugate for use 1B. An antibody-drug conjugate conjugate that binds to tissue factor (TF) for use in the treatment of cervical cancer in a subject, wherein the antibody-drug conjugate comprises an anti-TF antibody or its antigen-binding fragment conjugated to monomethyl auristatin or a functional analog or functional derivative thereof, and the antibody-drug conjugate is administered in doses ranging from about 0.9 mg / kg to about 2.1 mg / kg, wherein the subject has been previously treated with bevacizumab. 2B. The antibody-drug conjugate for use according to embodiment 1B, wherein the subject has an ECOG score of 0. 3B. The antibody-drug conjugate for use according to embodiment 1B, wherein the subject has an ECOG score of 1. 4B. An antibody-drug conjugate for use according to any one of embodiments 1B to 3B, wherein the subject is under 65 years of age. 5B. The aforementioned subject is a) Paclitaxel and cisplatin; b) Paclitaxel and carboplatin; or c) Paclitaxel and Topotecan An antibody-drug conjugate for use according to any one of embodiments 1B to 4B, which has been previously treated with [a specific method / method]. 6B. An antibody-drug conjugate conjugate that binds to tissue factor (TF) for use in the treatment of cervical cancer in a subject, wherein the antibody-drug conjugate comprises an anti-TF antibody or its antigen-binding fragment conjugated to monomethyl auristatin or a functional analog or functional derivative thereof, and the antibody-drug conjugate is administered in a dose ranging from about 0.9 mg / kg to about 2.1 mg / kg, and the subject has not been previously treated with bevacizumab. 7B. The antibody-drug conjugate for use according to embodiment 6B, wherein the subject has an ECOG score of 0. 8B. The antibody-drug conjugate for use according to embodiment 6B, wherein the subject has an ECOG score of 1. 9B. An antibody-drug conjugate for use according to any one of embodiments 6B to 8B, wherein the subject is under 65 years of age. 10B. The subject is, a) Paclitaxel and cisplatin; b) Paclitaxel and carboplatin; or c) Paclitaxel and Topotecan An antibody-drug conjugate for use as described in any one of embodiments 6B to 9B, which has been previously treated with [a specific method / method]. 11B. An antibody-drug conjugate conjugate that binds to tissue factor (TF) for use in the treatment of cervical cancer in a subject, wherein the antibody-drug conjugate comprises an anti-TF antibody or its antigen-binding fragment conjugated to monomethyl auristatin or a functional analog or functional derivative thereof, the antibody-drug conjugate is administered in doses ranging from approximately 0.9 mg / kg to approximately 2.1 mg / kg, and the subject has an East Coast Cancer Group (ECOG) score of 0. 12B. The antibody-drug conjugate for use according to embodiment 11B, wherein the subject is under 65 years of age. 13B. The aforementioned subject is a) Paclitaxel and cisplatin; b) Paclitaxel and carboplatin; or c) Paclitaxel and Topotecan An antibody-drug conjugate for use according to embodiment 11B or 12B, which has been previously treated with an antibody-drug conjugate. 14B. An antibody-drug conjugate conjugate that binds to tissue factor (TF) for use in the treatment of cervical cancer in a subject, wherein the antibody-drug conjugate comprises an anti-TF antibody or its antigen-binding fragment conjugated to monomethyl auristatin or a functional analog or functional derivative thereof, and the antibody-drug conjugate is administered in doses ranging from about 0.9 mg / kg to about 2.1 mg / kg, wherein the subject has an ECOG score of 1. 15B. The antibody-drug conjugate for use according to embodiment 14B, wherein the subject is under 65 years of age. 16B. The subject is, a) Paclitaxel and cisplatin; b) Paclitaxel and carboplatin; or c) Paclitaxel and Topotecan An antibody-drug conjugate for use according to embodiment 14B or 15B, which has been previously treated with an antibody-drug conjugate. 17B. An antibody-drug conjugate conjugate that binds to tissue factor (TF) for use in the treatment of cervical cancer in a subject, wherein the antibody-drug conjugate comprises an anti-TF antibody or its antigen-binding fragment conjugated to monomethyl auristatin or a functional analog or functional derivative thereof, the antibody-drug conjugate is administered in a dose in the range of about 0.9 mg / kg to about 2.1 mg / kg, and the subject is under 65 years of age. 18B. The antibody-drug conjugate for use according to embodiment 17B, wherein the subject has an ECOG score of 0. 19B. The antibody-drug conjugate for use according to embodiment 17B, wherein the subject has an ECOG score of 1. 20B. The aforementioned subject is a) Paclitaxel and cisplatin; b) Paclitaxel and carboplatin; or c) Paclitaxel and Topotecan An antibody-drug conjugate for use according to any one of embodiments 17B to 19B, which has been previously treated with [a specific method / method]. 21B. An antibody-drug conjugate for use according to any one of embodiments 1B to 20B, wherein the objective response rate is approximately 13% to approximately 35%, and optionally, the objective response rate is at least approximately 14%, approximately 19%, approximately 21%, 23.8%, approximately 24%, approximately 25%, approximately 26%, approximately 28%, approximately 30%, or approximately 33%. 22B. An antibody-drug conjugate for use according to any one of embodiments 1B to 21B, wherein the subject exhibits a progression-free survival of at least approximately 3 months after administration of the antibody-drug conjugate, and optionally, the subject exhibits a progression-free survival of at least approximately 4 months, approximately 5 months, or approximately 6 months after administration of the antibody-drug conjugate. 23B. An antibody-drug conjugate for use according to any one of embodiments 1B to 22B, wherein the subject exhibits an overall survival of at least about 10 months after administration of the antibody-drug conjugate, and optionally, the subject exhibits an overall survival of at least about 11 months, about 12 months, about 13 months, or 14 months after administration of the antibody-drug conjugate. 24B. An antibody-drug conjugate for use according to any one of embodiments 1B to 23B, wherein the duration of response to the antibody-drug conjugate is at least about 6 months after administration of the antibody-drug conjugate, and optionally, the duration of response to the antibody-drug conjugate is at least about 7 months, about 8 months, or about 10 months after administration of the antibody-drug conjugate. 25B. An antibody-drug conjugate for use according to any one of embodiments 1B to 24B, wherein the time to response is less than approximately 6 months after administration of the antibody-drug conjugate, and optionally, the time to response is shorter than approximately 4 months, approximately 2 months, 1.4 months, or approximately 1.2 months after administration of the antibody-drug conjugate. 26B. An antibody-drug conjugate conjugate that binds to tissue factor (TF) for use in the treatment of cervical cancer in a subject, wherein the antibody-drug conjugate comprises an anti-TF antibody or its antigen-binding fragment conjugated to monomethyl auristatin or a functional analog or functional derivative thereof, and the antibody-drug conjugate is administered in doses ranging from about 0.9 mg / kg to about 2.1 mg / kg, with an objective response rate of about 13% to about 35%, and optionally, an objective response rate of at least about 14%, about 19%, about 21%, 23.8%, about 24%, about 25%, about 26%, about 28%, about 30%, or about 33%. 27B. An antibody-drug conjugate for use according to embodiment 26B, wherein the subject exhibits a progression-free survival of at least approximately 3 months after administration of the antibody-drug conjugate, and optionally, the subject exhibits a progression-free survival of at least approximately 4 months, approximately 5 months, or approximately 6 months after administration of the antibody-drug conjugate. 28B. An antibody-drug conjugate for use according to embodiment 26B or 27B, wherein the subject exhibits an overall survival period of at least about 10 months after administration of the antibody-drug conjugate, and optionally, the subject exhibits an overall survival period of at least about 11 months, about 12 months, about 13 months, or 14 months after administration of the antibody-drug conjugate. 29B. An antibody-drug conjugate for use according to any one of embodiments 26B - 28B, wherein the duration of response to the antibody-drug conjugate is at least about 6 months after administration of the antibody-drug conjugate, and optionally, the duration of response to the antibody-drug conjugate is at least about 7 months, about 8 months, or about 10 months after administration of the antibody-drug conjugate. 30B. An antibody-drug conjugate for use according to any one of embodiments 26B - 29B, wherein the period to response is less than about 6 months after administration of the antibody-drug conjugate, and optionally, the period to response is shorter than about 4 months, about 2 months, 1.4 months, or about 1.2 months after administration of the antibody-drug conjugate. 31B. An antibody-drug conjugate that binds to tissue factor (TF) for use in treating cervical cancer in a subject, the antibody-drug conjugate comprising an anti-TF antibody or an antigen-binding fragment thereof conjugated to monomethyl auristatin or a functional analogue or derivative thereof, the antibody-drug conjugate being administered at a dose in the range of about 0.9 mg / kg to about 2.1 mg / kg, and the subject exhibiting an absence of disease progression survival period of at least about 3 months after administration of the antibody-drug conjugate, and optionally, the subject exhibiting an absence of disease progression survival period of at least about 4 months, about 5 months, or about 6 months after administration of the antibody-drug conjugate. 32B. An antibody-drug conjugate for use according to embodiment 31B, wherein the objective response rate is from about 13% to about 35%, and optionally, the objective response rate is at least about 14%, about 19%, about 21%, 23.8%, about 24%, about 25%, about 26%, about 28%, about 30%, or about 33%. 33B. An antibody-drug conjugate for use according to embodiment 31B or 32B, wherein the subject exhibits an overall survival of at least about 10 months after administration of the antibody-drug conjugate, and optionally, the subject exhibits an overall survival of at least about 11 months, about 12 months, about 13 months, or 14 months after administration of the antibody-drug conjugate. 34B. An antibody-drug conjugate for use according to any one of embodiments 31B to 33B, wherein the duration of response to the antibody-drug conjugate is at least about 6 months after administration of the antibody-drug conjugate, and optionally, the duration of response to the antibody-drug conjugate is at least about 7 months, about 8 months, or about 10 months after administration of the antibody-drug conjugate. 35B. An antibody-drug conjugate for use according to any one of embodiments 31B to 34B, wherein the time to response is less than approximately 6 months after administration of the antibody-drug conjugate, and optionally, the time to response is shorter than approximately 4 months, approximately 2 months, 1.4 months, or approximately 1.2 months after administration of the antibody-drug conjugate. 36B. An antibody-drug conjugate conjugate that binds to tissue factor (TF) for use in the treatment of cervical cancer in a subject, wherein the antibody-drug conjugate comprises an anti-TF antibody or its antigen-binding fragment conjugated to monomethyl auristatin or a functional analog or functional derivative thereof, wherein the antibody-drug conjugate is administered in doses ranging from about 0.9 mg / kg to about 2.1 mg / kg, and the subject exhibits an overall survival of at least about 10 months after administration of the antibody-drug conjugate, and optionally, the subject exhibits an overall survival of at least about 11 months, about 12 months, about 13 months, or 14 months after administration of the antibody-drug conjugate. 37B. An antibody-drug conjugate for use according to embodiment 36B, wherein the subject exhibits a progression-free survival of at least about 3 months after administration of the antibody-drug conjugate, and optionally, the subject exhibits a progression-free survival of at least about 4 months, about 5 months, or about 6 months after administration of the antibody-drug conjugate. 38B. An antibody-drug conjugate for use according to embodiment 36B or 37B, wherein the objective response rate is approximately 13% to approximately 35%, and optionally, the objective response rate is at least approximately 14%, approximately 19%, approximately 21%, 23.8%, approximately 24%, approximately 25%, approximately 26%, approximately 28%, approximately 30%, or approximately 33%. 39B. An antibody-drug conjugate for use according to any one of embodiments 36B to 38B, wherein the duration of response to the antibody-drug conjugate is at least about 6 months after administration of the antibody-drug conjugate, and optionally, the duration of response to the antibody-drug conjugate is at least about 7 months, about 8 months, or about 10 months after administration of the antibody-drug conjugate. 40B. An antibody-drug conjugate for use according to any one of embodiments 36B to 39B, wherein the time to response is less than approximately 6 months after administration of the antibody-drug conjugate, and optionally, the time to response is shorter than approximately 4 months, approximately 2 months, 1.4 months, or approximately 1.2 months after administration of the antibody-drug conjugate. 41B. An antibody-drug conjugate conjugate that binds to tissue factor (TF) for use in the treatment of cervical cancer in a subject, wherein the antibody-drug conjugate comprises an anti-TF antibody or its antigen-binding fragment conjugated to monomethyl auristatin or a functional analog or functional derivative thereof, the antibody-drug conjugate is administered in a dose in the range of about 0.9 mg / kg to about 2.1 mg / kg, the duration of response to the antibody-drug conjugate is at least about 6 months after administration of the antibody-drug conjugate, and optionally, the duration of response to the antibody-drug conjugate is at least about 7 months, about 8 months, or about 10 months after administration of the antibody-drug conjugate. 42B. An antibody-drug conjugate for use according to embodiment 41B, wherein the subject exhibits a progression-free survival of at least approximately 3 months after administration of the antibody-drug conjugate, and optionally, the subject exhibits a progression-free survival of at least approximately 4 months, approximately 5 months, or approximately 6 months after administration of the antibody-drug conjugate. 43B. An antibody-drug conjugate for use according to embodiment 41B or 42B, wherein the subject exhibits an overall survival of at least about 10 months after administration of the antibody-drug conjugate, and optionally, the subject exhibits an overall survival of at least about 11 months, about 12 months, about 13 months, or 14 months after administration of the antibody-drug conjugate. 44B. An antibody-drug conjugate for use according to any one of embodiments 41B to 43B, wherein the objective response rate is approximately 13% to approximately 35%, and optionally, the objective response rate is at least approximately 14%, approximately 19%, approximately 21%, 23.8%, approximately 24%, approximately 25%, approximately 26%, approximately 28%, approximately 30%, or approximately 33%. 45B. An antibody-drug conjugate for use according to any one of embodiments 41B to 44B, wherein the time to response is less than approximately 6 months after administration of the antibody-drug conjugate, and optionally, the time to response is shorter than approximately 4 months, approximately 2 months, 1.4 months, or approximately 1.2 months after administration of the antibody-drug conjugate. 46B. An antibody-drug conjugate conjugate that binds to tissue factor (TF) for use in the treatment of cervical cancer in a subject, wherein the antibody-drug conjugate comprises an anti-TF antibody or its antigen-binding fragment conjugated to monomethyl auristatin or a functional analog or functional derivative thereof, the antibody-drug conjugate is administered in a dose in the range of about 0.9 mg / kg to about 2.1 mg / kg, the time to response is less than about 6 months after administration of the antibody-drug conjugate, and optionally, the time to response is shorter than about 4 months, about 2 months, 1.4 months, or about 1.2 months after administration of the antibody-drug conjugate. 47B. An antibody-drug conjugate for use according to embodiment 46B, wherein the subject exhibits a progression-free survival of at least approximately 3 months after administration of the antibody-drug conjugate, and optionally, the subject exhibits a progression-free survival of at least approximately 4 months, approximately 5 months, or approximately 6 months after administration of the antibody-drug conjugate. 48B. An antibody-drug conjugate for use according to embodiment 46B or 47B, wherein the subject exhibits an overall survival of at least about 10 months after administration of the antibody-drug conjugate, and optionally, the subject exhibits an overall survival of at least about 11 months, about 12 months, about 13 months, or 14 months after administration of the antibody-drug conjugate. 49B. An antibody-drug conjugate for use according to any one of embodiments 46B to 48B, wherein the duration of response to the antibody-drug conjugate is at least about 6 months after administration of the antibody-drug conjugate, and optionally, the duration of response to the antibody-drug conjugate is at least about 7 months, about 8 months, or about 10 months after administration of the antibody-drug conjugate. 50B. An antibody-drug conjugate for use according to any one of embodiments 46B to 49B, wherein the objective response rate is at least about 13% to about 35%, and optionally, the objective response rate is at least about 14%, about 19%, about 21%, 23.8%, about 24%, about 25%, about 26%, about 28%, about 30%, or about 33%. 51B. An antibody-drug conjugate for use according to any one of embodiments 26B to 50B, wherein the subject has been previously treated with bevacizumab. 52B. An antibody-drug conjugate for use according to any one of embodiments 26B to 50B, wherein the subject has not been previously treated with bevacizumab. 53B. The subject is, a) Paclitaxel and cisplatin; b) Paclitaxel and carboplatin; c) Paclitaxel and topotecan; d) Bevacizumab, paclitaxel, and cisplatin; e) Bevacizumab, paclitaxel, and carboplatin; or f) Bevacizumab, paclitaxel, and topotecan An antibody-drug conjugate for use according to any one of embodiments 26B to 52B, for patients experiencing disease progression during or after treatment with the aforementioned method. 54B. An antibody-drug conjugate for use according to any one of embodiments 26B to 53B, wherein the subject is under 65 years of age. 55B. An antibody-drug conjugate for use according to any one of embodiments 26B to 54B, wherein the subject has an ECOG score of 0. 56B. An antibody-drug conjugate for use according to any one of embodiments 26B to 54B, wherein the subject has an ECOG score of 1. 57B. An antibody-drug conjugate for use according to any one of embodiments 1B to 56B, wherein the cervical cancer is adenocarcinoma. 58B. An antibody-drug conjugate for use according to any one of embodiments 1B to 56B, wherein the cervical cancer is adenosquamous carcinoma. 59B. An antibody-drug conjugate for use according to any one of embodiments 1B to 56B, wherein the cervical cancer is squamous cell carcinoma. 60B. An antibody-drug conjugate for use according to any one of embodiments 1B to 56B, wherein the cervical cancer is non-squamous cell carcinoma. 61B. An antibody-drug conjugate for use according to any one of embodiments 1B to 60B, wherein the dose is approximately 2.0 mg / kg. 62B. An antibody-drug conjugate for use according to any one of embodiments 1B to 60B, wherein the dose is 2.0 mg / kg. 63B. An antibody-drug conjugate for use according to any one of embodiments 1B to 62B, wherein the antibody-drug conjugate is administered once every approximately one week, two weeks, three weeks, or four weeks. 64B. An antibody-drug conjugate for use according to any one of embodiments 1B to 62B, wherein the antibody-drug conjugate is administered approximately once every three weeks. 65B. An antibody-drug conjugate for use according to any one of embodiments 1B to 64B, wherein the antibody-drug conjugate is administered once every three weeks. 66B. An antibody-drug conjugate for use according to any one of embodiments 1B to 65B, wherein the cervical cancer is recurrent or metastatic cervical cancer. 67B. The subject has been previously treated with one or more therapeutic agents and has not responded to such treatment; wherein the one or more therapeutic agents are not the antibody-drug conjugate, and the antibody-drug conjugate for use according to any one of embodiments 1B to 66B. 68B. The subject has been previously treated with one or more therapeutic agents and has experienced a relapse after such treatment; wherein the one or more therapeutic agents are not the antibody-drug conjugate, but an antibody-drug conjugate for use according to any one of embodiments 1B to 66B. 69B. The subject has been previously treated with one or more therapeutic agents and has experienced disease progression during such treatment; wherein the one or more therapeutic agents are not the antibody-drug conjugate, but an antibody-drug conjugate for use according to any one of embodiments 1B to 66B. 70B. An antibody-drug conjugate for use according to any one of embodiments 67B to 69B, wherein one or more therapeutic agents are platinum-based therapeutic agents. 71B. An antibody-drug conjugate for use according to any one of embodiments 67B to 69B, wherein one or more therapeutic agents are selected from the group consisting of paclitaxel, cisplatin, carboplatin, topotecan, gemcitabine, fluorouracil, ixabepyrone, imatinib mesylate, docetaxel, gefitinib, nab-paclitaxel, pemetrexed, vinorelbine, ...

Claims

1. A method for treating cervical cancer in a subject, comprising the step of administering to the subject an antibody-drug conjugate bound to tissue factor (TF), wherein the antibody-drug conjugate is tisotumab vedotin or a biosimilar thereof, the antibody-drug conjugate is administered at a dose of 2.0 mg / kg once every three weeks, and the subject has been previously treated with bevacizumab.

2. The method according to claim 1, wherein the subject has an ECOG score of 0.

3. The method according to claim 1, wherein the subject has an ECOG score of 1.

4. The method according to any one of claims 1 to 3, wherein the subject is under 65 years of age.

5. The aforementioned subject is, a) Paclitaxel and cisplatin; b) Paclitaxel and carboplatin; or c) Paclitaxel and Topotecan The method according to any one of claims 1 to 4, which has been previously treated with [a specific method].

6. A method for treating cervical cancer in a subject, comprising the step of administering to the subject an antibody-drug conjugate bound to tissue factor (TF), wherein the antibody-drug conjugate is tisotumab vedotin or a biosimilar thereof, the antibody-drug conjugate is administered at a dose of 2.0 mg / kg once every three weeks, and the subject has not been previously treated with bevacizumab.

7. The method according to claim 6, wherein the subject has an ECOG score of 0.

8. The method according to claim 6, wherein the subject has an ECOG score of 1.

9. The method according to any one of claims 6 to 8, wherein the subject is under 65 years of age.

10. The aforementioned subject is, a) Paclitaxel and cisplatin; b) Paclitaxel and carboplatin; or c) Paclitaxel and Topotecan The method according to any one of claims 6 to 9, which has been previously treated with

11. A method for treating cervical cancer in a subject, comprising the step of administering to the subject an antibody-drug conjugate bound to tissue factor (TF), wherein the antibody-drug conjugate is tisotumab vedotin or a biosimilar thereof, the antibody-drug conjugate is administered at a dose of 2.0 mg / kg once every three weeks, and the subject has an East Coast Clinical Oncology Group (ECOG) score of 0.

12. The method according to claim 11, wherein the subject is under 65 years of age.

13. The aforementioned subject is, a) Paclitaxel and cisplatin; b) Paclitaxel and carboplatin; or c) Paclitaxel and Topotecan The method according to claim 11 or 12, which has been previously treated with [a specific method].

14. A method for treating cervical cancer in a subject, comprising the step of administering to the subject an antibody-drug conjugate bound to tissue factor (TF), wherein the antibody-drug conjugate is tisotumab vedotin or a biosimilar thereof, the antibody-drug conjugate is administered at a dose of 2.0 mg / kg once every three weeks, and the subject has an ECOG score of 1.

15. The method according to claim 14, wherein the subject is under 65 years of age.

16. The aforementioned subject is, a) Paclitaxel and cisplatin; b) Paclitaxel and carboplatin; or c) Paclitaxel and Topotecan The method according to claim 14 or 15, which has been previously treated with [a specific method].

17. A method for treating cervical cancer in a subject, comprising the step of administering to the subject an antibody-drug conjugate bound to tissue factor (TF), wherein the antibody-drug conjugate is tisotumab vedotin or a biosimilar thereof, the antibody-drug conjugate is administered at a dose of 2.0 mg / kg once every three weeks, and the subject is under 65 years of age.

18. The method according to claim 17, wherein the subject has an ECOG score of 0.

19. The method according to claim 17, wherein the subject has an ECOG score of 1.

20. The aforementioned subject is, a) Paclitaxel and cisplatin; b) Paclitaxel and carboplatin; or c) Paclitaxel and Topotecan The method according to any one of claims 17 to 19, which has been previously treated with

21. The method according to any one of claims 1 to 20, wherein the objective response rate is approximately 13% to approximately 35%, and optionally, the objective response rate is at least approximately 14%, approximately 19%, approximately 21%, 23.8%, approximately 24%, approximately 25%, approximately 26%, approximately 28%, approximately 30%, or approximately 33%.

22. The method according to any one of claims 1 to 21, wherein the subject exhibits a progression-free survival of at least approximately 3 months after administration of the antibody-drug conjugate, and optionally, the subject exhibits a progression-free survival of at least approximately 4 months, approximately 5 months, or approximately 6 months after administration of the antibody-drug conjugate.

23. The method according to any one of claims 1 to 22, wherein the subject exhibits an overall survival of at least about 10 months after administration of the antibody-drug conjugate, and optionally, the subject exhibits an overall survival of at least about 11 months, about 12 months, about 13 months, or 14 months after administration of the antibody-drug conjugate.

24. The method according to any one of claims 1 to 23, wherein the duration of response to the antibody-drug conjugate is at least about 6 months after administration of the antibody-drug conjugate, and optionally, the duration of response to the antibody-drug conjugate is at least about 7 months, about 8 months, or about 10 months after administration of the antibody-drug conjugate.

25. The method according to any one of claims 1 to 24, wherein the time to response is shorter than approximately 6 months after administration of the antibody-drug conjugate, and optionally, the time to response is shorter than approximately 4 months, approximately 2 months, 1.4 months, or approximately 1.2 months after administration of the antibody-drug conjugate.

26. A method for treating cervical cancer in a subject, comprising the step of administering to the subject an antibody-drug conjugate bound to tissue factor (TF), wherein the antibody-drug conjugate is tisotumab vedotin or a biosimilar thereof, the antibody-drug conjugate is administered at a dose of 2.0 mg / kg once every three weeks, the objective response rate being approximately 13% to approximately 35%, and optionally, the objective response rate being at least approximately 14%, approximately 19%, approximately 21%, 23.8%, approximately 24%, approximately 25%, approximately 26%, approximately 28%, approximately 30%, or approximately 33%.

27. The method according to claim 26, wherein the subject exhibits a progression-free survival of at least approximately 3 months after administration of the antibody-drug conjugate, and optionally, the subject exhibits a progression-free survival of at least approximately 4 months, approximately 5 months, or approximately 6 months after administration of the antibody-drug conjugate.

28. The method according to claim 26 or 27, wherein the subject exhibits an overall survival of at least about 10 months after administration of the antibody-drug conjugate, and optionally, the subject exhibits an overall survival of at least about 11 months, about 12 months, about 13 months, or 14 months after administration of the antibody-drug conjugate.

29. The method according to any one of claims 26 to 28, wherein the duration of response to the antibody-drug conjugate is at least about 6 months after administration of the antibody-drug conjugate, and optionally, the duration of response to the antibody-drug conjugate is at least about 7 months, about 8 months, or about 10 months after administration of the antibody-drug conjugate.

30. The method according to any one of claims 26 to 29, wherein the time to response is shorter than approximately 6 months after administration of the antibody-drug conjugate, and optionally, the time to response is shorter than approximately 4 months, approximately 2 months, 1.4 months, or approximately 1.2 months after administration of the antibody-drug conjugate.

31. A method for treating cervical cancer in a subject, comprising the step of administering to the subject an antibody-drug conjugate bound to tissue factor (TF), wherein the antibody-drug conjugate is tisotumab vedotin or a biosimilar thereof, the antibody-drug conjugate is administered at a dose of 2.0 mg / kg once every three weeks, and the subject exhibits a progression-free survival of at least approximately three months after administration of the antibody-drug conjugate, and optionally, the subject exhibits a progression-free survival of at least approximately four months, approximately five months, or approximately six months after administration of the antibody-drug conjugate.

32. The method according to claim 31, wherein the objective response rate is approximately 13% to approximately 35%, and optionally, the objective response rate is at least approximately 14%, approximately 19%, approximately 21%, 23.8%, approximately 24%, approximately 25%, approximately 26%, approximately 28%, approximately 30%, or approximately 33%.

33. The method according to claim 31 or 32, wherein the subject exhibits an overall survival of at least about 10 months after administration of the antibody-drug conjugate, and optionally, the subject exhibits an overall survival of at least about 11 months, about 12 months, about 13 months, or 14 months after administration of the antibody-drug conjugate.

34. The method according to any one of claims 31 to 33, wherein the duration of response to the antibody-drug conjugate is at least about 6 months after administration of the antibody-drug conjugate, and optionally, the duration of response to the antibody-drug conjugate is at least about 7 months, about 8 months, or about 10 months after administration of the antibody-drug conjugate.

35. The method according to any one of claims 31 to 34, wherein the time to response is shorter than approximately 6 months after administration of the antibody-drug conjugate, and optionally, the time to response is shorter than approximately 4 months, approximately 2 months, 1.4 months, or approximately 1.2 months after administration of the antibody-drug conjugate.

36. A method for treating cervical cancer in a subject, comprising the step of administering to the subject an antibody-drug conjugate bound to tissue factor (TF), wherein the antibody-drug conjugate is tisotumab vedotin or a biosimilar thereof, the antibody-drug conjugate is administered at a dose of 2.0 mg / kg once every three weeks, and the subject exhibits an overall survival of at least about 10 months after administration of the antibody-drug conjugate, and optionally, the subject exhibits an overall survival of at least about 11 months, about 12 months, about 13 months, or 14 months after administration of the antibody-drug conjugate.

37. The method according to claim 36, wherein the subject exhibits a progression-free survival of at least about 3 months after administration of the antibody-drug conjugate, and optionally, the subject exhibits a progression-free survival of at least about 4 months, about 5 months, or about 6 months after administration of the antibody-drug conjugate.

38. The method according to claim 36 or 37, wherein the objective response rate is approximately 13% to approximately 35%, and optionally, the objective response rate is at least approximately 14%, approximately 19%, approximately 21%, 23.8%, approximately 24%, approximately 25%, approximately 26%, approximately 28%, approximately 30%, or approximately 33%.

39. The method according to any one of claims 36 to 38, wherein the duration of response to the antibody-drug conjugate is at least about 6 months after administration of the antibody-drug conjugate, and optionally, the duration of response to the antibody-drug conjugate is at least about 7 months, about 8 months, or about 10 months after administration of the antibody-drug conjugate.

40. The method according to any one of claims 36 to 39, wherein the time to response is shorter than approximately 6 months after administration of the antibody-drug conjugate, and optionally, the time to response is shorter than approximately 4 months, approximately 2 months, 1.4 months, or approximately 1.2 months after administration of the antibody-drug conjugate.

41. A method for treating cervical cancer in a subject, comprising the step of administering to the subject an antibody-drug conjugate bound to tissue factor (TF), wherein the antibody-drug conjugate is tisotumab vedotin or a biosimilar thereof, the antibody-drug conjugate is administered at a dose of 2.0 mg / kg once every three weeks, the duration of response to the antibody-drug conjugate is at least about six months after administration of the antibody-drug conjugate, and optionally, the duration of response to the antibody-drug conjugate is at least about seven months, about eight months, or about ten months after administration of the antibody-drug conjugate.

42. The method according to claim 41, wherein the subject exhibits a progression-free survival of at least about 3 months after administration of the antibody-drug conjugate, and optionally, the subject exhibits a progression-free survival of at least about 4 months, about 5 months, or about 6 months after administration of the antibody-drug conjugate.

43. The method according to claim 41 or 42, wherein the subject exhibits an overall survival of at least about 10 months after administration of the antibody-drug conjugate, and optionally, the subject exhibits an overall survival of at least about 11 months, about 12 months, about 13 months, or 14 months after administration of the antibody-drug conjugate.

44. The method according to any one of claims 41 to 43, wherein the objective response rate is approximately 13% to approximately 35%, and optionally, the objective response rate is at least approximately 14%, approximately 19%, approximately 21%, 23.8%, approximately 24%, approximately 25%, approximately 26%, approximately 28%, approximately 30%, or approximately 33%.

45. The method according to any one of claims 41 to 44, wherein the time to response is shorter than approximately 6 months after administration of the antibody-drug conjugate, and optionally, the time to response is shorter than approximately 4 months, approximately 2 months, 1.4 months, or approximately 1.2 months after administration of the antibody-drug conjugate.

46. A method for treating cervical cancer in a subject, comprising the step of administering to the subject an antibody-drug conjugate bound to tissue factor (TF), wherein the antibody-drug conjugate is tisotumab vedotin or a biosimilar thereof, and the antibody-drug conjugate is administered at a dose of 2.0 mg / kg once every three weeks, and the time to response is shorter than approximately six months after administration of the antibody-drug conjugate, and optionally, the time to response is shorter than approximately four months, approximately two months, 1.4 months, or approximately 1.2 months after administration of the antibody-drug conjugate.

47. The method according to claim 46, wherein the subject exhibits a progression-free survival of at least about 3 months after administration of the antibody-drug conjugate, and optionally, the subject exhibits a progression-free survival of at least about 4 months, about 5 months, or about 6 months after administration of the antibody-drug conjugate.

48. The method according to claim 46 or 47, wherein the subject exhibits an overall survival of at least about 10 months after administration of the antibody-drug conjugate, and optionally, the subject exhibits an overall survival of at least about 11 months, about 12 months, about 13 months, or 14 months after administration of the antibody-drug conjugate.

49. The method according to any one of claims 46 to 48, wherein the duration of response to the antibody-drug conjugate is at least about 6 months after administration of the antibody-drug conjugate, and optionally, the duration of response to the antibody-drug conjugate is at least about 7 months, about 8 months, or about 10 months after administration of the antibody-drug conjugate.

50. The method according to any one of claims 46 to 49, wherein the objective response rate is at least about 13% to about 35%, and optionally, the objective response rate is at least about 14%, about 19%, about 21%, 23.8%, about 24%, about 25%, about 26%, about 28%, about 30%, or about 33%.

51. The method according to any one of claims 26 to 50, wherein the subject has been previously treated with bevacizumab.

52. The method according to any one of claims 26 to 50, wherein the subject has not been previously treated with bevacizumab.

53. The aforementioned subject is, a) Paclitaxel and cisplatin; b) Paclitaxel and carboplatin; c) Paclitaxel and topotecan; d) Bevacizumab, paclitaxel, and cisplatin; e) Bevacizumab, paclitaxel, and carboplatin; or f) Bevacizumab, paclitaxel, and topotecan The method according to any one of claims 26 to 52, wherein the patient is experiencing disease progression during or after treatment with the method.

54. The method according to any one of claims 26 to 53, wherein the subject is under 65 years of age.

55. The method according to any one of claims 26 to 54, wherein the subject has an ECOG score of 0.

56. The method according to any one of claims 26 to 54, wherein the subject has an ECOG score of 1.

57. The method according to any one of claims 1 to 56, wherein the cervical cancer is an adenocarcinoma.

58. The method according to any one of claims 1 to 56, wherein the cervical cancer is adenosquamous carcinoma.

59. The method according to any one of claims 1 to 56, wherein the cervical cancer is squamous cell carcinoma.

60. The method according to any one of claims 1 to 56, wherein the cervical cancer is non-squamous cell carcinoma.

61. The method according to any one of claims 1 to 60, wherein the cervical cancer is recurrent or metastatic cervical cancer.

62. The method according to any one of claims 1 to 61, wherein the subject has been previously treated with one or more therapeutic agents and has not responded to such treatment; wherein the one or more therapeutic agents are not the antibody-drug conjugate.

63. The method according to any one of claims 1 to 61, wherein the subject has been previously treated with one or more therapeutic agents and has experienced a relapse after such treatment; wherein the one or more therapeutic agents are not the antibody-drug conjugate.

64. The method according to any one of claims 1 to 61, wherein the subject has been previously treated with one or more therapeutic agents and has experienced disease progression during such treatment; wherein the one or more therapeutic agents are not the antibody-drug conjugate.

65. The method according to any one of claims 62 to 64, wherein one or more therapeutic agents are platinum-based therapeutic agents.

66. The method according to any one of claims 62 to 64, wherein the one or more therapeutic agents are selected from the group consisting of paclitaxel, cisplatin, carboplatin, topotecan, gemcitabine, fluorouracil, isabepyrone, imatinib mesylate, docetaxel, gefitinib, nab-paclitaxel, pemetrexed, vinorelbine, doxil, cetuximab, pembrolizumab, nivolumab, and bevacizumab.

67. The method according to any one of claims 1 to 66, wherein the subject is not a candidate for a curative treatment.

68. The method according to claim 67, wherein the curative treatment includes radiotherapy and / or viscerectomy.

69. The method according to any one of claims 1 to 66, wherein the subject has previously received radiation therapy to the pelvis.

70. The method according to any one of claims 1 to 66, wherein the subject has not previously received radiation to the pelvis.

71. The method according to any one of claims 1 to 70, wherein the subject has previously received one systemic therapy for recurrent, relapsed, or metastatic cancer.

72. The method according to any one of claims 1 to 70, wherein the subject has previously received two systemic therapies for recurrent, relapsed, or metastatic cancer.

73. The method according to claim 71 or 72, wherein the subject has not responded to prior systemic therapy.

74. The method according to claim 71 or 72, wherein the subject has experienced a relapse after prior treatment with systemic therapy.

75. The method according to any one of claims 1 to 74, wherein the cervical cancer is advanced cervical cancer, for example, stage 3 or stage 4 cervical cancer, for example, metastatic cervical cancer.

76. The method according to any one of claims 1 to 75, wherein the cervical cancer is recurrent cervical cancer.

77. The method according to any one of claims 1 to 76, wherein the route of administration of the antibody-drug conjugate is intravenous.

78. The method according to any one of claims 1 to 77, wherein at least about 0.1%, at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, or at least about 80% of the cervical cancer cells express TF.

79. The method according to any one of claims 1 to 78, wherein the subject has at least one TF histological score (H score).

80. The method according to any one of claims 1 to 79, wherein the subject has one or more adverse events and is further administered an additional therapeutic agent to eliminate or reduce the severity of the one or more adverse events.

81. The method according to any one of claims 1 to 79, wherein the subject is at risk of developing one or more adverse events and is further administered an additional therapeutic agent to prevent or reduce the severity of the one or more adverse events.

82. The method according to any one of claims 1 to 80, wherein the subject has one or more adverse events, and the dose of the antibody-drug conjugate is reduced after the one or more adverse events.

83. The method according to claim 82, wherein the dose is reduced from 2.0 mg / kg to 1.3 mg / kg.

84. The method according to claim 83, wherein the dose is reduced from 1.3 mg / kg to 0.9 mg / kg.

85. The method according to any one of claims 80 to 84, wherein the one or more adverse events are anemia, abdominal pain, hypokalemia, hyponatremia, epistaxis, fatigue, nausea, alopecia, conjunctivitis, constipation, loss of appetite, diarrhea, vomiting, peripheral neuropathy, or deterioration of general health.

86. The method according to any one of claims 80 to 85, wherein the one or more adverse events are grade 3 or higher adverse events.

87. The method according to any one of claims 80 to 85, wherein the one or more adverse events are serious adverse events.

88. The method according to claim 80 or 81, wherein the one or more adverse events are conjunctivitis and / or keratitis, and the additional therapeutic agent is a preservative-free lubricating eye drop, an ocular vasoconstrictor, and / or a steroid eye drop.

89. The method according to any one of claims 1 to 88, wherein the antibody-drug conjugate is administered as monotherapy.

90. The method according to any one of claims 1 to 89, wherein the subject is a human.

91. The method according to any one of claims 1 to 90, wherein the antibody-drug conjugate is in a pharmaceutical composition comprising the antibody-drug conjugate and a pharmaceutically acceptable carrier.

92. An antibody-drug conjugate that binds to TF, for use in the method according to any one of claims 1 to 91.

93. Use of an antibody-drug conjugate that binds to TF for manufacturing a pharmaceutical product for use in the method of any one of claims 1 to 91.

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